Simultaneous versus staged major hepatectomy (≥3 liver segments) for outcomes of synchronous colorectal liver metastases: A systematic review and meta‐analysis

Abstract Background Hepatectomy is an effective treatment for synchronous colorectal liver metastases (SCLM) patients. However, whether to choose simultaneous hepatectomy (SIH) or staged hepatectomy (STH) is still controversial, especially during major hepatectomy (≥3 liver segments). Aims Compare the difference between the SCLM patients underwent SIH and STH, especially during major hepatectomy (≥3 liver segments). Methods and Results A meta‐analysis was conducted by analyzing the published data on the outcomes of SCLM patients underwent SIH or STH from January 2010 to December 2020 from the electronic databases. A random‐effects model was used to derive pooled estimates of odds ratio (OR) with 95% confidence interval (CI) for the explored outcomes. Eventually, 18 studies, including 5101 patients, were included this study. The result of meta‐analysis showed that SIH did not increase postoperative complications (pooled OR: 1.037; 95% CI: 0.897–1.200), perioperative mortality (pooled OR: 0.942; 95% CI: 0.552–1.607), 3‐year mortality (pooled OR: 1.090; 95% CI: 0.903–1.316) or 5‐year mortality (pooled OR: 1.077; 95% CI: 0.926–1.253), as compared with STH. Subgroup analysis showed that, simultaneous major hepatectomy (SIMH) also did not increase postoperative complications (pooled OR: 0.863; 95% CI: 0.627–1.188) or perioperative mortality (pooled OR: 0.689; 95% CI: 0.290–1.637) as compared with staged major hepatectomy (STMH). Conclusion Postoperative complications, perioperative mortality and long‐term prognosis had no significant difference between SIH and STH for SCLM patients. Besides, postoperative complications and perioperative mortality also had no significant difference between SIMH and STMH.


| INTRODUCTION
Colorectal cancer is the most common malignant tumor in the world, which seriously threatens human health. According to the latest global tumor statistics, colorectal cancer is the fourth most common cancer and the second leading cause of cancer related death in the world. 1 About 15%-25% of colorectal cancer is accompanied with synchronous colorectal liver metastases (SCLM), [2][3][4][5] and only one quarter of them are eligible for surgical resection. 6 The simultaneous hepatectomy (SIH) and staged hepatectomy (STH) are effective surgical methods. 7,8 According to articles, the 5-year overall survival (OS) rate of surgical treatment for SCLM can reach more than 50%. 9,10 However, the timing of surgery remains controversial. [11][12][13][14][15][16][17][18][19] Some studies suggested that SIH could increase the risk of postoperative complications and perioperative mortality, [11][12][13] while other studies did not support this conclusion. [14][15][16] In addition, the difference in long-term survival is also unclear between the SIH and STH. [17][18][19] By reviewing the previous articles, we found that major hepatectomy (≥3 liver segments) is rarely reported in SIH for SCLM before 2010. However, articles on major hepatectomy in SIH have significantly increased in the past decade. [10][11][12][13][14][15][20][21][22][23][24][25][26] Whether more patients received major hepatectomy can lead to differences in postoperative complications and perioperative mortality between simultaneous major hepatectomy (SIMH) and staged major hepatectomy (STMH) is unclear. And no meta-analysis has been performed to investigate this issue.
In this study, we reviewed large number of articles published after 2010 to compare the difference in postoperative complications, perioperative mortality and long-term prognosis between SIH and STH.
Besides, stratified meta-analyses were performed to compare postoperative complications and perioperative mortality between SIMH and STMH.

| Search strategy
Relevant articles published from January 2010 to December 2020 was searched by Medline, Embase, Ovid and Cochrane. The search terms included "colorectal cancer", "liver metastases", "simultaneous resection", "staged resections", "delayed resections" and "liver surgery". All relevant titles, abstracts, conference and so on were evaluated independently by two investigators to determine whether they meet our research objectives and requirements. Then the full-text of related articles were carefully reviewed and independent quality assessment was done by the two investigators. A third scholar would be consulted and make the decision when disagreement occured.  Figure 1 showed the flow-diagram of this study. And the study design conformed to the PRISMA guideline. 27

| Study selection
To ensure the quality of our study, only studies with complete articles were included, and abstracts, case reports and reviews were excluded.
The inclusion criteria were: (1) English articles published from January 2010 to December 2020; (2) the patients were diagnosed with SCLM at the first diagnosis; (3) SCLM was confirmed by pathology; (4) SCLM patients underwent SIH or STH in the same study; (5) There was at least one clearly reported including postoperative 3-year OS, postoperative 5-year OS, postoperative complications or perioperative mortality. Studies that did not meet the inclusion criteria were excluded.

| Data extraction
After downloaded the full texts of related articles, data regarding the following aspects were extracted and recorded: authors, countries or regions, population, type of study (prospective or retrospective), number of patients underwent SIH and STH; sex and age of patients, location of the primary tumor (colon or rectum), number of transfusions, proportion of patients underwent major hepatectomy (≥3 liver segments), postoperative complications, perioperative mortality, 3-year, 5-year OS and the corresponding mortality. Ethics committee approval not received for this study as there are no human or animal subjects directly recruited.

| Quality assessment
Two researchers independently evaluated the quality of articles according to the quality in prognosis studies (QUIPS) tool. 28,29 The authenticity and bias were evaluated through six aspects: participation; attrition; prognostic factor measurement; confounding measurement and account; outcome measurement; analysis and reporting.

| Outcomes
Surgical safety which included postoperative complications and perioperative mortality was the primary focus of this study. Long-term survival which included 3-year and 5-year mortality was the secondary focus. Postoperative complications or perioperative mortality were defined as adverse events or death within 90 days after surgery, and complications were classified according to Clavien classification. 30 Stratified meta-analyses was performed on patients who underwent SIMH and STMH.
T A B L E 2 3-, 5-year OS and mortality, corresponding complications and perioperative mortality of literatures included in this systematic review and meta-analysis

| Quality of the included studies
In this analysis, there were mild and high heterogeneities for postoperative complications and perioperative mortality, respectively (p = .382; I 2 = 6.3%; p = .029; I 2 = 53.3%). The sensitivity analysis showed that there was little difference among the 15 studies for postoperative complications ( Figure S1A). However, for perioperative mortality, there was one article that was significantly different as other articles, 12 while the others were relatively similar ( Figure S1B).

| DISCUSSION
Colorectal cancer is a common clinical malignant tumor, and liver is the most common distant metastasis organ. About 15%-25% of colorectal cancers are accompanied with SCLM. [2][3][4][5] In 1980s, surgery was not a treatment option for SCLM patients, and the life expectancy of these patients was only 6-12 months. 33,34 For these patients, systemic chemotherapy or interventional therapy were attempted to improve the prognosis, but the effect was poor. 35 Thus, some surgeons began to try to implement surgery for the SCLM patients. Although the incidence of postoperative complications was high at that time, some patients still achieved satisfactory long-term prognosis. 33,36 Gradually, SCLM were no longer the absolute taboo of surgery.
However, the timing of surgery for SCLM patients has always been under clinical debate since it was proposed that surgery was suitable for these patients. 37 For more than 40 years, whether SIH or STH should be performed for SCLM patients has always been controversy. [11][12][13][14][15][16][17][18][19] Previous articles reported that SIH increased the risk of surgery, leading to higher incidence of surgical complications or perioperative mortality. 38 However, thanks to the improvement of preoperative imaging, anesthesia and intensive care (28), and the improvement of surgical techniques, especially the progress of hepatectomy technology, the risk of postoperative complications and perioperative mortality have significantly reduced in recent years. 39 Some studies suggested that SIH could combine colorectal cancer surgery and liver metastasis surgery into one operation, thus reducing the number of operations, and preventing postoperative immunosuppression and tumor growth caused by repeated operations. 40 In addition, SIH can avoid the delayed treatment of liver metastases during STH, and early resection of liver metastases can improve the prognosis. 41 However, some studies suggested that STH could contribute to detect the subclinical liver metastases and more underwent thorough hepatectomy. 24 In addition, the pathology of lymph node metastasis can be obtained before hepatectomy for patients underwent STH, which can contribute to the choice of treatment options. 42 Therefore, to resolve the controversy between SIH and STH,  44 Therefore, the differences in age distribution between SIH and STH may be other reason for the heterogeneity in this study.
There are two limitations in this study. Firstly, there is a lack of sufficient data on long-term prognosis of major hepatectomy. Thus, more data is needed to analyze the differences in long-term prognosis between SIMH and STMH. In addition, due to the limitations of the included articles, we cannot well distinguish the differences in preoperative and postoperative chemotherapy between SIH and STH. Fortunately, our sensitivity analysis showed that the heterogeneity among include literatures is small. Therefore, we have reason to believe that there is little difference in preoperative or postoperative chemotherapy among include literatures. Of course, our research needs further prospective researches to confirm.

| CONCLUSION
There is no significant difference in postoperative complications, perioperative mortality and long-term prognosis between SIH and STH for SCLM patients. Furthermore, postoperative complications and perioperative mortality also had no significant difference between SIMH and STMH. According to recent articles, the proportion of major hepatectomy in SIH was much lower than that in STH. Therefore, for patients who need major hepatectomy, STH is still the main method, and some patients may be considered for SIH after a comprehensive assessment of the patient's age, physical condition and other factors.