Long-term outcomes of modified enhanced recovery after surgery (mERAS) protocols in peri-operative management of minimally invasive esophagectomy

Introduction

Globally, esophageal cancer is a common malignant tumor, ranking seventh in cancer-related mortality worldwide (1). The treatment outcomes have improved significantly due to advancements in surgical techniques and integrated therapeutic approaches (2,3). Esophagectomy, a key treatment for esophageal cancer, is recognized as a particularly complex procedure, associated with high levels of perioperative morbidity and mortality (4,5). Enhanced recovery after surgery (ERAS) programs consists of a set of pre-, intra- and post-operative protocols to minimize perioperative burden, reduce postoperative complications and morbidity, optimize postoperative recovery, and shorten hospital stay. Initially designed for colorectal surgeries, ERAS protocols have since been adopted across various surgical specialties, revolutionizing surgical care and patient recovery (6-8).

In the field of esophagectomy, the growing adoption of minimally invasive techniques, greater emphasis on organ function preservation, and advancements in gastric conduit construction and anastomosis methods have spurred interest in ERAS application (9,10). While limited studies have demonstrated promising long-term survival benefits of ERAS in gastric, colon, and rectal cancers, its impact on the long-term prognosis of esophageal cancer remains unclear due to the lack of high volume studies (11,12).

This study aims to compare post-operative morbidity, functional recovery, and hospital stay in patients undergoing esophagectomy with modified ERAS (mERAS) protocols versus conventional standard care (SC), and to assess the effect of ERAS on long-term survival outcomes. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2061/rc).

Methods

Patients

This retrospective clinical study, conducted between June 1, 2017 and March 30, 2019, included patients with esophageal squamous cell carcinoma who underwent esophagectomy. The inclusion criteria were as follows: age under 75 years, pathologically confirmed diagnosis of esophageal squamous cell carcinoma, and the performance of minimally invasive esophagectomy. Exclusion criteria included a history of malignancy within the past 5 years, severe comorbidities, emergency or palliative esophagectomy, and loss to follow-up. All surgeries were performed by experienced surgeons from our department. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by The Ethics Committees of Fujian Medical University Union Hospital (No. 2025KY079) and individual consent for this analysis was waived due to the retrospective nature of the study.

mERAS protocols and SC

The mERAS protocols in our study were based on the protocols that have been described in the patients who have undergone colonic surgery or esophagectomy (13,14), reported studies and our previous experiences.

Preoperative protocols

In the mERAS group, patients were given preoperative counseling and evaluation. Nutrition was evaluated through the reported abbreviated patient-generated subjective global assessment (abPG-SGA) (15). For patients at risk for malnutrition or those moderately to severely malnourished, interventions were implemented, including nutrition education, an enriched diet to increase caloric and protein intake, and enteral nutrition via nasogastric tube for those with moderate to severe malnutrition. Nutritional support, tailored to each patient’s needs by specialized nutritionists, was started 7–10 days before surgery to improve nutritional status, enhance surgical tolerance, and reduce postoperative complications. In the SC group, nutritional evaluation was at the surgeon’s discretion, and interventions were not standardized. According to the reported studies, oral hygiene care can reduce ventilator-associated pneumonia (16,17). Because the patients who underwent esophagectomy had to receive long-time tracheal intubation during the operation and pneumonia was one of the most common post-operative complications, patients in the mERAS group received additional oral care. In mERAS group, the patients started the mouthwash three times a day with 15 mL of 0.1% cetylpyridinium chloride from 3 days before the operation to the day of discharge. In SC group, oral hygiene care was not standardized. The mERAS group was instructed to implement all of the pre-operative elements that are listed in Table 1.

Intra-operative protocols

The patients were intubated with a common single lumen tube without bronchial blocker, and turned to the semi-prone-position. The surgical techniques employed in our study were standardized minimally invasive esophagectomy procedures, including left cervical anastomosis using both mechanical staplers and hand suturing, as well as a two- or three-field lymph node dissection. The recurrent laryngeal nerve (RLN) was dissected through skeletonization, and en bloc resection of the para-nerve lymph nodes and surrounding soft tissues was performed, using the esophageal suspension method. The feasibility and safety of this approach in extensive thoracoscopic lymphadenectomy along the RLN in the semi-prone position have been reported (18).

In the SC group, minimally invasive esophagectomy was performed using standard techniques, including cervical anastomosis with a circular end-to-end stapler, placement of a nasogastric tube, stump closure with a linear stapler, and reinforcement of potentially weak areas with interrupted silk sutures (4-0, SILK). In the mERAS group, to minimize contamination of the surgical field and reduce the incidence of postoperative leakage, we modified the technique by reinforcing all mechanically stapled anastomoses with VCP771D (VICRYL Plus, ETHICON), in addition to cervical anastomosis with a circular end-to-end stapler, stump closure with a linear stapler, and nasogastric tube placement.

In mERAS group, the Bair Hugger™ Normothermia System and warned intravenous fluid were used to prevent hypothermia during the operation. Pneumatic compression stockings were also used in mERAS group. And they are not standard protocol in SC group. In mERAS group, patient controlled intravenous analgesia (PCIA) was placed during the operation. A dose of 3 mL of sufentanil 5% was diluted to 150 mL. The first dose was 3–6 mL, and top-up was 2–4 mL/h, depending on the different situations of the patients. The dose of each patient-controlled analgesic was 2 mL. The PCIA was not standard protocol in SC group. Patients were extubated immediately after the operation or on arrival in the ward of intensive care unit. The main intra-operative elements implemented in mERAS group are shown in Table 1.

Post-operative protocols

In mERAS group, we suggested patients practiced early ambulation on the first post-operative day (POD 1), and it was not standard protocol in SC group. If it was possible, we used low molecular dextran 500 mL per day from POD 1 to POD 7, and low-molecular-weight heparin 2,500–5,000 IU from POD 2 to the day when the patients had good ambulation. They were not standard protocols in SC group as well.

In both groups, we started enteral nutrition on POD 1 with jejunal feeding tube. We encouraged active use of bronchoscope sputum suction in the patients with dys-expectoration, which could also help to confirm the presence of vocal cord paralysis. We routinely did the ultrasonic examination on POD 4 to assess the volume of the pleural effusion, and if it was necessary, we did the thoracocentesis.

In SC group, after esophageal radiography showing no leakage on POD 7, the patients were routinely encouraged to start oral feeding. If the intake was good, the nasogastric tubes were removed, and the patients were discharged from the hospital. In mERAS group, after cervical-thoracic CT scan showing no leakage on POD 7, the nasogastric tubes were removed, and the patients were discharged from the hospital. We postponed the fasting time. And on POD 10–14, patients received the esophageal radiography. If there was no sign of leakage, the patients were encouraged to start oral feeding.

Statistical analysis

Statistical analysis was performed using SPSS statistical software (version 22.0, SPSS Inc., Chicago, IL, USA) and R version 2.8.1 (R Foundation for Statistical Computing). Descriptive statistics for continuous variables, such as clinical and pathological parameters, were presented as mean or mean ± standard deviation, while categorical variables were expressed as frequency (%). Comparisons between two groups were conducted using Student’s t-test, the χ² test, or Fisher’s exact test, as appropriate for the data type. Survival curves were generated using the Kaplan-Meier method, and differences between survival curves were assessed with the log-rank test. A two-sided P value of less than 0.05 was considered statistically significant.

Results

Between June 1, 2017 and March 30, 2019, a total of 230 patients diagnosed with esophageal squamous cell carcinoma who underwent minimally invasive esophagectomy were included in this study (Figure 1). Among these patients, 136 were assigned to the mERAS group, while 94 were included in the SC group. Baseline characteristics of the two groups are summarized in Table 2. No significant differences were observed between the groups, except for the prevalence of comorbidities, with a higher proportion of cardiac diseases or hypertension in the mERAS group compared to the SC group (24.4% vs. 13.8%).

Figure 1 Study flowchart. ERAS, enhanced recovery after surgery.

Patients in the mERAS group experienced a significantly shorter time to their first postoperative bowel movement compared to those in the SC group (2.9±1.3 vs. 4.3±1.8 days, P=0.047). Moreover, the median length of hospital stay was markedly reduced in the mERAS group (9.3±4.4 vs. 13.9±9.1 days, P<0.001) (Table 3).

Postoperative complications were also significantly lower in the mERAS group. The incidence of anastomotic leakage was 1.5% in the mERAS group, compared to 13.8% in the SC group (P<0.001). Similarly, the incidence of chylous leakage was 0.7% in the mERAS group, significantly lower than the 6.4% observed in the SC group (P=0.02). Furthermore, the readmission rate was reduced in the mERAS group (1.5% vs. 9.6%, P=0.005), with six readmissions in the SC group attributed to anastomotic leakage after discharge. There were no significant differences between the groups in terms of other complications, including vocal cord paresis, pulmonary infections, reoperation rates, and in-hospital mortality (Table 4).

The disease-free survival (DFS) rates at 1, 3, and 5 years were 85.4%, 66.8%, and 63.1% in the mERAS group, compared to 88.0%, 63.2%, and 57.0% in the SC group (P=0.41). Similarly, the overall survival (OS) rates at 1, 3, and 5 years were 95.6%, 73.7%, and 65.0% in the mERAS group, compared to 96.7%, 68.5%, and 52.2% in the SC group (P=0.07). While the mERAS group showed numerically higher DFS and OS rates, the differences were not statistically significant (Figure 2). Subgroup analysis of patients with preoperative weight loss exceeding 5% demonstrated a significant survival advantage in the mERAS group. In this subgroup, the OS rates at 1, 3, and 5 years were 97.1%, 79.7%, and 69.6%, respectively, in the mERAS group, compared to 93.8%, 66.7%, and 45.8% in the SC group (P=0.02) (Figure 3).

Figure 2 Comparison of survival outcomes between the two groups. (A) DFS comparison. (B) OS comparison. DFS, disease-free survival; OS, overall survival.

Figure 3 Comparison of survival outcomes between the two groups with ≥5% preoperative weight loss. (A) DFS comparison. (B) OS comparison. DFS, disease-free survival. OS, overall survival.

Discussion

Surgery represents a major trauma to the body, triggering a cascade of physiological responses, collectively termed the stress response (19). Surgical recovery after esophagectomy is a complex process. ERAS protocols involve evidence-based perioperative care items aimed at rapid recovery after the operation (19,20). However, limited studies have evaluated the benefits of ERAS protocols specifically in patients undergoing esophagectomy. Most available data come from small-scale case series, and few studies compare the outcomes of ERAS protocols with SC (13,21). To the best of our knowledge, our study is the largest reported series of ERAS protocols in patients with esophageal carcinoma who received esophagectomy, comparing with the SC. Notably, all the procedures included in this study were performed using minimally invasive techniques.

Despite the higher prevalence of comorbidities in the mERAS group, patients treated with mERAS protocols demonstrated shorter times to the first postoperative bowel movement and reduced postoperative hospital stays compared to the SC group. This earlier return of bowel function in the mERAS group can be attributed to early ambulation and the initiation of enteral nutrition, which not only promote gastrointestinal recovery but also enhance cardiopulmonary function, thereby reducing the risk of complications and shortening hospitalization (22). Notably, the reduction in hospital stay in the mERAS group was primarily driven by a significantly lower incidence of anastomotic leakage.

Meta-analyses of ERAS protocols in various surgical fields consistently show significant reductions in overall complications, with no differences in mortality or readmission rates. However, no meta-analyses have yet been conducted for esophageal carcinoma patients undergoing ERAS protocols. The reported complication rates in esophagectomy under ERAS protocols vary widely, ranging from 5.9% to 71%, which is likely due to differences in the definition and severity of complications across studies (13,21,23,24). In line with these findings, our study also observed a reduced complication rate in the mERAS group, particularly in terms of anastomotic leakage, chylous leakage, and readmissions. These results suggest that the mERAS protocol not only improves recovery times but also reduces the incidence of key complications.

Our study reported a relatively low incidence of anastomotic leakage after esophagectomy as compared with previously published studies (25,26). Preventing anastomotic leakage requires a multifaceted approach. In the mERAS group, we implemented various strategies, such as utilizing a modified nasogastric tube placement technique, suturing with VCP771D, administering low molecular weight dextran and heparin to enhance microcirculation, and prolonging fasting duration, among others. Interestingly, while some studies advocate for early oral feeding post-esophagectomy (27), our findings suggest that most anastomotic leakage cases in the SC group occurred after oral feeding, rather than early after the procedure. This led us to suspect the presence of potential weak spots at the anastomosis site post-esophagectomy, suggesting that prolonging fasting time could allow these weak spots to heal without the added variable of oral intake. By extending the fasting period in the mERAS group while maintaining enteral nutrition via jejunal feeding tubes, we achieved a notably low leakage rate of 1.5%. Further research is warranted to determine the optimal fasting duration post-esophagectomy.

Our study observed a favorable 5-year OS rate, which surpasses those reported in previous studies, with variations primarily depending on tumor stage (28). This improved outcome may be attributed to several factors. First, the mERAS group demonstrated a lower incidence of postoperative complications, particularly anastomotic leakage, which is known to negatively affect prognosis. Second, the meticulous and thorough lymph node dissection performed, especially of the bilateral RLN lymph nodes, likely contributed to better outcomes. Radical lymph node dissection is not only a critical component of successful radical esophageal cancer surgery but also essential for accurate pathological staging, which plays a pivotal role in guiding postoperative treatment decisions and determining patient survival prognosis (29). In addition, we observed a significant survival benefit in patients with preoperative weight loss exceeding 5%, a subgroup that showed improved outcomes when treated with the mERAS protocol. This benefit is likely due to the preoperative nutritional interventions, which aimed to improve the patients’ overall nutritional status. These interventions, including enteral nutrition, were designed to optimize the patients’ metabolic condition and reduce the risk of postoperative complications, particularly in those with significant preoperative weight loss.

Furthermore, patients in the mERAS group exhibited better long-term DFS compared to the SC group. Further analysis revealed that a significantly higher proportion of mERAS patients received and completed adjuvant therapy, which could be attributed to the lower complication rates in this group. With fewer postoperative complications, these patients were better able to tolerate and adhere to adjuvant therapy, which has been shown in numerous studies to improve survival outcomes (30,31). These findings suggest that the mERAS protocol not only reduces immediate postoperative risks but may also contribute to enhanced long-term survival through better adjuvant therapy compliance and improved overall clinical management.

Limitations

There are several limitations in this study. First, its non-randomized, retrospective design may have introduced selection and reporting biases, as patients were not randomly assigned to the mERAS or SC group. Second, while baseline characteristics were generally comparable, the higher prevalence of comorbidities in the mERAS group could have influenced the outcomes. Third, while we reported a 5-year follow-up period, longer-term outcomes and potential late complications were not assessed. Lastly, although we observed significant improvements in certain outcomes, the underlying mechanisms driving these benefits, such as the optimal duration of postoperative fasting and the precise role of individual ERAS components, warrant further investigation.

Conclusions

In conclusion, the implementation of mERAS protocols can significantly optimize postoperative recovery, reduce complications, and improve survival outcomes, especially in high-risk esophageal cancer patients. Despite the promising results, the limitations of this study underscore the need for well-designed, multicenter, randomized controlled trials to validate these findings and further refine ERAS protocols for esophageal carcinoma patients.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2061/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2061/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2061/prf

Funding: This work was sponsored by Fujian Minimally Invasive Medical Center (Thoracic Surgery), China; and Fujian Provincial Natural Science Foundation of China (grant No. 2024J01634); and National Natural Science Foundation of China (grant No. 82372728); and Funding for the Collaborative Innovation Platform Project of Fuzhou-Xiamen-Quanzhou National Independent Innovation Demonstration Zone (2023-P-004).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2061/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by The Ethics Committees of Fujian Medical University Union Hospital (No. 2025KY079) and individual consent for this analysis was waived due to the retrospective nature of the study.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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