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Department of Cardiothoracic Surgery, The Affiliated Suqian Hospital of Xuzhou Medical University, Nanjing Drum Tower Hospital Group Suqian Hospital, Suqian, China
Department of Cardiothoracic Surgery, The Affiliated Suqian Hospital of Xuzhou Medical University, Nanjing Drum Tower Hospital Group Suqian Hospital, Suqian, China
Department of Cardiothoracic Surgery, The Affiliated Suqian Hospital of Xuzhou Medical University, Nanjing Drum Tower Hospital Group Suqian Hospital, Suqian, China
Department of Cardiothoracic Surgery, The Affiliated Suqian Hospital of Xuzhou Medical University, Nanjing Drum Tower Hospital Group Suqian Hospital, Suqian, China
Department of Cardiothoracic Surgery, The Affiliated Suqian Hospital of Xuzhou Medical University, Nanjing Drum Tower Hospital Group Suqian Hospital, Suqian, China
Department of Cardiothoracic Surgery, The Affiliated Suqian Hospital of Xuzhou Medical University, Nanjing Drum Tower Hospital Group Suqian Hospital, Suqian, China
Department of Cardiothoracic Surgery, The Affiliated Suqian Hospital of Xuzhou Medical University, Nanjing Drum Tower Hospital Group Suqian Hospital, Suqian, China
Intrathoracic anastomosis and cervical anastomosis are very common in the esophagectomy of esophageal cancer; we aimed to evaluate the effects and safety of intrathoracic anastomosis versus cervical anastomosis in the esophagectomy.
Methods
We searched PubMed, EMBASE, Cochrane Library, Web of Knowledge, China National Knowledge Infrastructure, and WanFang databases up to September 30, 2021, for randomized controlled trials focused on cervical anastomosis versus intrathoracic anastomosis for the treatment of esophageal cancer.
Results
In total, 12 randomized controlled trials involving 1,493 patients were finally included. The incidence of anastomotic leak [relative risk = 2.76, 95% confidence interval (1.94∼3.94), P < .001] and recurrent laryngeal nerve injury [relative risk = 6.12, 95% confidence interval (3.02∼12.41), P < .001] in the intrathoracic anastomosis group were less than that of the cervical anastomosis group. There were no significant differences in the incidence of anastomotic stenosis [relative risk = 1.33, 95% confidence interval (0.88∼2.00), P = .18], pneumonia [relative risk = 1.31, 95% confidence interval (0.82∼2.09), P = .25], postoperative chylothorax [relative risk = 1.01, 95% confidence interval (0.40∼2.52), P = .99], and mortality [relative risk = 0.93, 95% confidence interval (0.52∼1.68), P = .82] between the 2 groups.
Conclusion
Intrathoracic anastomosis is associated with significantly reduced risk of leak and recurrent laryngeal nerve injury compared with cervical anastomosis.
Background
Esophageal cancer is one of the most common gastrointestinal tumors. It is highly aggressive and has very low survivorship. Its 1-year, 5-year, and 10-year survival are only 78.04%, 42.11%, and 31.98%, respectively.
Surgery is currently the main method for the treatment of early and mid-stage esophageal cancer. For the reconstruction of the digestive tract after esophageal cancer resection, the stomach has a reliable blood supply and is relatively easy to anastomose the esophageal stump.
However, the esophagectomy for esophageal cancer is also closely associated with many complications, including anastomotic leak, stenosis, and recurrent laryngeal nerve injury.
The early prevention and early intervention of postoperative complications are essential to the prognosis of patients.
There are 2 most common methods of anastomosis between the stomach and the esophagus stump—that is, cervical anastomosis (CA) and intrathoracic anastomosis (IA)—but there are still controversies over those 2 surgical methods. Some studies
Intrathoracic versus cervical anastomosis after minimally invasive esophagectomy for esophageal cancer: study protocol of the ICAN randomized controlled trial.
McKeown or Ivor Lewis totally minimally invasive esophagectomy for cancer of the esophagus and gastroesophageal junction: systematic review and meta-analysis.
Comparison of short-term outcomes between minimally invasive McKeown and Ivor Lewis esophagectomy for esophageal or junctional cancer: a systematic review and meta-analysis.
have reported that compared with IA, CA may increase the incidence of postoperative anastomotic leakage and anastomotic stenosis, but it can be cured by conservative treatment, and the patient will bear a smaller surgical risk. In recent years, many studies
have explored the effectiveness and safety of CA and IA, but there have not been reports of large-sample, multicenter clinical trials, and the results of reports remain unclear. To this end, we systematically collected relevant literature reports and conducted a meta-analysis of randomized controlled trials (RCT) on the effects and safety of CA versus IA, to provide reliable basis for the clinical surgery treatment of esophageal cancer.
Methods
This present systematic review and meta-analysis was performed and reported based on the guidelines for preferred reporting items for systematic reviews and meta-analyses statement.
We searched PubMed, EMBASE, Cochrane Library, Web of Knowledge, China National Knowledge Infrastructure (CNKI), and WanFang databases for relevant RCTs on the effects and safety of CA versus IA for the treatment of esophageal cancer. The search time limit was up to September 30, 2021. The search terms were as follows: “cervical anastomosis” AND “thoracic anastomosis” OR “intrathoracic anastomosis” AND “esophageal cancer” OR “esophageal carcinoma” OR “esophageal neoplasms.” We used a combination of subject terms and free words for the literature search. Additionally, we tracked the references of included RCTs and associated reviews for more potential related studies.
Inclusion and exclusion criteria
The inclusion criteria for this meta-analysis were as follows: The type of study was RCT study design. Languages were limited to Chinese and English. Research populations were patients with primary esophageal cancer confirmed by pathological or cytological examinations. Intervention measures included the comparison of CA and IA for esophageal cancer resections. Related outcome indicators including incidence of anastomotic leak, anastomotic stenosis, recurrent laryngeal nerve injury, pneumonia, and postoperative chylothorax were reported.
The exclusion criteria of this meta-analysis were as follows: the literature of which data could not be extracted and the data could not be obtained by contacting the corresponding author, and the literature with repeated publications.
Literature screening and data extraction
Two reviewers independently screened the literature and extracted data according to the inclusion and exclusion criteria and cross-checked them. In case of disagreement, it would be handed over to a third party for judgment. We first screened the title and abstract, and then excluded obviously irrelevant literature and further read the full text to determine whether it could be included in the end. We used a self-made data extraction table to extract data. The content of the data extraction mainly included the following data: basic information of the included research including title, first author, publication time; basic characteristics of the research object including sample size, gender, age, tumor stage and location; specific details of intervention measures; key elements of bias risk assessment; and outcome indicators and measurement.
Quality evaluation
The risk of bias tool from Cochrane Collaborations was used by 2 reviewers independently to evaluate the methodological quality and risk of bias of the included RCTs; any disagreements were resolved by discussion and consensus. This tool was also used to examine and measure 7 specific contents including: sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective outcome reporting, and other issues. Each domain was rated as low risk of bias, high risk of bias, or unclear risk of bias based on the judgment criteria.
Data analysis
All statistical analyses were conducted with RevMan 5.3 software. All the data were input and double-checked by 2 authors. Data syntheses and interpretations were also conducted by 2 investigators to ensure the accuracy of the results. Binary outcomes were presented as Mantel–Haenszel-style relative risk (RR) with 95% confidence intervals (CIs). Continuous outcomes were presented as mean differences. A fixed-effect model was used in the cases of homogeneity (P value of χ2 test >.10 and I2 <50%), and a random-effect model was used in the cases of obvious heterogeneity (P value of χ2 test >.10 and I2 ≥50%). Publication bias was evaluated by funnel plots, and asymmetry was evaluated by conducting Egger regression test.
Results
Literature search results
A total of 199 related literatures were obtained in the initial search, and after layer-by-layer screening, 12 RCTs were finally included. The literature screening process and results are shown in Figure 1.
Figure 1Preferred reporting items for systematic reviews and meta-analyses flow diagram of study selection.
Of the included 12 RCTs, a total of 1,493 patients were included, of whom 749 underwent CA and 744 underwent IA. The open approach was selected for most studies; only 1 study reported MIS. The surgery was all performed by experienced surgeons as reported. All the included RCTs have reported that the baseline characteristics of included patients were compared. Most included studies did not report the methods that anastomosis assessed intraoperatively. The characteristics of included 12 RCTs are presented in Table I.
Table IThe characteristics of included randomized controlled trials
The short-term effect analysis of thoracolaparoscopic intrathoracic anastomosis and neck anastomosis in the treatment of middle and lower thoracic esophageal cancer.
Hand-sewn cervical anastomosis versus stapled intrathoracic anastomosis after esophagectomy for middle or lower thoracic esophageal cancer: a prospective randomized controlled study.
Cervical or thoracic anastomosis after esophageal resection and gastric tube reconstruction: a prospective randomized trial comparing sutured neck anastomosis with stapled intrathoracic anastomosis.
The short-term effect analysis of thoracolaparoscopic intrathoracic anastomosis and neck anastomosis in the treatment of middle and lower thoracic esophageal cancer.
The short-term effect analysis of thoracolaparoscopic intrathoracic anastomosis and neck anastomosis in the treatment of middle and lower thoracic esophageal cancer.
Hand-sewn cervical anastomosis versus stapled intrathoracic anastomosis after esophagectomy for middle or lower thoracic esophageal cancer: a prospective randomized controlled study.
had indicated the details of allocation concealment. All included RCTs did not report allocation blinding or the personnel blinding. For the blinding of outcome assessment, all included studies did not report the related information. No selective reporting or other significant biases among the 12 included RCTs were found.
The short-term effect analysis of thoracolaparoscopic intrathoracic anastomosis and neck anastomosis in the treatment of middle and lower thoracic esophageal cancer.
Hand-sewn cervical anastomosis versus stapled intrathoracic anastomosis after esophagectomy for middle or lower thoracic esophageal cancer: a prospective randomized controlled study.
Cervical or thoracic anastomosis after esophageal resection and gastric tube reconstruction: a prospective randomized trial comparing sutured neck anastomosis with stapled intrathoracic anastomosis.
reported the incidence of anastomotic leak. There was no significant statistical heterogeneity among the studies (I2 = 4%, P = .41). A fixed-effect model was used for statistical analysis. The results showed that the incidence of anastomotic leak in the IA group was less than that of CA group, and the difference was significant (RR = 2.76, 95% CI [1.94∼3.94], P < 0.001; Figure 4, A).
Figure 4The forest plots for synthesized outcomes. CA, cervical anastomosis; CI, confidence interval; IA, intrathoracic anastomosis.
The short-term effect analysis of thoracolaparoscopic intrathoracic anastomosis and neck anastomosis in the treatment of middle and lower thoracic esophageal cancer.
Hand-sewn cervical anastomosis versus stapled intrathoracic anastomosis after esophagectomy for middle or lower thoracic esophageal cancer: a prospective randomized controlled study.
Cervical or thoracic anastomosis after esophageal resection and gastric tube reconstruction: a prospective randomized trial comparing sutured neck anastomosis with stapled intrathoracic anastomosis.
reported the incidence of anastomotic stenosis. There was no significant statistical heterogeneity among the studies (I2 = 45%, P = .07). A fixed-effect model was used for statistical analysis. The results showed that there was no significant difference in the incidence of anastomotic stenosis between the 2 groups (RR = 1.33, 95% CI [0.88∼2.00], P = .18, Figure 4, B).
The short-term effect analysis of thoracolaparoscopic intrathoracic anastomosis and neck anastomosis in the treatment of middle and lower thoracic esophageal cancer.
Hand-sewn cervical anastomosis versus stapled intrathoracic anastomosis after esophagectomy for middle or lower thoracic esophageal cancer: a prospective randomized controlled study.
Cervical or thoracic anastomosis after esophageal resection and gastric tube reconstruction: a prospective randomized trial comparing sutured neck anastomosis with stapled intrathoracic anastomosis.
reported the incidence of pneumonia. There was significant statistical heterogeneity among the studies (I2 = 55%, P = .01). A random-effect model was used for statistical analysis. The results showed that there was no significant difference in the incidence of pneumonia between the 2 groups (RR = 1.31, 95% CI [0.82∼2.09], P = .25, Figure 4, C).
The short-term effect analysis of thoracolaparoscopic intrathoracic anastomosis and neck anastomosis in the treatment of middle and lower thoracic esophageal cancer.
Hand-sewn cervical anastomosis versus stapled intrathoracic anastomosis after esophagectomy for middle or lower thoracic esophageal cancer: a prospective randomized controlled study.
Cervical or thoracic anastomosis after esophageal resection and gastric tube reconstruction: a prospective randomized trial comparing sutured neck anastomosis with stapled intrathoracic anastomosis.
reported the incidence of a recurrent laryngeal nerve injury. There was no significant statistical heterogeneity among the studies (I2 = 0%, P = .77). A fixed-effect model was used for statistical analysis. The results showed that the incidence of recurrent laryngeal nerve injury in the IA group was less than that of CA group, and the difference was statistically significant (RR = 6.12, 95% CI [3.02∼12.41], P < .001, Figure 5, A).
The short-term effect analysis of thoracolaparoscopic intrathoracic anastomosis and neck anastomosis in the treatment of middle and lower thoracic esophageal cancer.
Cervical or thoracic anastomosis after esophageal resection and gastric tube reconstruction: a prospective randomized trial comparing sutured neck anastomosis with stapled intrathoracic anastomosis.
reported the incidence of postoperative chylothorax. There was no significant statistical heterogeneity among the studies (I2 = 0%, P = .92). A fixed-effect model was used for statistical analysis. The results showed that there was no significant difference in the incidence of postoperative chylothorax between the 2 groups (RR = 1.01, 95% CI [0.40∼2.52], P = .99, Figure 5, B).
Hand-sewn cervical anastomosis versus stapled intrathoracic anastomosis after esophagectomy for middle or lower thoracic esophageal cancer: a prospective randomized controlled study.
Cervical or thoracic anastomosis after esophageal resection and gastric tube reconstruction: a prospective randomized trial comparing sutured neck anastomosis with stapled intrathoracic anastomosis.
reported the mortality. There was no significant statistical heterogeneity among the studies (I2 = 0%, P = .80). A fixed-effect model was used for statistical analysis. The results showed that there was no significant difference in the mortality between the 2 groups (RR = 0.93, 95% CI [0.52∼1.68], P = .82, Figure 5, C).
Publication bias analysis
We attempted to evaluate publication bias by using funnel plots. As indicated in Figure 6, the dots in the funnel plots were evenly distributed, and the result of Egger regression tests indicated there were no significant publication biases among the synthesized outcomes (all P > .05).
Sensitivity analyses, which investigate the influence of 1 study on the overall risk estimate by removing 1 study in each turn, indicated that the overall risk estimates were not substantially changed by any single study.
have reported the selection of anastomosis site after esophageal cancer resection, no consensus has been reached so far, the relevant literature has not given relatively convincing conclusions, and the reported results are widely divergent. The results of this meta-analysis have indicated that IA is associated with lower incidence of anastomotic leak and recurrent laryngeal nerve injury; no significant difference in the incidence of anastomotic stenosis, pneumonia, postoperative chylothorax, and mortality between IA and CA are found. Therefore, the application of IA in esophageal cancer resection may have more advantages.
Due to the biological characteristics of multiple origins and submucosal skipping metastasis of esophageal cancer, the residual rate of cancer cells at the margin of the esophagus undergoing partial esophagus resection is high.
Anastomotic leakage after intrathoracic versus cervical oesophagogastric anastomosis for oesophageal carcinoma in Chinese population: a retrospective cohort study.
have reported that the postoperative stump positive rate can reach 15.11% to 29.07%. When the resection margin is 5 cm from the tumor, the positive rate of stump is still 6.7%, and when the resection is 10 cm, it drops to 2% to 0.9%. In this case, it is sufficient that the margin of esophageal cancer is no less than 5 cm above and below the tumor. Therefore, some scholars
advocate subtotal esophageal resection and CA with another incision. They believe that the CA does not miss multifocal lesions and expands the scope of esophageal cancer resection, increases the length of esophagus resection, and sweeps lymph nodes, which is consistent with the principle of complete tumor resection. If the length of the resection is insufficient, it may lead to local recurrence of the remaining esophagus anastomosis.
At present, there is still no definite explanation for the reasons why the incidence of anastomotic leakage after CA is significantly higher than that of IA. Some scholars
Management and outcomes of anastomotic leakage after McKeown esophagectomy: a retrospective analysis of 749 consecutive patients with esophageal cancer.
believe that the high incidence may be related to the high anastomotic position of the neck and the greater anastomotic tension, the poorer anastomotic arterial blood supply and venous return than the chest, and the lack of pleural tissue coverage in the CA. Some studies
Comparison of short-term outcomes between minimally invasive McKeown and Ivor Lewis esophagectomy for esophageal or junctional cancer: a systematic review and meta-analysis.
believe that with the significant improvement in the quality of digestive tract staplers in recent years, it overcomes the shortcomings of poor exposure and difficulty in manual chest anastomosis in the past and greatly improves the success rate of anastomosis. Studies
have reported that the occurrence of anastomotic leakage after esophageal cancer surgery not only depends on the anastomosis site, but also is influenced by multiple factors. We have found that cervical anastomosis is not associated with increased risk of pneumonia, since it has a significantly higher risk or recurrent nerve injury and is expected to have a higher rate of dysphagia. It may be related that the open approach was done for most patients; the sample size may be not enough to detect the group difference. In addition, the results of this meta-analysis have showed that there is no significant difference in perioperative mortality between the 2 groups of patients. However, the occurrence of postoperative anastomotic leakage can affect the patient’s quality of life during the perioperative period and increase the medical burden.
Analysis of the effect and complications of lymph node dissection adjacent to the recurrent laryngeal nerve by thoracoscopic laparoscopy combined with minimally invasive radical esophagectomy.
Perioperative effect of radical cervical anastomosis for esophageal cancer under thoracoscopic laparoscopy in the treatment of elderly patients with esophageal cancer.
Still, the impact of the anastomotic site on the survival and quality of life of patients remains unclear; future studies on the role of IA and CA on the survival and quality of life of patients are needed.
It is worth noting that CA is prone to damage of the recurrent laryngeal nerve. The main reason is that the recurrent laryngeal nerve in the tracheoesophageal groove is easily damaged when the neck esophagus and stomach are reconstructed, and the lymph nodes are freed from the cervical esophagus.
Although most of the recurrent laryngeal nerve palsy is not bilateral and does not require tracheotomy, it is not life-threatening, and as long as the nerve has not been cut, the symptoms of hoarseness may be restored,
Thoracoscopic esophagectomy with left recurrent laryngeal nerve monitoring for thoracic esophageal cancer in a patient with a right aortic arch: a case report.
have reported postoperative recurrent laryngeal nerve injury is associated with many pulmonary infections, suggesting that we should pay more attention to recurrent laryngeal nerve injury. As postoperative anastomotic stenosis is closely related to scar healing after anastomotic leakage, anastomotic stenosis is related to the anastomosis method, and the difficulty in swallowing and repeated expansion caused by postoperative anastomotic stenosis affect the quality of life of patients, so anastomotic stenosis is also one of the important outcome indicators after esophageal cancer resection.
Anastomosis behind the sternoclavicular joint is associated with increased incidence of anastomotic stenosis in retrosternal reconstruction with a gastric conduit after esophagectomy.
A single blinded randomized controlled trial comparing semi-mechanical with hand-sewn cervical anastomosis after esophagectomy for cancer (SHARE-study).
it may be associated with the anastomosis method; stapled anastomosis is used in the CA, but handsewn anastomosis is mostly used in the IA. More studies on the role of IA and CA on the postoperative anastomotic stenosis needs further elucidation in the future.
Several limitations of this present meta-analysis must be considered. First, anastomotic leak appears more common in cervical anastomosis based on this meta-analysis. It is consistent with many studies, while there is a great controversy in published evidence. Burden of complications and associated treatment, however, substantially differ between relatively benign cervical leaks and intrathoracic leaks. We cannot analyze other relevant measures, such as total complication burden by Clavien-Dindo or accordion complication burden limited by collected data; further investigations on the burden of complications are needed. Second, the association between recurrent nerve palsy and upper mediastinal lymph node dissection is highly relevant; it is important to compare the presence or absence of recurrent nerve surrounding lymph node dissection in cervical anastomosis and intrathoracic anastomosis, or 2-field dissection and 3-field dissection, and yet the included studies did not report the data of recurrent nerve surrounding lymph node dissection; therefore, we cannot include the data for synthesized analysis. Third, the most included RCTs were reported from the United States and China, and there may be some population and region biases. Furthermore, the sample size of synthesized outcomes is small in this meta-analysis, and it may underpower to detect the group differences. Future studies with a larger sample size in different populations and areas are warranted to evaluate the effects and safety of IA and CA. Additionally, the majority of the studies reviewed focused on an open-only approach to esophagectomy, while MIS approaches are recognized as a viable option in esophagectomy; the results of our meta-analysis article are further limited by reviewing primarily the open approach for esophagectomy.
In conclusion, this present meta-analysis has found that IA is associated with significantly decreased risk of leak and RLN injury. There are no significant differences in the incidence of anastomotic stenosis, pneumonia, postoperative chylothorax, and mortality between IA and CA. However, limited by the number and quality of included studies, the long-term efficacy and postoperative quality of life of CA and IA still need to be further evaluated by high-quality studies in the future.
Funding/Support
The study was funded by 2020 Suqian Municipal Guiding Science and Technology Project (approval number: 2020108).
Conflicts of interest/Disclosure
All authors declare that they have no competing interests.
References
Huang F.L.
Yu S.J.
Esophageal cancer: risk factors, genetic association, and treatment.
Intrathoracic versus cervical anastomosis after minimally invasive esophagectomy for esophageal cancer: study protocol of the ICAN randomized controlled trial.
McKeown or Ivor Lewis totally minimally invasive esophagectomy for cancer of the esophagus and gastroesophageal junction: systematic review and meta-analysis.
Comparison of short-term outcomes between minimally invasive McKeown and Ivor Lewis esophagectomy for esophageal or junctional cancer: a systematic review and meta-analysis.
The short-term effect analysis of thoracolaparoscopic intrathoracic anastomosis and neck anastomosis in the treatment of middle and lower thoracic esophageal cancer.
Hand-sewn cervical anastomosis versus stapled intrathoracic anastomosis after esophagectomy for middle or lower thoracic esophageal cancer: a prospective randomized controlled study.
Cervical or thoracic anastomosis after esophageal resection and gastric tube reconstruction: a prospective randomized trial comparing sutured neck anastomosis with stapled intrathoracic anastomosis.
Anastomotic leakage after intrathoracic versus cervical oesophagogastric anastomosis for oesophageal carcinoma in Chinese population: a retrospective cohort study.
Management and outcomes of anastomotic leakage after McKeown esophagectomy: a retrospective analysis of 749 consecutive patients with esophageal cancer.
Analysis of the effect and complications of lymph node dissection adjacent to the recurrent laryngeal nerve by thoracoscopic laparoscopy combined with minimally invasive radical esophagectomy.
Perioperative effect of radical cervical anastomosis for esophageal cancer under thoracoscopic laparoscopy in the treatment of elderly patients with esophageal cancer.
Thoracoscopic esophagectomy with left recurrent laryngeal nerve monitoring for thoracic esophageal cancer in a patient with a right aortic arch: a case report.
Anastomosis behind the sternoclavicular joint is associated with increased incidence of anastomotic stenosis in retrosternal reconstruction with a gastric conduit after esophagectomy.
A single blinded randomized controlled trial comparing semi-mechanical with hand-sewn cervical anastomosis after esophagectomy for cancer (SHARE-study).
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