Randomized controlled trials (RCTs) of surgical interventions represent the highest level of clinical evidence and often can lead to the widespread adoption of new surgical techniques. However, surgical RCTs are often undertaken in highly controlled clinical environments, in selected patients, and with procedures performed by a selected experienced group of surgeons, often in high-volume centers. Therefore, the generalizability of findings from surgical RCTs to the comparatively uncontrolled environment of national practice is questionable.1,2

The Laparoscopic versus Open Gastrectomy for Gastric Cancer trial published in 2021, recruited and randomized patients from 2015 to 2018 between laparoscopic and open gastrectomy.3 This multicenter RCT showed reduced blood loss in the laparoscopic group; however, operative time was longer. There were no significant differences between the groups in postoperative complications, in-hospital mortality, 30-day readmissions, R0 resection, median lymph node yield, 1-year overall survival, and global health-related quality of life. The primary outcome of this RCT was length of hospital stay, which laparoscopic gastrectomy failed to improve; however, importantly, the clinical and oncological safety of a laparoscopic approach was demonstrated within the trial.

For the patient, gastrectomy may be considered a technically less demanding operation with a lower complication rate when compared with esophagectomy.4–6 Furthermore, LOGICA included a robust surgical quality assurance program and the majority of Dutch centers performing gastrectomy, which may lead to broader and safer dissemination of laparoscopic gastrectomy within the Netherlands. Thus, the external validity of the LOGICA trial may be more likely to be replicated when examining this issue through the national Dutch Upper Gastrointestinal Cancer Audit (DUCA).7

The aim of this present study was to examine the influence of the LOGICA trial upon the practice and clinical outcomes from laparoscopic gastrectomy nationally within the Netherlands. To achieve this aim, specific objectives of this study were to (1) evaluate patient and tumor factors driving allocation to laparoscopic gastrectomy at a national level; (2) compare clinical outcomes from laparoscopic with open gastrectomy in both the RCT (LOGICA)3 and national clinical practice environments (DUCA)7; (3) examine changes over time in relation to the LOGICA trial (pre, during, and post), in the practice and outcomes from laparoscopic gastrectomy within the Netherlands.

METHODS Data Sets

Data were obtained from the DUCA, which provided comprehensive data on all gastrectomies performed in the Netherlands between 2012 and 2021, and the LOGICA RCT, which ran from February 2015 to August 2018. The LOGICA data set included 46 variables, registering postoperative complications in accordance with the requirements of the DUCA registry at that time, and 516 variables were included within DUCA data set. All variables from the DUCA data set with >50% of data missing and those not relevant to the study objectives were excluded.

Patients

All patients who underwent gastrectomy within the LOGICA RCT were included. From the DUCA data set, all patients who underwent a gastrectomy for gastric or gastroesophageal junction adenocarcinoma were included. We excluded all patients with missing data regarding overall complications (n=4), 30-day or in-hospital mortality (n=3), and surgical approach (n=1). The flowchart with inclusion and exclusion criteria is shown in Supplementary Fig. 1, Supplemental Digital Content 1, https://links.lww.com/SLA/E950. Patients who underwent a gastrectomy starting minimally invasive were classified as laparoscopic, as an intention-to-treat analysis was performed primarily, and a per-protocol analysis is presented within the Supplementary Material, Supplemental Digital Content 1, https://links.lww.com/SLA/E950.

Statistical Analysis

Patient, tumor, and treatment characteristics of patients who underwent laparoscopic versus open gastrectomy were compared within the LOGICA and DUCA data sets using univariate analyses. These characteristics included sex, age, body mass index, American Society of Anesthesiologists score, Charlson Comorbidity Index, tumor location, cT, cN, cM, neoadjuvant treatment, surgical procedure, and year of surgery. Mann-Whitney U tests were used for continuous variables, and the X2 or Fisher exact test was used for categorical variables.

Multilevel multivariable logistic regression analyses were performed to assess the effect of laparoscopic versus open gastrectomy upon clinical outcomes, including length of hospital stay, readmission, reoperation and endoscopic/radiologic reintervention, oncological outcomes, including resection radicality (R0) and number of resected lymph nodes; and complications including; intraoperative complications, overall complications, severe complications ≥Clavien-Dindo grade IIIa), anastomotic leakage, cardiac complications, pulmonary complications, pneumonia, and 30-day/in-hospital mortality), while adjusting for patient, tumor and treatment variables, as described above. To adjust for potential changes over time, year of surgery was added as a random effect factor within the multivariate model in the event the log-likelihood ratio test showed a better fit compared with the original model. In case of insufficient degrees of freedom to correct for the entire correction model, only confounders leading to a >10% change in odds ratio of the outcome were included in the multivariate model. These analyses were repeated to assess the effect of laparoscopic gastrectomy upon outcomes before (January 2012 to January 2015), during (February 2015 to August 2018), and after (September 2018 to December 2021) the LOGICA trial in the DUCA data set. Subgroup analyses were performed to match the DUCA data set to the inclusion and exclusion criteria of the LOGICA trial (curative resection, D2-lymphadenectomy, and M0), to classify conversions in the open cohort (per-protocol), and by excluding the first 20 laparoscopic gastrectomy cases of each center in the DUCA data set. Overall, P values were estimated using ANOVA analyses. All P values <0.05 were considered significant. Multicollinearity of variables was assessed by calculating the variance inflation factor, with a variance inflation factor of ≤2.5 considered indicative of the absence of multicollinearity. All outcomes were specifically registered through all years of the DUCA data set, except for pneumonia, which was only registered separately from 2016 onward. Patients with missing outcome data were excluded from the analysis. All statistical analyses were performed, and all figures were generated using R-studio version 4.2.1.8

RESULTS Baseline Characteristics

In total, 211 patients from the LOGICA RCT (105 open vs 106 laparoscopic) and 4131 patients from the DUCA data set (1884 open vs 2247 laparoscopic) were included. In the LOGICA RCT, patients who underwent laparoscopic gastrectomy had a significantly higher body mass index and more often did not receive neoadjuvant therapy when compared with open gastrectomy. At a national level, the DUCA database showed laparoscopic gastrectomy was used more often in female patients, higher American Society of Anesthesiologist-score patients, and M0 patients when compared with open surgery. Further significant differences were seen in age, Charlson Comorbidity Index, tumor location, cT, cN, neoadjuvant therapy, and year of surgery (Table 1). In 2012, laparoscopic gastrectomy was performed in 6% of patients before sharply rising, with a small decline in 2017, to 82% of patients in 2021 (Fig. 1).

TABLE 1 - Patient, Tumor, and Treatment Characteristics of Patients That Underwent Laparoscopic Versus Open Gastrectomy in the LOGICA and DUCA Data Sets LOGICA DUCA Characteristic Open, N=105*, n (%) Laparoscopic, N=106*, n (%) P† Open, N=1884*, n (%) Laparoscopic, N=2247*, n (%) P† Sex — — 0.346 — — <0.001  Male 69 (66) 63 (59) — 1231 (65) 1356 (60) —  Female 36 (34) 43 (41) — 653 (35) 891 (40) — Age 70 (60, 75) 70 (62, 76) 0.593 70 (62, 77) 72 (63, 78) 0.005 Age categories (y) — — 0.721 — — 0.057  <65 38 (36) 33 (31) — 597 (32) 643 (29) —  65–75 41 (39) 46 (43) — 696 (37) 835 (37) —  >75 26 (25) 27 (25) — 590 (31) 767 (34) — BMI — — 0.002 — — 0.078  <20 11 (10) 2 (1.9) — 145 (8) 165 (7) —  20–25 54 (51) 58 (55) — 965 (51) 1211 (54) —  26–30 34 (32) 26 (25) — 570 (30) 606 (27) —  >30 kg 6 (5.7) 20 (19) — 176 (9) 236 (11) —  Missing — — — 28 (2) 29 (1) — ASA-score — — 0.498 — — <0.001  1–2 77 (73) 82 (77) — 1232 (65) 1383 (62) —  3+ 28 (27) 24 (23) — 633 (34) 858 (38) —  Missing — — — 19 (1) 6 (<1) — Charlson comorbidity index — — — — — 0.002  0 — — — 823 (44) 894 (40) —  1 — — — 401 (21) 580 (26) —  2+ — — — 660 (35) 773 (34) — Tumor location — — 0.856 — — <0.001  Fundus 10 (9.5) 12 (11) — 129 (7) 173 (8) —  Corpus 33 (31) 35 (33) — 568 (30) 693 (31) —  Antrum/pylorus 62 (59) 59 (56) — 860 (46) 1107 (50) —  Total stomach — — — 112 (6) 83 (4) —  Rest stomach/anastomosis — — — 107 (6) 24 (1) —  Unknown location — — — 22 (1) 24 (1) —  Gastro-esophageal junction — — — 75 (4) 113 (5) —  Missing — — — 11 30 — Clinical tumor stage — — 0.419 — — <0.001  T0–2 35 (33) 41 (39) — 519 (28) 609 (27) —  T3–4 70 (67) 65 (61) — 944 (50) 1297 (58) —  Tx — — — 399 (21) 335 (15) —  Missing — — — 22 (1) 6 (<1) — Clinical node stage — — 0.372 — — <0.001  N0 54 (51) 61 (58) — 939 (50) 1198 (53) —  N+ 51 (49) 45 (42) — 740 (39) 895 (40) —  Nx — — — 183 (10) 147 (7) —  Missing — — — 22 (1) 7 (<1) — Clinical metastasis stage — — 0.999 — — <0.001  M0 105 (100) 106 (100) — 1718 (91) 2114 (94) —  M+ — — — 77 (4) 33 (2) —  Mx — — — 89 (5) 100 (5) — Neoadjuvant therapy — — 0.021 — — <0.001  Chemotherapy 85 (81) 71 (67) — 1072 (57) 1313 (58) —  None 20 (19) 35 (33) — 766 (41) 827 (37) —  Chemoradiotherapy — — — 39 (2) 98 (4) —  Radiotherapy — — — 1 (<1) 1 (<1) —  Missing — — — 6 (<1) 8 (<1) — Surgical procedure — — 0.359 — — 0.798  Total gastrectomy 41 (39) 48 (45) — 856 (45) 1012 (45) —  Partial gastrectomy 64 (61) 58 (55) — 1028 (55) 1235 (55) — Year of surgery — — 0.987 — — <0.001  2012–2013 — — — 674 (36) 129 (6) —  2014–2015 9 (9) 10 (9) — 496 (26) 451 (20) —  2016–2017 64 (61) 63 (59) — 355 (19) 477 (21) —  2018–2019 32 (30) 33 (31) — 213 (11) 582 (26) —  2020–2021 — — — 146 (8) 608 (27) —

Bold values are statistically significant.

*n (%); Median (IQR).

†Pearson χ2 test; Wilcoxon rank sum test; Fisher exact test.

FIGURE 1:

Overall complication and 30-day/in-hospital mortality rates after minimally invasive (MI) versus open gastrectomy, as well as the percentage of minimally invasive resections of all gastrectomies. The time frame of the LOGICA trial is represented by the gray background fill.

Effects of Laparoscopic Gastrectomy on Clinical Outcomes Compared With Open Gastrectomy

Besides a significantly reduced risk of an in-hospital stay above the median of 7 days [adjusted odds ratio (aOR): 0.56; 95% CI: 0.31–0.99], no significant effect of laparoscopic gastrectomy on postoperative clinical outcomes was observed within the LOGICA RCT (Table 2). At a national level within the DUCA data set, laparoscopic gastrectomy was associated with a significant reduction in overall complications (aOR: 0.75; 95% CI: 0.65–0.87), severe complications (aOR: 0.84; 95% CI: 0.71–0.99), cardiac complications (aOR: 0.74; 95% CI: 0.55–0.99), and in-hospital stay above the median of 8 days (aOR: 0.41; 95% CI: 0.35–0.48), with a greater probability of a radical (R0) resection (aOR: 1.28; 95% CI: 1.03–1.59). However, laparoscopic gastrectomy was associated with an increase in endoscopic/radiologic reinterventions (aOR: 1.46; 95% CI: 1.02–2.13), with no effect upon reoperations. No significant effect of laparoscopic gastrectomy on all other outcomes (intraoperative complications, 30-day/in-hospital mortality, anastomotic leak, pulmonary complications, pneumonia, readmissions, and >15 resected lymph nodes) were observed over the entire study period in multivariate analyses.

TABLE 2 - Multivariate Comparison of Clinical and Pathologic Outcomes of Laparoscopic Versus Open Gastrectomy in the LOGICA and DUCA Data Sets LOGICA DUCA Characteristic N Open, N=105*, n (%) Laparoscopic, N=106*, n (%) aOR† N Open, N=1884*, n (%) Laparoscopic, N=2247*, n (%) aOR† Intraoperative complications 211 8 (8) 6 (6) 0.73 (0.23–2.17) 4118 67 (4) 81 (4) 1.20 (0.83–1.75) 30-day/in-hospital mortality 211 7 (7) 5 (5) 0.69 (0.20–2.24) 4131 96 (5) 95 (4) 0.86 (0.64–1.16) All overall complications 211 44 (42) 48 (45) 1.03 (0.59–1.80)‡ 4131 802 (43) 826 (37) 0.75 (0.65–0.87) Severe complications (≥CD3) 211 23 (22) 19 (18) 0.67 (0.33–1.34)‡ 4131 393 (21) 414 (18) 0.84 (0.71–0.99) Anastomotic leak 211 10 (10) 10 (9.4) 0.73 (0.26–1.97)‡,§ 4131 143 (8) 175 (8) 1.02 (0.79–1.32) Cardiac complications 211 7 (7) 12 (11) 1.60 (0.60–4.53)‡ 4130 116 (6) 114 (5) 0.74 (0.55–0.99) Pulmonary complications 211 15 (14) 17 (16) 0.96 (0.44–2.12)∥ 4130 302 (16) 313 (14) 0.83 (0.69–1.00) Pneumonia 211 13 (12) 16 (15) 1.03 (0.45–2.35)∥ 1751 91 (13) 171 (10) 0.78 (0.58-1.04) Reoperations 211 15 (14) 13 (12) 0.74 (0.32–1.68)‡ 4131 238 (13) 261 (12) 0.90 (0.74–1.10) Endoscopic/radiologic reintervention 211 — — — 4131 50 (3) 86 (4) 1.46 (1.02–2.13) Length of hospital stay (over median of 8 days) 211 51 (49) 40 (38) 0.56 (0.31–0.99)§ 4121 1099 (58) 1751 (33) 0.41 (0.35–0.48) Readmissions 211 10 (10) 11 (10) 1.22 (0.48–3.08)‡ 4077 224 (12) 294 (13) 1.12 (0.92–1.36) Resection radicality 211 100 (95) 101 (95) 0.99 (0.27–3.66)