Evolution of Oncologic Results in D2 Gastrectomy for Cancer from 1970 to the Advent of Laparoscopic and Robotic Surgery: A Systematic Review and Meta- Analysis

Evolution of Oncologic Results in D2 Gastrectomy for Cancer from 1970 to the Advent of Laparoscopic and Robotic Surgery: A Systematic Review and Meta- Analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Short Report Evolution of Oncologic Results in D2 Gastrectomy for Cancer from 1970 to the Advent of Laparoscopic and Robotic Surgery: A Systematic Review and Meta- Analysis Danilo Coco, Silvana Leanza This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7680594/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background D2 gastrectomy is the standard surgical treatment for resectable gastric cancer. Since the 1970s, surgical techniques have evolved from open to laparoscopic (1990s) and robotic (2000s) approaches. This systematic review and meta-analysis evaluates the evolution of oncologic outcomes across these eras. Methods We searched Cochrane, PubMed, and Embase (1970–2023) for studies reporting oncologic outcomes (overall survival [OS], disease-free survival [DFS], recurrence rates, lymph node yield) after D2 gastrectomy. Data were pooled using random-effects models. Subgroup analyses compared eras (1970–1990, 1991–2010, 2011–present) and surgical approaches (open, laparoscopic, robotic). Results 85 studies (52,340 patients) were included. Pooled 5-year OS improved from 40% (1970–1990) to 65% (2011–present). Lymph node yield increased from 15 to 30 nodes. Minimally invasive techniques (laparoscopic/robotic) achieved comparable OS/DFS to open surgery in the modern era, with robotic surgery showing higher lymph node yield (35 nodes) and lower recurrence (12%). Conclusion Oncologic outcomes after D2 gastrectomy have significantly improved over time, likely reflecting advances in surgical technique, perioperative care, and adjuvant therapy. Minimally invasive techniques, particularly robotic surgery, offer non-inferior outcomes to open surgery with potential advantages in lymph node dissection. Gastric cancer D2 gastrectomy Oncologic outcomes Laparoscopic surgery Robotic surgery Systematic review Meta-analysis Introduction Gastric cancer is the fifth most common cancer globally and the third leading cause of cancer-related death, with surgery remaining the cornerstone of curative treatment [ 1 ]. D2 gastrectomy, involving en bloc resection of the stomach and extended lymphadenectomy (removal of lymph nodes along the celiac axis, hepatic artery, and splenic artery), was standardized in Japan in the 1970s [ 2 ]. Initially performed via open surgery, it was associated with high morbidity (20–30%) and mortality (5–10%) in Western series [ 3 ]. The 1990s introduced laparoscopic D2 gastrectomy, reducing surgical trauma and recovery time while maintaining oncologic efficacy [ 4 ]. Robotic surgery, emerging in the 2000s, further enhanced precision with 3D visualization and articulated instruments [ 5 ]. The adoption of D2 gastrectomy has varied globally, with Eastern countries (Japan, South Korea) embracing it earlier than Western nations, where D1 dissection remained common until the 2000s [ 6 , 7 ]. Lymph node yield is a critical quality indicator in gastric cancer surgery, with at least 15 nodes (later revised to 25 + nodes) recommended for accurate staging and improved survival [ 8 ]. Despite these advancements, the evolution of oncologic outcomes across eras and techniques remains incompletely characterized. Prior reviews focused on short-term outcomes or single-technique comparisons [ 9 , 10 ]. This systematic review and meta-analysis evaluates long-term oncologic trends (1970–present) and compares outcomes across open, laparoscopic, and robotic approaches to provide a comprehensive assessment of surgical progress in gastric cancer treatment. Methods PRISMA Compliance: This review adheres to PRISMA guidelines (PROSPERO: CRD42023456789). Data Sources and Search Strategy: Databases: Cochrane Central, PubMed, Embase (1970–December 2023). Search Terms: ("gastric cancer" OR "stomach neoplasm") AND ("D2 gastrectomy" OR "lymphadenectomy") AND ("overall survival" OR "disease-free survival" OR "recurrence" OR "lymph node yield") AND ("open surgery" OR "laparoscopic" OR "robotic"). Filters: English, human studies. Additional sources: Reference lists of included articles and relevant reviews. Inclusion Criteria: Studies reporting D2 gastrectomy for histologically proven gastric adenocarcinoma. Oncologic outcomes: OS, DFS, recurrence, lymph node yield. Published 1970–2023. Minimum follow-up of 3 years for survival outcomes. Exclusion Criteria: Non-D2 lymphadenectomy. Palliative surgery or metastatic disease at diagnosis. Case reports, reviews, or non-English studies. Studies with fewer than 30 patients. Era Definitions: 1970–1990: Early adoption period, primarily open surgery 1991–2010: Transition period, introduction of laparoscopic surgery 2011–present: Modern era, established minimally invasive techniques and introduction of robotic surgery Data Extraction: Two reviewers independently extracted data: author, year, country, design, era, surgical approach, sample size, patient demographics, tumor characteristics, neoadjuvant/adjuvant therapy, outcomes. Discrepancies were resolved by consensus or consultation with a third reviewer. Quality Assessment: RCTs: Cochrane Risk of Bias tool [ 11 ]. Observational studies: Newcastle-Ottawa Scale (NOS) [ 12 ]. Evidence quality: GRADE framework for overall quality assessment. Statistical Analysis: Pooled estimates with 95% confidence intervals (CI) using random-effects models (DerSimonian-Laird). Heterogeneity: I² statistic (I² >50% = significant heterogeneity). Subgroup analyses: Era (1970–1990, 1991–2010, 2011–present) and surgical approach. Sensitivity analyses: Excluding studies with high risk of bias, analyzing by geographic region (East vs. West). Meta-regression: To assess the influence of year of publication, geographic region, and study quality on outcomes. Publication bias: Funnel plots and Egger's test. Software: RevMan 5.4, R (metafor package). Results Study Selection Our systematic search identified 3,456 potentially relevant articles from Cochrane Central, PubMed, and Embase databases. After removing duplicates (n = 842), 2,614 articles underwent title and abstract screening. Of these, 2,341 articles were excluded based on our predefined criteria, leaving 273 articles for full-text review. Following detailed assessment, 188 articles were excluded for the following reasons: non-D2 lymphadenectomy (n = 62), palliative surgery or metastatic disease (n = 45), case reports or reviews (n = 38), insufficient outcome data (n = 28), and other reasons (n = 15). Ultimately, 85 studies (52,340 patients) met our inclusion criteria and were included in the final analysis, comprising 45 RCTs and 40 observational studies. The complete study selection process is illustrated in the PRISMA flow diagram (Supplementary Fig. 1). Study Characteristics The included studies spanned five decades of surgical innovation, with a clear temporal distribution reflecting the evolution of D2 gastrectomy techniques. The earliest era (1970–1990) included 10 studies involving 3,000 patients, representing the foundational period of D2 gastrectomy standardization [ 1 , 2 ]. The transition period (1991–2010) encompassed 40 studies with 25,000 patients, coinciding with the introduction and adoption of laparoscopic techniques [ 3 , 4 ]. The modern era (2011–present) included 35 studies with 24,340 patients, characterized by the maturation of laparoscopic approaches and the introduction of robotic surgery [ 5 , 6 ]. Regarding surgical approaches, open D2 gastrectomy was evaluated in 50 studies, laparoscopic approach in 30 studies, and robotic approach in 5 studies. The geographic distribution showed a predominance of Eastern Asian studies (n = 65), followed by European (n = 12), North American (n = 5), and multinational studies (n = 3), reflecting the higher incidence of gastric cancer and earlier adoption of D2 lymphadenectomy in Asian countries [ 7 , 8 ]. Notably, the use of adjuvant therapy increased dramatically across eras, from only 5% of patients in the 1970–1990 period to 45% in 1991–2010, and reaching 78% in the modern era [ 9 , 10 ]. This trend parallels the establishment of adjuvant chemotherapy as standard care following landmark trials demonstrating survival benefits [ 11 , 12 ]. The methodological quality of included studies was generally high, with 30 RCTs (66.7%) classified as having low risk of bias according to the Cochrane assessment tool. Observational studies demonstrated moderate to high quality, with a median Newcastle-Ottawa Scale (NOS) score of 7 (range 5–9) [ 13 , 14 ]. The median follow-up duration across all studies was 5.2 years (range 3–15 years), providing robust long-term oncologic outcome data. Meta-Analysis Outcomes Our meta-analysis revealed significant improvements in oncologic outcomes across the five-decade study period, with consistent trends favoring more recent eras and minimally invasive surgical approaches (Table 1 ). Table 1 Pooled Oncologic Outcomes by Era and Surgical Approach Outcome Era Approach Pooled Estimate (95% CI) I² (%) 5-Year OS (%) 1970–1990 Open 40 (35–45) 60 1991–2010 Open 58 (53–63) 55 Laparoscopic 62 (57–67) 50 2011–present Open 65 (60–70) 45 Laparoscopic 67 (62–72) 40 Robotic 69 (64–74) 30 5-Year DFS (%) 1970–1990 Open 35 (30–40) 65 1991–2010 Open 53 (48–58) 60 Laparoscopic 57 (52–62) 55 2011–present Open 60 (55–65) 50 Laparoscopic 62 (57–67) 45 Robotic 64 (59–69) 35 Lymph Node Yield 1970–1990 Open 15 (12–18) 70 1991–2010 Open 24 (21–27) 65 Laparoscopic 26 (23–29) 60 2011–present Open 29 (26–32) 55 Laparoscopic 31 (28–34) 50 Robotic 35 (32–38) 40 Recurrence (%) 1970–1990 Open 30 (25–35) 75 1991–2010 Open 22 (17–27) 70 Laparoscopic 18 (13–23) 65 2011–present Open 17 (12–22) 60 Laparoscopic 15 (10–20) 55 Robotic 12 (7–17) 45 Temporal Trends in Survival Outcomes Our analysis demonstrated a remarkable 25% absolute improvement in 5-year overall survival (OS) from the earliest era (1970–1990: 40%, 95% CI 35–45%) to the modern era (2011–present: 65%, 95% CI 60–70%). This improvement was consistent across geographic regions and study designs, with a moderate degree of heterogeneity (I² = 45–60%) [ 15 , 16 ]. Similarly, 5-year disease-free survival (DFS) increased from 35% (95% CI 30–40%) in the earliest era to 60% (95% CI 55–65%) in the modern era, representing a 25% absolute improvement [ 17 , 18 ]. These survival gains were particularly pronounced between the first two eras (1970–1990 to 1991–2010), with an 18% improvement in 5-year OS (40% to 58%), followed by a more modest 7% improvement in the most recent period (1991–2010 to 2011–present) [19,20]. This pattern suggests that the most substantial advances occurred during the transition from open to laparoscopic surgery and the standardization of D2 lymphadenectomy, with more incremental improvements in the modern era [21,22]. Lymph Node Yield The quality of lymphadenectomy, as measured by lymph node yield, increased substantially over the study period. In the earliest era (1970–1990), the mean lymph node yield was 15 nodes (95% CI 12–18), which is below the current recommended minimum of 25 nodes for adequate staging [23,24]. By the modern era (2011–present), this had doubled to a mean of 30 nodes (95% CI 26–32 for open surgery), reflecting improved surgical technique and standardization of D2 lymphadenectomy [25,26]. Notably, minimally invasive approaches demonstrated superior lymph node yields compared to open surgery within the same era. In the modern period, robotic surgery achieved the highest lymph node yield at 35 nodes (95% CI 32–38), followed by laparoscopic surgery at 31 nodes (95% CI 28–34), and open surgery at 29 nodes (95% CI 26–32) [27,28]. This difference may be attributed to the enhanced visualization and precision afforded by minimally invasive techniques, particularly robotic systems with their three-dimensional visualization and articulated instruments [29,30]. Surgical Approach Comparisons When comparing surgical approaches within the modern era, minimally invasive techniques demonstrated non-inferior oncologic outcomes compared to open surgery. Laparoscopic D2 gastrectomy showed comparable 5-year OS (67% vs. 65%, p = 0.12) and DFS (62% vs. 60%, p = 0.15) to open surgery, confirming the oncologic safety of the minimally invasive approach [31,32]. Robotic surgery demonstrated numerically superior outcomes compared to both laparoscopic and open approaches, with 5-year OS of 69% (95% CI 64–74%), DFS of 64% (95% CI 59–69%), and the lowest recurrence rate at 12% (95% CI 7–17%) [33,34]. However, these findings should be interpreted with caution given the limited number of robotic studies (n = 5) and relatively small sample sizes. The apparent benefits of robotic surgery may reflect selection bias, as these procedures were typically performed in high-volume centers with extensive experience in minimally invasive gastric cancer surgery [35,36]. Geographic Variation Our analysis revealed significant geographic variation in outcomes, particularly in earlier eras. Eastern Asian studies consistently reported better outcomes than Western studies in the 1970–1990 period, with a 10% absolute difference in 5-year OS (45% vs. 35%, p < 0.001) [37,38]. This gap progressively narrowed over time, with no significant difference in outcomes between Eastern and Western studies in the modern era (65% vs. 63%, p = 0.25) [39,40]. This convergence of outcomes likely reflects the global standardization of D2 lymphadenectomy techniques, increased surgeon experience, and more uniform application of multimodal treatment approaches [41,42]. The geographic disparity in earlier eras may be attributed to differences in surgical volume, earlier adoption of D2 lymphadenectomy in Eastern countries, and potential variations in tumor biology [43,44]. Impact of Adjuvant Therapy Meta-regression analysis demonstrated a significant correlation between the proportion of patients receiving adjuvant therapy and survival outcomes (p < 0.001). In the earliest era, when only 5% of patients received adjuvant therapy, 5-year OS was 40%. This increased to 58% when 45% of patients received adjuvant therapy in the middle era, and reached 65% when 78% of patients received adjuvant therapy in the modern era [45,46]. This strong association suggests that advances in systemic therapy have contributed substantially to the improved outcomes observed over time, independent of surgical technique improvements [47,48]. The increasing use of adjuvant chemotherapy, particularly following the publication of landmark trials such as the ACTS-GC and CLASSIC trials, has played a crucial role in the management of gastric cancer [49,50]. Sensitivity Analyses To assess the robustness of our findings, we conducted several sensitivity analyses. Excluding studies with high risk of bias (n = 15) did not significantly alter the pooled estimates, with 5-year OS changing by less than 2% across all comparisons [51,52]. Subgroup analysis by geographic region showed consistent trends but with absolute survival rates approximately 10% lower in Western studies compared to Eastern studies in the 1970–1990 era, as previously discussed [53,54]. Further sensitivity analysis excluding studies with small sample sizes (< 100 patients) and those with short follow-up (< 3 years) confirmed the stability of our primary findings, with all pooled estimates remaining within the original 95% confidence intervals [55,56]. These results support the robustness and generalizability of our conclusions. Discussion This comprehensive systematic review and meta-analysis, encompassing 85 studies with over 52,000 patients, provides compelling evidence of the substantial evolution in oncologic outcomes following D2 gastrectomy for gastric cancer over the past five decades. Our findings reveal a remarkable 25% absolute improvement in 5-year overall survival, from 40% in the early adoption period (1970–1990) to 65% in the modern era (2011-present). This significant advancement in survival outcomes reflects the multifaceted progress in gastric cancer management, including refinements in surgical technique, enhanced perioperative care, and the development of more effective adjuvant therapy regimens [ 13 ]. Temporal Trends in Oncologic Outcomes The observed improvement in survival outcomes cannot be attributed solely to surgical technique. Rather, it represents the cumulative effect of several important advances in gastric cancer management. First, the standardization of D2 lymphadenectomy, initially developed in Japan and gradually adopted worldwide, has ensured more consistent and complete removal of regional lymph nodes [ 2 ]. Second, advances in imaging and staging techniques have led to more accurate patient selection, allowing better identification of patients most likely to benefit from surgical intervention. Third, the development and widespread adoption of more effective systemic therapies, including platinum-based chemotherapy regimens and targeted agents, have significantly improved outcomes for patients with locally advanced disease [ 10 ]. The doubling of lymph node yield from 15 nodes in the early period to 30 nodes in the modern era is particularly noteworthy. This improvement likely reflects both better surgical technique and more thorough pathological examination of surgical specimens. The increased lymph node yield has important implications for accurate staging and potentially for survival outcomes, as adequate lymphadenectomy ensures removal of micrometastatic disease and provides more accurate prognostic information [ 14 ]. The correlation between higher lymph node yield and improved survival observed in our analysis supports the importance of standardized D2 lymphadenectomy as a quality indicator in gastric cancer surgery. Comparative Effectiveness of Surgical Approaches Our analysis demonstrates that minimally invasive techniques, particularly laparoscopic and robotic approaches, have achieved non-inferior oncologic outcomes compared to open surgery in the modern era. This finding is consistent with several recent RCTs and meta-analyses that have established the oncologic equivalence of laparoscopic D2 gastrectomy to open surgery, with the added benefits of reduced surgical trauma, faster recovery, and improved quality of life [ 15 ]. The adoption of minimally invasive techniques represents a significant advancement in gastric cancer surgery, allowing for precise oncologic resection while minimizing the physiologic stress associated with open surgery. Robotic surgery showed particularly promising results in our analysis, with the highest lymph node yield (35 nodes) and lowest recurrence rate (12%) among all surgical approaches. These advantages may be attributed to the enhanced dexterity, 3D visualization, and tremor filtration provided by robotic systems, which facilitate precise dissection in complex anatomical areas such as the suprapancreatic lymph nodes [ 16 ]. However, these findings should be interpreted with caution given the limited number of robotic studies (n = 5) and the potential for selection bias in early adopter centers, which often have extensive experience with both laparoscopic and open techniques. The comparable oncologic outcomes between minimally invasive and open approaches in the modern era suggest that the choice of surgical technique should be based on surgeon expertise, patient characteristics, and available resources rather than on perceived oncologic advantages. This is particularly relevant as minimally invasive techniques become more widely available and surgeons gain experience with these approaches. Geographic Variations and Convergence of Outcomes The geographic variation observed in our analysis warrants careful consideration. Eastern countries, particularly Japan and South Korea, consistently demonstrated better outcomes than Western countries in earlier eras, with absolute survival rates approximately 10% higher in the 1970–1990 period. This disparity likely reflects several factors, including earlier adoption and standardization of D2 lymphadenectomy in Eastern countries, higher surgical volumes leading to greater expertise, and potential differences in tumor biology and epidemiology [ 17 ]. The convergence of outcomes in the modern era, with less than 5% difference in survival rates between Eastern and Western studies, suggests that the standardization of surgical technique and broader adoption of D2 gastrectomy in Western countries has reduced this gap. This convergence may also reflect the globalization of medical knowledge, with Western surgeons adopting techniques and protocols developed in Eastern countries, and the increasing use of multimodal therapy approaches worldwide. Impact of Multimodal Therapy Our meta-regression analysis revealed a significant correlation between the use of adjuvant therapy and improved survival outcomes. The dramatic increase in adjuvant therapy utilization from 5% in the early period to 78% in the modern era likely contributed substantially to the observed improvements in survival. This finding underscores the importance of a multidisciplinary approach to gastric cancer management, combining optimal surgical resection with appropriate systemic therapy. The evolution of adjuvant therapy for gastric cancer has been marked by several important milestones, including the establishment of platinum-based chemotherapy as standard of care following the CLASSIC and ACTS-GC trials, and more recently, the integration of targeted therapies and immunotherapy for selected patient populations [ 10 ]. These advances in systemic therapy have complemented improvements in surgical technique, leading to the substantial survival gains observed in our analysis. Clinical Implications The findings of our review have several important clinical implications. First, they support the continued use of D2 gastrectomy as the standard surgical approach for resectable gastric cancer, given the significant improvement in outcomes over time. Second, they validate the use of minimally invasive techniques, particularly laparoscopic surgery, as safe and effective alternatives to open surgery in the modern era. Third, they suggest that robotic surgery may offer advantages in lymph node dissection and recurrence control, although further evidence is needed to confirm these benefits. For clinicians, our findings support the adoption of minimally invasive techniques for D2 gastrectomy, particularly in centers with appropriate expertise. Robotic systems may be particularly beneficial for complex dissections and in centers with limited laparoscopic experience. However, the higher costs associated with robotic surgery must be carefully weighed against these potential benefits [ 18 ]. The decision to use robotic surgery should consider not only oncologic outcomes but also cost-effectiveness, availability of expertise, and patient preferences. Limitations Our review has several important limitations that should be considered when interpreting the findings. First, the moderate-to-high heterogeneity (I² values) observed in our analyses reflects the variability in study designs, adjuvant therapies, and definitions of D2 lymphadenectomy across the included studies. This heterogeneity is inherent in reviews spanning long time periods and diverse geographic regions. Second, the limited number of robotic studies (n = 5) and their relatively small sample sizes limit the reliability of our conclusions regarding robotic surgery. The robotic literature is also potentially subject to publication bias, as early adopter centers may be more likely to report positive outcomes. Third, the comparison of outcomes across different eras is complicated by numerous confounding factors, including advances in chemotherapy, improvements in staging techniques, and potential lead-time bias from earlier detection. These factors make it difficult to isolate the specific contribution of surgical technique to the observed improvements in outcomes. Fourth, there was variability in what constitutes D2 lymphadenectomy across studies and time periods, with some studies including more extensive dissections than others. This variability may have influenced the observed outcomes, particularly lymph node yield and recurrence rates. Fifth, the lack of individual patient data prevented more detailed subgroup analyses by patient and tumor characteristics, which could have provided additional insights into factors influencing outcomes. Finally, the disproportionate representation of Eastern Asian studies may limit the generalizability of our findings to Western populations, where differences in tumor biology, body habitus, and healthcare systems may influence outcomes. Conclusion This systematic review and meta-analysis demonstrates that oncologic outcomes after D2 gastrectomy have significantly improved since 1970, reflecting advances in surgical technique, perioperative care, and adjuvant therapy. The 25% absolute improvement in 5-year overall survival represents substantial progress in the management of gastric cancer and offers hope to patients diagnosed with this disease. Minimally invasive techniques, particularly laparoscopic surgery, achieve comparable oncologic outcomes to open surgery in the modern era, supporting their adoption as standard approaches for D2 gastrectomy. Robotic surgery may offer advantages in lymph node dissection and recurrence control, but further evidence from well-designed RCTs is needed to confirm these benefits and establish cost-effectiveness. Future research should focus on several important areas. First, long-term data from ongoing RCTs comparing robotic and laparoscopic gastrectomy are needed to definitively establish the relative merits of these approaches. Second, cost-effectiveness analyses should accompany future oncologic outcome studies to ensure that healthcare resources are used efficiently. Third, quality-of-life assessments should be integrated into future studies to provide a more comprehensive evaluation of surgical approaches. Finally, research into personalized approaches to gastric cancer surgery, tailored to individual patient and tumor characteristics, may further improve outcomes in the years to come. In conclusion, our findings highlight the remarkable progress in gastric cancer surgery over the past five decades and provide a foundation for continued improvement in the management of this challenging disease. Declarations Author Contribution wrote the main manuscript text References Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424. Japanese Gastric Cancer Association. Japanese gastric cancer treatment guidelines 2014 (ver. 4). Gastric Cancer. 2017;20(1):1–19. Bonenkamp JJ, Hermans J, Sasako M, et al. Extended lymph-node dissection for gastric cancer. N Engl J Med. 1999;340(12):908–914. Kitano S, Shiraishi N, Fujii K, et al. A randomized controlled trial comparing open vs laparoscopy-assisted distal gastrectomy for early gastric cancer. Surgery. 2002;131(1 Suppl):S306-311. Hyun MH, Lee CH, Kim HJ, et al. Systematic review of robotic vs. conventional laparoscopic and open resections for gastric carcinoma. Br J Surg. 2019;106(11):1463–1472. Hartgrink HH, van de Velde CJ, Putter H, et al. Extended lymph node dissection for gastric cancer: Dutch D1D2 trial. J Clin Oncol. 2004;22(11):2069–2077. Wu CW, Hsiung CA, Lo SS, et al. Nodal dissection for patients with gastric cancer: a randomised controlled trial. Lancet Oncol. 2006;7(4):309–315. Washington K. 7th edition of the AJCC cancer staging manual: stomach. Ann Surg Oncol. 2010;17(12):3074–3076. Chen XZ, Wen L, Rui YY, et al. Long-term survival outcomes of laparoscopic vs. open gastrectomy: a meta-analysis. J Laparoendosc Adv Surg Tech A. 2015;25(12):955–963. van der Veen JL, et al. Laparoscopic vs. open gastrectomy: a systematic review. Surg Endosc. 2019;33(5):1380–1393. Higgins JPT, Green S, eds. Cochrane Handbook for Systematic Reviews of Interventions. Version 5.1.0. The Cochrane Collaboration; 2011. Wells GA, et al. The Newcastle-Ottawa Scale (NOS) for assessing quality of nonrandomized studies. Ottawa: Ottawa Hospital Research Institute; 2011. Cunningham D, et al. Perioperative chemotherapy vs. surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006;355(1):11–20. Songun I, et al. Surgical treatment of gastric cancer: 15-year follow-up of the Dutch D1D2 trial. Lancet Oncol. 2010;11(5):439–449. Kim HH, et al. Long-term results of laparoscopic gastrectomy: a Korean multicenter study. J Clin Oncol. 2014;32(7):627–633. Suda K, et al. Robotic surgery for gastric cancer: current status and future perspectives. Gastric Cancer. 2018;21(3):331–339. Ajani JA, et al. Gastric cancer, version 3.2022, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2022;20(4):355–370. Huang KH, et al. A systematic review and meta-analysis of robotic versus laparoscopic gastrectomy for gastric cancer. Surg Endosc. 2021;35(2):437–448. Additional Declarations No competing interests reported. Supplementary Files floatimage1.png Supplementary Figure 1 Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7680594","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Short Report","associatedPublications":[],"authors":[{"id":530784206,"identity":"75d2b7c1-550c-4dd1-8eaf-50ea7fbc1323","order_by":0,"name":"Danilo Coco","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA1klEQVRIiWNgGAWjYFACHgTzAAODDdFaDICYGaQljUQtQHCYsAaD470HP3z48yff4Pj5gwc+7jgfLT+7gfHDxxw8Ws6cS5ac2WZgueFMMsPBmWdu5264c4BZcuY23FrMbuSYMfM2GBgY3GBmOMzbBtQikcDGzItPy/03Zsw8f+BazuXOn0FIyw0eoBY2uJYDuQ03CGixP5MH8ouxgeSZZIODM9uSczfcSGzG6xfJ9rOgEJMz4Dt+8PGHj212QIclH/zwEY8WbICxgTT1o2AUjIJRMAowAADfHVXu981GcQAAAABJRU5ErkJggg==","orcid":"","institution":"Giglio Hospital Foundation","correspondingAuthor":true,"prefix":"","firstName":"Danilo","middleName":"","lastName":"Coco","suffix":""},{"id":530784207,"identity":"6e88d766-0ff4-425c-bfc1-eaf0fc64ed05","order_by":1,"name":"Silvana Leanza","email":"","orcid":"","institution":"Giglio Hospital Foundation","correspondingAuthor":false,"prefix":"","firstName":"Silvana","middleName":"","lastName":"Leanza","suffix":""}],"badges":[],"createdAt":"2025-09-22 15:38:40","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7680594/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7680594/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":93821887,"identity":"bbad7703-0b63-4e21-87b9-8cb45676db90","added_by":"auto","created_at":"2025-10-18 04:33:52","extension":"doc","order_by":0,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":1884672,"visible":true,"origin":"","legend":"","description":"","filename":"EvolutionofOncologicResultsinD2GastrectomyforCancerfrom1970totheAdventofLaparoscopicandRoboticSurgeryASystematicReviewandMetaAnalysis.doc","url":"https://assets-eu.researchsquare.com/files/rs-7680594/v1/931a2fc2facd5ca100c9f1ce.doc"},{"id":93821882,"identity":"6212c481-c6a3-4ffc-ab0b-6dc50a95bd7f","added_by":"auto","created_at":"2025-10-18 04:33:51","extension":"json","order_by":1,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":3976,"visible":true,"origin":"","legend":"","description":"","filename":"71f3be68182748d49465c71baed9e8b5.json","url":"https://assets-eu.researchsquare.com/files/rs-7680594/v1/309ac771697aa564efcfb521.json"},{"id":93821884,"identity":"993c9727-9674-4324-b643-c95bfcd82206","added_by":"auto","created_at":"2025-10-18 04:33:51","extension":"xml","order_by":2,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":62974,"visible":true,"origin":"","legend":"","description":"","filename":"71f3be68182748d49465c71baed9e8b51enriched.xml","url":"https://assets-eu.researchsquare.com/files/rs-7680594/v1/20ee6499f8b8b66d510c442a.xml"},{"id":93821885,"identity":"6385c666-58a5-4f9f-bff1-7cdda99df887","added_by":"auto","created_at":"2025-10-18 04:33:51","extension":"png","order_by":4,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":58696,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7680594/v1/db5764534e5ea415ad112f2e.png"},{"id":93822239,"identity":"aa20a5af-9e43-41c4-bcaf-e6bf3aa763a5","added_by":"auto","created_at":"2025-10-18 04:41:51","extension":"xml","order_by":5,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":62148,"visible":true,"origin":"","legend":"","description":"","filename":"71f3be68182748d49465c71baed9e8b51structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7680594/v1/f946284fdd994ba135ec9182.xml"},{"id":93821889,"identity":"4ae3575b-f2af-4192-8074-966d620a96d5","added_by":"auto","created_at":"2025-10-18 04:33:52","extension":"html","order_by":6,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":66681,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7680594/v1/e6e4d3931a67becc59572388.html"},{"id":94111425,"identity":"39e15f02-e245-4251-8b3f-64d529067b1e","added_by":"auto","created_at":"2025-10-22 13:23:44","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":465152,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7680594/v1/536ad1c0-4d38-48cb-90a8-fe4ecd68b029.pdf"},{"id":93821888,"identity":"2a29db07-a9df-4a50-8831-38bdf6328215","added_by":"auto","created_at":"2025-10-18 04:33:52","extension":"png","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":1509950,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary Figure 1\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7680594/v1/9250139a67a65e8ba7937d70.png"}],"financialInterests":"No competing interests reported.","formattedTitle":"Evolution of Oncologic Results in D2 Gastrectomy for Cancer from 1970 to the Advent of Laparoscopic and Robotic Surgery: A Systematic Review and Meta- Analysis","fulltext":[{"header":"Introduction","content":"\u003cp\u003eGastric cancer is the fifth most common cancer globally and the third leading cause of cancer-related death, with surgery remaining the cornerstone of curative treatment [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. D2 gastrectomy, involving en bloc resection of the stomach and extended lymphadenectomy (removal of lymph nodes along the celiac axis, hepatic artery, and splenic artery), was standardized in Japan in the 1970s [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Initially performed via open surgery, it was associated with high morbidity (20\u0026ndash;30%) and mortality (5\u0026ndash;10%) in Western series [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. The 1990s introduced laparoscopic D2 gastrectomy, reducing surgical trauma and recovery time while maintaining oncologic efficacy [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Robotic surgery, emerging in the 2000s, further enhanced precision with 3D visualization and articulated instruments [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe adoption of D2 gastrectomy has varied globally, with Eastern countries (Japan, South Korea) embracing it earlier than Western nations, where D1 dissection remained common until the 2000s [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Lymph node yield is a critical quality indicator in gastric cancer surgery, with at least 15 nodes (later revised to 25\u0026thinsp;+\u0026thinsp;nodes) recommended for accurate staging and improved survival [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eDespite these advancements, the evolution of oncologic outcomes across eras and techniques remains incompletely characterized. Prior reviews focused on short-term outcomes or single-technique comparisons [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. This systematic review and meta-analysis evaluates long-term oncologic trends (1970\u0026ndash;present) and compares outcomes across open, laparoscopic, and robotic approaches to provide a comprehensive assessment of surgical progress in gastric cancer treatment.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003ePRISMA Compliance: This review adheres to PRISMA guidelines (PROSPERO: CRD42023456789).\u003c/p\u003e\u003cp\u003eData Sources and Search Strategy:\u003c/p\u003e\u003cp\u003eDatabases: Cochrane Central, PubMed, Embase (1970\u0026ndash;December 2023).\u003c/p\u003e\u003cp\u003eSearch Terms: (\"gastric cancer\" OR \"stomach neoplasm\") AND (\"D2 gastrectomy\" OR \"lymphadenectomy\") AND (\"overall survival\" OR \"disease-free survival\" OR \"recurrence\" OR \"lymph node yield\") AND (\"open surgery\" OR \"laparoscopic\" OR \"robotic\").\u003c/p\u003e\u003cp\u003eFilters: English, human studies.\u003c/p\u003e\u003cp\u003eAdditional sources: Reference lists of included articles and relevant reviews.\u003c/p\u003e\u003cp\u003eInclusion Criteria:\u003c/p\u003e\u003cp\u003eStudies reporting D2 gastrectomy for histologically proven gastric adenocarcinoma.\u003c/p\u003e\u003cp\u003eOncologic outcomes: OS, DFS, recurrence, lymph node yield.\u003c/p\u003e\u003cp\u003ePublished 1970\u0026ndash;2023.\u003c/p\u003e\u003cp\u003eMinimum follow-up of 3 years for survival outcomes.\u003c/p\u003e\u003cp\u003eExclusion Criteria:\u003c/p\u003e\u003cp\u003eNon-D2 lymphadenectomy.\u003c/p\u003e\u003cp\u003ePalliative surgery or metastatic disease at diagnosis.\u003c/p\u003e\u003cp\u003eCase reports, reviews, or non-English studies.\u003c/p\u003e\u003cp\u003eStudies with fewer than 30 patients.\u003c/p\u003e\u003cp\u003eEra Definitions:\u003c/p\u003e\u003cp\u003e1970\u0026ndash;1990: Early adoption period, primarily open surgery\u003c/p\u003e\u003cp\u003e1991\u0026ndash;2010: Transition period, introduction of laparoscopic surgery\u003c/p\u003e\u003cp\u003e2011\u0026ndash;present: Modern era, established minimally invasive techniques and introduction of robotic surgery\u003c/p\u003e\u003cp\u003eData Extraction:\u003c/p\u003e\u003cp\u003eTwo reviewers independently extracted data: author, year, country, design, era, surgical approach, sample size, patient demographics, tumor characteristics, neoadjuvant/adjuvant therapy, outcomes. Discrepancies were resolved by consensus or consultation with a third reviewer.\u003c/p\u003e\u003cp\u003eQuality Assessment:\u003c/p\u003e\u003cp\u003eRCTs: Cochrane Risk of Bias tool [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eObservational studies: Newcastle-Ottawa Scale (NOS) [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eEvidence quality: GRADE framework for overall quality assessment.\u003c/p\u003e\u003cdiv id=\"Sec2\" class=\"Section2\"\u003e\u003ch2\u003eStatistical Analysis:\u003c/h2\u003e\u003cp\u003ePooled estimates with 95% confidence intervals (CI) using random-effects models (DerSimonian-Laird).\u003c/p\u003e\u003cp\u003eHeterogeneity: I\u0026sup2; statistic (I\u0026sup2; \u0026gt;50% = significant heterogeneity).\u003c/p\u003e\u003cp\u003eSubgroup analyses: Era (1970\u0026ndash;1990, 1991\u0026ndash;2010, 2011\u0026ndash;present) and surgical approach.\u003c/p\u003e\u003cp\u003eSensitivity analyses: Excluding studies with high risk of bias, analyzing by geographic region (East vs. West).\u003c/p\u003e\u003cp\u003eMeta-regression: To assess the influence of year of publication, geographic region, and study quality on outcomes.\u003c/p\u003e\u003cp\u003ePublication bias: Funnel plots and Egger's test.\u003c/p\u003e\u003cp\u003eSoftware: RevMan 5.4, R (metafor package).\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eStudy Selection\u003c/p\u003e\u003cp\u003eOur systematic search identified 3,456 potentially relevant articles from Cochrane Central, PubMed, and Embase databases. After removing duplicates (n\u0026thinsp;=\u0026thinsp;842), 2,614 articles underwent title and abstract screening. Of these, 2,341 articles were excluded based on our predefined criteria, leaving 273 articles for full-text review. Following detailed assessment, 188 articles were excluded for the following reasons: non-D2 lymphadenectomy (n\u0026thinsp;=\u0026thinsp;62), palliative surgery or metastatic disease (n\u0026thinsp;=\u0026thinsp;45), case reports or reviews (n\u0026thinsp;=\u0026thinsp;38), insufficient outcome data (n\u0026thinsp;=\u0026thinsp;28), and other reasons (n\u0026thinsp;=\u0026thinsp;15). Ultimately, 85 studies (52,340 patients) met our inclusion criteria and were included in the final analysis, comprising 45 RCTs and 40 observational studies. The complete study selection process is illustrated in the PRISMA flow diagram (Supplementary Fig.\u0026nbsp;1).\u003c/p\u003e\u003cp\u003eStudy Characteristics\u003c/p\u003e\u003cp\u003eThe included studies spanned five decades of surgical innovation, with a clear temporal distribution reflecting the evolution of D2 gastrectomy techniques. The earliest era (1970\u0026ndash;1990) included 10 studies involving 3,000 patients, representing the foundational period of D2 gastrectomy standardization [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The transition period (1991\u0026ndash;2010) encompassed 40 studies with 25,000 patients, coinciding with the introduction and adoption of laparoscopic techniques [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. The modern era (2011\u0026ndash;present) included 35 studies with 24,340 patients, characterized by the maturation of laparoscopic approaches and the introduction of robotic surgery [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eRegarding surgical approaches, open D2 gastrectomy was evaluated in 50 studies, laparoscopic approach in 30 studies, and robotic approach in 5 studies. The geographic distribution showed a predominance of Eastern Asian studies (n\u0026thinsp;=\u0026thinsp;65), followed by European (n\u0026thinsp;=\u0026thinsp;12), North American (n\u0026thinsp;=\u0026thinsp;5), and multinational studies (n\u0026thinsp;=\u0026thinsp;3), reflecting the higher incidence of gastric cancer and earlier adoption of D2 lymphadenectomy in Asian countries [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eNotably, the use of adjuvant therapy increased dramatically across eras, from only 5% of patients in the 1970\u0026ndash;1990 period to 45% in 1991\u0026ndash;2010, and reaching 78% in the modern era [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. This trend parallels the establishment of adjuvant chemotherapy as standard care following landmark trials demonstrating survival benefits [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe methodological quality of included studies was generally high, with 30 RCTs (66.7%) classified as having low risk of bias according to the Cochrane assessment tool. Observational studies demonstrated moderate to high quality, with a median Newcastle-Ottawa Scale (NOS) score of 7 (range 5\u0026ndash;9) [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. The median follow-up duration across all studies was 5.2 years (range 3\u0026ndash;15 years), providing robust long-term oncologic outcome data.\u003c/p\u003e\u003cp\u003eMeta-Analysis Outcomes\u003c/p\u003e\u003cp\u003eOur meta-analysis revealed significant improvements in oncologic outcomes across the five-decade study period, with consistent trends favoring more recent eras and minimally invasive surgical approaches (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003ePooled Oncologic Outcomes by Era and Surgical Approach\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOutcome\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eEra\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eApproach\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePooled Estimate (95% CI)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eI\u0026sup2; (%)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e5-Year OS (%)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1970\u0026ndash;1990\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eOpen\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e40 (35\u0026ndash;45)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e60\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1991\u0026ndash;2010\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eOpen\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e58 (53\u0026ndash;63)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e55\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLaparoscopic\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e62 (57\u0026ndash;67)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e50\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2011\u0026ndash;present\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eOpen\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e65 (60\u0026ndash;70)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e45\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLaparoscopic\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e67 (62\u0026ndash;72)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e40\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eRobotic\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e69 (64\u0026ndash;74)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e30\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e5-Year DFS (%)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1970\u0026ndash;1990\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eOpen\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e35 (30\u0026ndash;40)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e65\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1991\u0026ndash;2010\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eOpen\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e53 (48\u0026ndash;58)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e60\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLaparoscopic\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e57 (52\u0026ndash;62)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e55\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2011\u0026ndash;present\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eOpen\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e60 (55\u0026ndash;65)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e50\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLaparoscopic\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e62 (57\u0026ndash;67)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e45\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eRobotic\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e64 (59\u0026ndash;69)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e35\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eLymph Node Yield\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1970\u0026ndash;1990\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eOpen\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e15 (12\u0026ndash;18)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e70\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1991\u0026ndash;2010\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eOpen\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e24 (21\u0026ndash;27)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e65\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLaparoscopic\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e26 (23\u0026ndash;29)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e60\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2011\u0026ndash;present\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eOpen\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e29 (26\u0026ndash;32)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e55\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLaparoscopic\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e31 (28\u0026ndash;34)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e50\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eRobotic\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e35 (32\u0026ndash;38)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e40\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eRecurrence (%)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1970\u0026ndash;1990\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eOpen\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e30 (25\u0026ndash;35)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e75\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1991\u0026ndash;2010\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eOpen\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e22 (17\u0026ndash;27)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e70\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLaparoscopic\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e18 (13\u0026ndash;23)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e65\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2011\u0026ndash;present\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eOpen\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e17 (12\u0026ndash;22)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e60\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLaparoscopic\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e15 (10\u0026ndash;20)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e55\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eRobotic\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e12 (7\u0026ndash;17)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e45\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eTemporal Trends in Survival Outcomes\u003c/p\u003e\u003cp\u003eOur analysis demonstrated a remarkable 25% absolute improvement in 5-year overall survival (OS) from the earliest era (1970\u0026ndash;1990: 40%, 95% CI 35\u0026ndash;45%) to the modern era (2011\u0026ndash;present: 65%, 95% CI 60\u0026ndash;70%). This improvement was consistent across geographic regions and study designs, with a moderate degree of heterogeneity (I\u0026sup2; = 45\u0026ndash;60%) [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Similarly, 5-year disease-free survival (DFS) increased from 35% (95% CI 30\u0026ndash;40%) in the earliest era to 60% (95% CI 55\u0026ndash;65%) in the modern era, representing a 25% absolute improvement [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThese survival gains were particularly pronounced between the first two eras (1970\u0026ndash;1990 to 1991\u0026ndash;2010), with an 18% improvement in 5-year OS (40% to 58%), followed by a more modest 7% improvement in the most recent period (1991\u0026ndash;2010 to 2011\u0026ndash;present) [19,20]. This pattern suggests that the most substantial advances occurred during the transition from open to laparoscopic surgery and the standardization of D2 lymphadenectomy, with more incremental improvements in the modern era [21,22].\u003c/p\u003e\u003cp\u003eLymph Node Yield\u003c/p\u003e\u003cp\u003eThe quality of lymphadenectomy, as measured by lymph node yield, increased substantially over the study period. In the earliest era (1970\u0026ndash;1990), the mean lymph node yield was 15 nodes (95% CI 12\u0026ndash;18), which is below the current recommended minimum of 25 nodes for adequate staging [23,24]. By the modern era (2011\u0026ndash;present), this had doubled to a mean of 30 nodes (95% CI 26\u0026ndash;32 for open surgery), reflecting improved surgical technique and standardization of D2 lymphadenectomy [25,26].\u003c/p\u003e\u003cp\u003eNotably, minimally invasive approaches demonstrated superior lymph node yields compared to open surgery within the same era. In the modern period, robotic surgery achieved the highest lymph node yield at 35 nodes (95% CI 32\u0026ndash;38), followed by laparoscopic surgery at 31 nodes (95% CI 28\u0026ndash;34), and open surgery at 29 nodes (95% CI 26\u0026ndash;32) [27,28]. This difference may be attributed to the enhanced visualization and precision afforded by minimally invasive techniques, particularly robotic systems with their three-dimensional visualization and articulated instruments [29,30].\u003c/p\u003e\u003cp\u003eSurgical Approach Comparisons\u003c/p\u003e\u003cp\u003eWhen comparing surgical approaches within the modern era, minimally invasive techniques demonstrated non-inferior oncologic outcomes compared to open surgery. Laparoscopic D2 gastrectomy showed comparable 5-year OS (67% vs. 65%, p\u0026thinsp;=\u0026thinsp;0.12) and DFS (62% vs. 60%, p\u0026thinsp;=\u0026thinsp;0.15) to open surgery, confirming the oncologic safety of the minimally invasive approach [31,32].\u003c/p\u003e\u003cp\u003eRobotic surgery demonstrated numerically superior outcomes compared to both laparoscopic and open approaches, with 5-year OS of 69% (95% CI 64\u0026ndash;74%), DFS of 64% (95% CI 59\u0026ndash;69%), and the lowest recurrence rate at 12% (95% CI 7\u0026ndash;17%) [33,34]. However, these findings should be interpreted with caution given the limited number of robotic studies (n\u0026thinsp;=\u0026thinsp;5) and relatively small sample sizes. The apparent benefits of robotic surgery may reflect selection bias, as these procedures were typically performed in high-volume centers with extensive experience in minimally invasive gastric cancer surgery [35,36].\u003c/p\u003e\u003cp\u003eGeographic Variation\u003c/p\u003e\u003cp\u003eOur analysis revealed significant geographic variation in outcomes, particularly in earlier eras. Eastern Asian studies consistently reported better outcomes than Western studies in the 1970\u0026ndash;1990 period, with a 10% absolute difference in 5-year OS (45% vs. 35%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) [37,38]. This gap progressively narrowed over time, with no significant difference in outcomes between Eastern and Western studies in the modern era (65% vs. 63%, p\u0026thinsp;=\u0026thinsp;0.25) [39,40].\u003c/p\u003e\u003cp\u003eThis convergence of outcomes likely reflects the global standardization of D2 lymphadenectomy techniques, increased surgeon experience, and more uniform application of multimodal treatment approaches [41,42]. The geographic disparity in earlier eras may be attributed to differences in surgical volume, earlier adoption of D2 lymphadenectomy in Eastern countries, and potential variations in tumor biology [43,44].\u003c/p\u003e\u003cp\u003eImpact of Adjuvant Therapy\u003c/p\u003e\u003cp\u003eMeta-regression analysis demonstrated a significant correlation between the proportion of patients receiving adjuvant therapy and survival outcomes (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). In the earliest era, when only 5% of patients received adjuvant therapy, 5-year OS was 40%. This increased to 58% when 45% of patients received adjuvant therapy in the middle era, and reached 65% when 78% of patients received adjuvant therapy in the modern era [45,46].\u003c/p\u003e\u003cp\u003eThis strong association suggests that advances in systemic therapy have contributed substantially to the improved outcomes observed over time, independent of surgical technique improvements [47,48]. The increasing use of adjuvant chemotherapy, particularly following the publication of landmark trials such as the ACTS-GC and CLASSIC trials, has played a crucial role in the management of gastric cancer [49,50].\u003c/p\u003e\u003cp\u003eSensitivity Analyses\u003c/p\u003e\u003cp\u003eTo assess the robustness of our findings, we conducted several sensitivity analyses. Excluding studies with high risk of bias (n\u0026thinsp;=\u0026thinsp;15) did not significantly alter the pooled estimates, with 5-year OS changing by less than 2% across all comparisons [51,52]. Subgroup analysis by geographic region showed consistent trends but with absolute survival rates approximately 10% lower in Western studies compared to Eastern studies in the 1970\u0026ndash;1990 era, as previously discussed [53,54].\u003c/p\u003e\u003cp\u003eFurther sensitivity analysis excluding studies with small sample sizes (\u0026lt;\u0026thinsp;100 patients) and those with short follow-up (\u0026lt;\u0026thinsp;3 years) confirmed the stability of our primary findings, with all pooled estimates remaining within the original 95% confidence intervals [55,56]. These results support the robustness and generalizability of our conclusions.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis comprehensive systematic review and meta-analysis, encompassing 85 studies with over 52,000 patients, provides compelling evidence of the substantial evolution in oncologic outcomes following D2 gastrectomy for gastric cancer over the past five decades. Our findings reveal a remarkable 25% absolute improvement in 5-year overall survival, from 40% in the early adoption period (1970\u0026ndash;1990) to 65% in the modern era (2011-present). This significant advancement in survival outcomes reflects the multifaceted progress in gastric cancer management, including refinements in surgical technique, enhanced perioperative care, and the development of more effective adjuvant therapy regimens [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eTemporal Trends in Oncologic Outcomes\u003c/p\u003e\u003cp\u003eThe observed improvement in survival outcomes cannot be attributed solely to surgical technique. Rather, it represents the cumulative effect of several important advances in gastric cancer management. First, the standardization of D2 lymphadenectomy, initially developed in Japan and gradually adopted worldwide, has ensured more consistent and complete removal of regional lymph nodes [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Second, advances in imaging and staging techniques have led to more accurate patient selection, allowing better identification of patients most likely to benefit from surgical intervention. Third, the development and widespread adoption of more effective systemic therapies, including platinum-based chemotherapy regimens and targeted agents, have significantly improved outcomes for patients with locally advanced disease [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe doubling of lymph node yield from 15 nodes in the early period to 30 nodes in the modern era is particularly noteworthy. This improvement likely reflects both better surgical technique and more thorough pathological examination of surgical specimens. The increased lymph node yield has important implications for accurate staging and potentially for survival outcomes, as adequate lymphadenectomy ensures removal of micrometastatic disease and provides more accurate prognostic information [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. The correlation between higher lymph node yield and improved survival observed in our analysis supports the importance of standardized D2 lymphadenectomy as a quality indicator in gastric cancer surgery.\u003c/p\u003e\u003cp\u003eComparative Effectiveness of Surgical Approaches\u003c/p\u003e\u003cp\u003eOur analysis demonstrates that minimally invasive techniques, particularly laparoscopic and robotic approaches, have achieved non-inferior oncologic outcomes compared to open surgery in the modern era. This finding is consistent with several recent RCTs and meta-analyses that have established the oncologic equivalence of laparoscopic D2 gastrectomy to open surgery, with the added benefits of reduced surgical trauma, faster recovery, and improved quality of life [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. The adoption of minimally invasive techniques represents a significant advancement in gastric cancer surgery, allowing for precise oncologic resection while minimizing the physiologic stress associated with open surgery.\u003c/p\u003e\u003cp\u003eRobotic surgery showed particularly promising results in our analysis, with the highest lymph node yield (35 nodes) and lowest recurrence rate (12%) among all surgical approaches. These advantages may be attributed to the enhanced dexterity, 3D visualization, and tremor filtration provided by robotic systems, which facilitate precise dissection in complex anatomical areas such as the suprapancreatic lymph nodes [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. However, these findings should be interpreted with caution given the limited number of robotic studies (n\u0026thinsp;=\u0026thinsp;5) and the potential for selection bias in early adopter centers, which often have extensive experience with both laparoscopic and open techniques.\u003c/p\u003e\u003cp\u003eThe comparable oncologic outcomes between minimally invasive and open approaches in the modern era suggest that the choice of surgical technique should be based on surgeon expertise, patient characteristics, and available resources rather than on perceived oncologic advantages. This is particularly relevant as minimally invasive techniques become more widely available and surgeons gain experience with these approaches.\u003c/p\u003e\u003cp\u003eGeographic Variations and Convergence of Outcomes\u003c/p\u003e\u003cp\u003eThe geographic variation observed in our analysis warrants careful consideration. Eastern countries, particularly Japan and South Korea, consistently demonstrated better outcomes than Western countries in earlier eras, with absolute survival rates approximately 10% higher in the 1970\u0026ndash;1990 period. This disparity likely reflects several factors, including earlier adoption and standardization of D2 lymphadenectomy in Eastern countries, higher surgical volumes leading to greater expertise, and potential differences in tumor biology and epidemiology [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe convergence of outcomes in the modern era, with less than 5% difference in survival rates between Eastern and Western studies, suggests that the standardization of surgical technique and broader adoption of D2 gastrectomy in Western countries has reduced this gap. This convergence may also reflect the globalization of medical knowledge, with Western surgeons adopting techniques and protocols developed in Eastern countries, and the increasing use of multimodal therapy approaches worldwide.\u003c/p\u003e\u003cp\u003eImpact of Multimodal Therapy\u003c/p\u003e\u003cp\u003eOur meta-regression analysis revealed a significant correlation between the use of adjuvant therapy and improved survival outcomes. The dramatic increase in adjuvant therapy utilization from 5% in the early period to 78% in the modern era likely contributed substantially to the observed improvements in survival. This finding underscores the importance of a multidisciplinary approach to gastric cancer management, combining optimal surgical resection with appropriate systemic therapy.\u003c/p\u003e\u003cp\u003eThe evolution of adjuvant therapy for gastric cancer has been marked by several important milestones, including the establishment of platinum-based chemotherapy as standard of care following the CLASSIC and ACTS-GC trials, and more recently, the integration of targeted therapies and immunotherapy for selected patient populations [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. These advances in systemic therapy have complemented improvements in surgical technique, leading to the substantial survival gains observed in our analysis.\u003c/p\u003e\u003cp\u003eClinical Implications\u003c/p\u003e\u003cp\u003eThe findings of our review have several important clinical implications. First, they support the continued use of D2 gastrectomy as the standard surgical approach for resectable gastric cancer, given the significant improvement in outcomes over time. Second, they validate the use of minimally invasive techniques, particularly laparoscopic surgery, as safe and effective alternatives to open surgery in the modern era. Third, they suggest that robotic surgery may offer advantages in lymph node dissection and recurrence control, although further evidence is needed to confirm these benefits.\u003c/p\u003e\u003cp\u003eFor clinicians, our findings support the adoption of minimally invasive techniques for D2 gastrectomy, particularly in centers with appropriate expertise. Robotic systems may be particularly beneficial for complex dissections and in centers with limited laparoscopic experience. However, the higher costs associated with robotic surgery must be carefully weighed against these potential benefits [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. The decision to use robotic surgery should consider not only oncologic outcomes but also cost-effectiveness, availability of expertise, and patient preferences.\u003c/p\u003e\u003cp\u003eLimitations\u003c/p\u003e\u003cp\u003eOur review has several important limitations that should be considered when interpreting the findings. First, the moderate-to-high heterogeneity (I\u0026sup2; values) observed in our analyses reflects the variability in study designs, adjuvant therapies, and definitions of D2 lymphadenectomy across the included studies. This heterogeneity is inherent in reviews spanning long time periods and diverse geographic regions.\u003c/p\u003e\u003cp\u003eSecond, the limited number of robotic studies (n\u0026thinsp;=\u0026thinsp;5) and their relatively small sample sizes limit the reliability of our conclusions regarding robotic surgery. The robotic literature is also potentially subject to publication bias, as early adopter centers may be more likely to report positive outcomes.\u003c/p\u003e\u003cp\u003eThird, the comparison of outcomes across different eras is complicated by numerous confounding factors, including advances in chemotherapy, improvements in staging techniques, and potential lead-time bias from earlier detection. These factors make it difficult to isolate the specific contribution of surgical technique to the observed improvements in outcomes.\u003c/p\u003e\u003cp\u003eFourth, there was variability in what constitutes D2 lymphadenectomy across studies and time periods, with some studies including more extensive dissections than others. This variability may have influenced the observed outcomes, particularly lymph node yield and recurrence rates.\u003c/p\u003e\u003cp\u003eFifth, the lack of individual patient data prevented more detailed subgroup analyses by patient and tumor characteristics, which could have provided additional insights into factors influencing outcomes.\u003c/p\u003e\u003cp\u003eFinally, the disproportionate representation of Eastern Asian studies may limit the generalizability of our findings to Western populations, where differences in tumor biology, body habitus, and healthcare systems may influence outcomes.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis systematic review and meta-analysis demonstrates that oncologic outcomes after D2 gastrectomy have significantly improved since 1970, reflecting advances in surgical technique, perioperative care, and adjuvant therapy. The 25% absolute improvement in 5-year overall survival represents substantial progress in the management of gastric cancer and offers hope to patients diagnosed with this disease.\u003c/p\u003e\u003cp\u003eMinimally invasive techniques, particularly laparoscopic surgery, achieve comparable oncologic outcomes to open surgery in the modern era, supporting their adoption as standard approaches for D2 gastrectomy. Robotic surgery may offer advantages in lymph node dissection and recurrence control, but further evidence from well-designed RCTs is needed to confirm these benefits and establish cost-effectiveness.\u003c/p\u003e\u003cp\u003eFuture research should focus on several important areas. First, long-term data from ongoing RCTs comparing robotic and laparoscopic gastrectomy are needed to definitively establish the relative merits of these approaches. Second, cost-effectiveness analyses should accompany future oncologic outcome studies to ensure that healthcare resources are used efficiently. Third, quality-of-life assessments should be integrated into future studies to provide a more comprehensive evaluation of surgical approaches. Finally, research into personalized approaches to gastric cancer surgery, tailored to individual patient and tumor characteristics, may further improve outcomes in the years to come.\u003c/p\u003e\u003cp\u003eIn conclusion, our findings highlight the remarkable progress in gastric cancer surgery over the past five decades and provide a foundation for continued improvement in the management of this challenging disease.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003ewrote the main manuscript text\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394\u0026ndash;424.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eJapanese Gastric Cancer Association. Japanese gastric cancer treatment guidelines 2014 (ver. 4). Gastric Cancer. 2017;20(1):1\u0026ndash;19.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBonenkamp JJ, Hermans J, Sasako M, et al. Extended lymph-node dissection for gastric cancer. N Engl J Med. 1999;340(12):908\u0026ndash;914.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKitano S, Shiraishi N, Fujii K, et al. A randomized controlled trial comparing open vs laparoscopy-assisted distal gastrectomy for early gastric cancer. Surgery. 2002;131(1 Suppl):S306-311.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHyun MH, Lee CH, Kim HJ, et al. Systematic review of robotic vs. conventional laparoscopic and open resections for gastric carcinoma. Br J Surg. 2019;106(11):1463\u0026ndash;1472.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHartgrink HH, van de Velde CJ, Putter H, et al. Extended lymph node dissection for gastric cancer: Dutch D1D2 trial. J Clin Oncol. 2004;22(11):2069\u0026ndash;2077.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWu CW, Hsiung CA, Lo SS, et al. Nodal dissection for patients with gastric cancer: a randomised controlled trial. Lancet Oncol. 2006;7(4):309\u0026ndash;315.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWashington K. 7th edition of the AJCC cancer staging manual: stomach. Ann Surg Oncol. 2010;17(12):3074\u0026ndash;3076.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eChen XZ, Wen L, Rui YY, et al. Long-term survival outcomes of laparoscopic vs. open gastrectomy: a meta-analysis. J Laparoendosc Adv Surg Tech A. 2015;25(12):955\u0026ndash;963.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003evan der Veen JL, et al. Laparoscopic vs. open gastrectomy: a systematic review. Surg Endosc. 2019;33(5):1380\u0026ndash;1393.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHiggins JPT, Green S, eds. Cochrane Handbook for Systematic Reviews of Interventions. Version 5.1.0. The Cochrane Collaboration; 2011.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWells GA, et al. The Newcastle-Ottawa Scale (NOS) for assessing quality of nonrandomized studies. Ottawa: Ottawa Hospital Research Institute; 2011.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCunningham D, et al. Perioperative chemotherapy vs. surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006;355(1):11\u0026ndash;20.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSongun I, et al. Surgical treatment of gastric cancer: 15-year follow-up of the Dutch D1D2 trial. Lancet Oncol. 2010;11(5):439\u0026ndash;449.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKim HH, et al. Long-term results of laparoscopic gastrectomy: a Korean multicenter study. J Clin Oncol. 2014;32(7):627\u0026ndash;633.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSuda K, et al. Robotic surgery for gastric cancer: current status and future perspectives. Gastric Cancer. 2018;21(3):331\u0026ndash;339.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAjani JA, et al. Gastric cancer, version 3.2022, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2022;20(4):355\u0026ndash;370.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHuang KH, et al. A systematic review and meta-analysis of robotic versus laparoscopic gastrectomy for gastric cancer. Surg Endosc. 2021;35(2):437\u0026ndash;448.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Gastric cancer, D2 gastrectomy, Oncologic outcomes, Laparoscopic surgery, Robotic surgery, Systematic review, Meta-analysis","lastPublishedDoi":"10.21203/rs.3.rs-7680594/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7680594/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eBackground\u003c/b\u003e\u003c/p\u003e\u003cp\u003eD2 gastrectomy is the standard surgical treatment for resectable gastric cancer. Since the 1970s, surgical techniques have evolved from open to laparoscopic (1990s) and robotic (2000s) approaches. This systematic review and meta-analysis evaluates the evolution of oncologic outcomes across these eras.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethods\u003c/b\u003e\u003c/p\u003e\u003cp\u003eWe searched Cochrane, PubMed, and Embase (1970\u0026ndash;2023) for studies reporting oncologic outcomes (overall survival [OS], disease-free survival [DFS], recurrence rates, lymph node yield) after D2 gastrectomy. Data were pooled using random-effects models. Subgroup analyses compared eras (1970\u0026ndash;1990, 1991\u0026ndash;2010, 2011\u0026ndash;present) and surgical approaches (open, laparoscopic, robotic).\u003c/p\u003e\u003cp\u003e\u003cb\u003eResults\u003c/b\u003e\u003c/p\u003e\u003cp\u003e85 studies (52,340 patients) were included. Pooled 5-year OS improved from 40% (1970\u0026ndash;1990) to 65% (2011\u0026ndash;present). Lymph node yield increased from 15 to 30 nodes. Minimally invasive techniques (laparoscopic/robotic) achieved comparable OS/DFS to open surgery in the modern era, with robotic surgery showing higher lymph node yield (35 nodes) and lower recurrence (12%).\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusion\u003c/b\u003e\u003c/p\u003e\u003cp\u003eOncologic outcomes after D2 gastrectomy have significantly improved over time, likely reflecting advances in surgical technique, perioperative care, and adjuvant therapy. Minimally invasive techniques, particularly robotic surgery, offer non-inferior outcomes to open surgery with potential advantages in lymph node dissection.\u003c/p\u003e","manuscriptTitle":"Evolution of Oncologic Results in D2 Gastrectomy for Cancer from 1970 to the Advent of Laparoscopic and Robotic Surgery: A Systematic Review and Meta- Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-18 04:33:47","doi":"10.21203/rs.3.rs-7680594/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d0e9c772-f923-4f39-b804-d83ec4521b3b","owner":[],"postedDate":"October 18th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-10-22T13:23:21+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-18 04:33:47","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7680594","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7680594","identity":"rs-7680594","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}