Efficacy of Surgery for the Treatment of Gastric Cancer Liver Metastases: A Systematic Review of the Literature and Meta-Analysis of Prognostic Factors

Background: In the last 10 years, the management of patients with gastric cancer liver metastases (GCLM) has changed from chemotherapy alone, towards a multidisciplinary treatment with liver surgery playing a leading role. The aim of this systematic review and meta-analysis is to assess the efficacy of hepatectomy for GCLM and to analyze the impact of related prognostic factors on long-term outcomes. Methods: The databases PubMed (Medline), EMBASE, and Google Scholar were searched for relevant articles from January 2010 to September 2020. We included prospective and retrospective studies that reported the outcomes after hepatectomy for GCLM. A systematic review of the literature and meta-analysis of prognostic factors was performed. Results: We included 40 studies, including 1573 participants who underwent hepatic resection for GCLM. Post-operative morbidity and 30-day mortality rates were 24.7% and 1.6%, respectively. One-year, 3-years, and 5-years overall survival (OS) were 72%, 37%, and 26%, respectively. The 1-year, 3-years, and 5-years disease-free survival (DFS) were 44%, 24%, and 22%, respectively. Well-moderately differentiated tumors, pT1–2 and pN0–1 adenocarcinoma, R0 resection, the presence of solitary metastasis, unilobar metastases, metachronous metastasis, and chemotherapy were all strongly positively associated to better OS and DFS. Conclusion: In the present study, we demonstrated that hepatectomy for GCLM is feasible and provides benefits in terms of long-term survival. Identification of patient subgroups that could benefit from surgical treatment is mandatory in a multidisciplinary setting.


Introduction
Gastric cancer (GC) is the fourth most common cancer worldwide and the second among cancer deaths [1]. Distant metastases are found in 30-35% of patients at their first clinical observation and they spread commonly to the liver (48% of metastatic cancer patients), peritoneum (32%), lung (15%), and bone (12%). Patients with stage IV GC have a median survival of 3 months, which is worst among those with bone and liver metastases (2 months) [2]. According to current guidelines, systemic chemotherapy is recommended as a single modality treatment for stage IV GC [3]. However, despite the development of new molecular targeting agents, the prognosis remains unsatisfactory, with a reported median overall survival (OS) of 13.8 months [4,5].
The role of surgical resection of GC metastases has always been debated. However, in the last 10 years, many studies showed encouraging results. Recently, Yoshida et al. proposed a new classification of stage IV GC, dividing the stage IV in four categories which results in different treatment approaches (Figure 1) [6]. Gastric cancer liver metastases (GCLM) without peritoneal carcinomatosis belong to categories 1 and 2; in those patients, the authors suggest using the so-called "conversion therapy", which consists of intensive chemotherapy followed by adjuvant surgery if radical resection is achievable. In addition, the last revision of the Japanese Gastric Cancer guidelines stated that hepatectomy can be considered for a subset of patients such as cases with solitary liver metastasis [7]. This approach is also endorsed by the Italian Group on Gastric Cancer Research [8].
patients, the authors suggest using the so-called "conversion therapy", which consists of intensive chemotherapy followed by adjuvant surgery if radical resection is achievable. In addition, the last revision of the Japanese Gastric Cancer guidelines stated that hepatectomy can be considered for a subset of patients such as cases with solitary liver metastasis [7]. This approach is also endorsed by the Italian Group on Gastric Cancer Research [8].
However, GC patients often present with metastases in multiple sites and only 0.4-1% of patients have liver metastases amenable to radical resection [7]. Most recent reports in the literature showed promising results after adopting aggressive multidisciplinary management, including surgery, to treat patients with GCLM [9].
In our study, we performed a systematic review of the literature of the last decade to evaluate the OS and disease-free survival (DFS) after hepatectomy for GCLM, and a metaanalysis of the prognostic factors, in order to clarify which patients would benefit more from surgical treatment.

Materials and Methods
A systematic review protocol was registered at the International Prospective Register of Systematic Reviews (PROSPERO): database registration number CRD42021218350 [10]. This study is reported in compliance with the Transparent Reporting of Systematic Reviews and Meta-analyses (PRISMA) statement [11].

Type of Studies
We included prospective and retrospective studies reporting survival outcomes after hepatectomy for GCLM. We have selected only studies involving humans and available as full text in English published in the last decade. We excluded case reports, animal and other experimental, as well as purely imaging studies.

Type of Participants
We included studies where all participants who had hepatectomy for GCLM were eligible for upfront radical resection (R0) of both primary tumor and metastasis in the liver. In order to avoid selection bias, studies including participants with metastatic sites other than the liver were excluded. However, GC patients often present with metastases in multiple sites and only 0.4-1% of patients have liver metastases amenable to radical resection [7]. Most recent reports in the literature showed promising results after adopting aggressive multidisciplinary management, including surgery, to treat patients with GCLM [9].
In our study, we performed a systematic review of the literature of the last decade to evaluate the OS and disease-free survival (DFS) after hepatectomy for GCLM, and a meta-analysis of the prognostic factors, in order to clarify which patients would benefit more from surgical treatment.

Materials and Methods
A systematic review protocol was registered at the International Prospective Register of Systematic Reviews (PROSPERO): database registration number CRD42021218350 [10]. This study is reported in compliance with the Transparent Reporting of Systematic Reviews and Meta-analyses (PRISMA) statement [11].

Type of Studies
We included prospective and retrospective studies reporting survival outcomes after hepatectomy for GCLM. We have selected only studies involving humans and available as full text in English published in the last decade. We excluded case reports, animal and other experimental, as well as purely imaging studies.

Type of Participants
We included studies where all participants who had hepatectomy for GCLM were eligible for upfront radical resection (R0) of both primary tumor and metastasis in the liver. In order to avoid selection bias, studies including participants with metastatic sites other than the liver were excluded.

Type of Interventions and Outcomes
We included only studies in which there were reported short-term outcomes (postoperative morbidity and 30-day mortality) and long-term outcomes (1-, 3-, 5-years OS and DFS) after hepatectomy for GCLM. We investigated the impact of the prognostic factors collected from the studies on OS and DFS.

Electronic Searches
Two independent reviewers (G.M. and F.S.) performed a systematic search of the literature, from January 2010 to September 2020. The authors did not consider previous articles as the management of gastric liver metastases has changed significantly over the last decade.
We searched the PubMed (Medline), Cochrane, EMBASE, and Google Scholar databases using MeSH and free text words (tw) for GC and liver metastases.
We performed the search using different combinations of the following keywords: "gastric AND cancer AND hepatectomy", "gastric AND cancer AND metastases" "gastric AND cancer AND metastasectomy", "stomach AND cancer AND hepatectomy", "stomach AND cancer AND metastasectomy". The same search was then repeated changing the word "cancer" with "carcinoma", "cancer" with "neoplasm", "metastases with "metastasis", and "hepatectomy" with "liver resection".

Searching Other Resources
We also checked the references of the selected studies in order to find further relevant trials.

Data Collection and Analysis
Two authors (G.M. and F.S.) independently selected studies and two authors (G.M. and A.T.) extracted data from those trials in a pre-piloted data extraction form created using Microsoft Excel (Microsoft, Redmond, WA, USA).

Study Selection
Study selection was performed by first screening the titles and abstracts in order to exclude the studies that were clearly not eligible. Then, using the predefined inclusion and exclusion criteria, the full texts of the studies were screened. Figure 2 illustrates the flow-chart diagram of the study selection.  Then, some papers were excluded after discussion between the two reviewers (G.M. and F.S.), because they were not strictly linked to the topic of the review.
Ethical approval and informed consent were not needed for this paper as per local rules at our institution.

Data Extraction and Management
Two independent reviewers performed data collection (G.M. and A.T.) and included the following data: 1.
Year of publication.

3.
Study interval (year(s) in which the trial was conducted). 4.
Inclusion and exclusion criteria.

5.
Population details, such as age, sex, characteristics of the primary tumor, and liver metastases. 6.
Outcomes (mentioned in 'Type of interventions and outcomes'). 7.
Details of the prognostic factor(s).
The reviewer extract survival data from tables, directly from the text whenever possible or by manual interpolation in case of data available only in graphs. The clarification of unclear or missing information was done by direct contact with the authors of each study. We solved any differences in opinion through discussion.

Assessment of Risk of Bias in Included Studies
Due to the nature of this systematic review, the study quality or risk of bias was assessed by the Oxford Centre for Evidence-Based Medicine (CEBM) classification only for descriptive purposes [12].

Data Synthesis
One, three, and five-year OS and DFS were calculated as the proportion of patients alive and free from the tumor at 1, 3, and 5 years and the total of patients included in the study. Median Survival Time (MST) was also calculated. StatsDirect Software (StatsDirect Ltd., Birkenhead, UK) was used to calculate the meta-analysis of proportion [13].
Hazard ratio (HR) with corresponding 95% confidence intervals (95% CIs) were calculated to assess the impact on OS and DFS of the liver metastases related prognostic factors using the inverse variance method with Review Manager 5.4 (Cochrane Collaboration) [14].
The HR and its variance were obtained from the study or calculated according to the data presentation: annual mortality rates, survival curves, number of deaths, or percentage freedom from death [15].
A random-effects model was used to perform a meta-analysis due to the clinical heterogeneity among studies. Funnel plots were used to graphically represent publication bias and in order to find asymmetry and any outliers. Heterogeneity across the studies was assessed using the Cochran Q test and/or the I 2 statistic to measure the degree of variation not attributable to chance alone. This was graded as low (I 2 < 25%), moderate (I 2 = 25% to 75%), or high (I 2 > 75%) [16].
A significant p value < 0.05 was considered in order to assess statistically significant differences in each analysis. Forest plots showed the results of the current meta-analysis. Calculations were performed by A.T. and verified by G.M.

Subgroup Analysis
We performed a subgroup analysis of the OS and DFS based on ethnicity. One, three, and five-year OS and DFS were calculated as the proportion of patients alive and free from tumor at 1, 3, and 5 years and the total patients included in the study. StatsDirect Software was used to calculate the meta-analysis of proportion [17].

Results
We identified 2499 references through electronic searches of Medline (n = 1212), EMBASE (n = 551), and Google Scholar (n = 736). We excluded 2439 duplicates and clearly irrelevant references through reading the abstracts. The remaining 60 records were retrieved as full text for further assessment. Then, we discharged the other 4 references (for further details, see the section "Characteristic of excluded studies" below). At least, 40 studies were included in the study and were finally analyzed.

Characteristics of the Included Studies
The 40 included studies [8, included 1573 participants who underwent hepatic resection for GCLM. All studies were reported in English. All studies were retrospective analyses. No prospective studies or randomized trials were found (Tables 1 and 2). The majority of the studies were conducted in Asia (33 studies: 82.5%), whereas only 7 trials included data from Western countries (17.5%).
The median time between gastrectomy and the onset of hepatic metastases was 12.5 months (range 7-135) in 12 studies reporting this data.

Characteristics of the Excluded Studies, Risk of Bias, and Applicability Concerns
Three studies were excluded because authors included also patients with peritoneal metastasis [58][59][60].
Data from one study were excluded from all the analyses because the authors did not specify if the patients underwent liver resection or other treatments (Radiofrequency ablation (RFA), Microwave ablation, others) [60]. Data from 4 studies were included from the analysis of the short-term outcomes (morbidity and mortality) but excluded from the analysis of the OS, DFS, and the analysis of the prognostic factors because the authors did not specify if the patients underwent liver resection or other treatments [33,39,41,42].
All the studies included in the analysis had a type 2b quality of evidence, according to the Oxford Centre for Evidence-Based Medicine scoring system.

Morbidity and Mortality
Surgical resection of GCLM was performed with 24.7% of morbidity from the 19 studies reporting this data (250/1011) and 1.6% of 30-day mortality from the 30 studies reporting this data (22/1338). Short-and long-term outcomes are shown in Table 3.

Survival Data
After a median follow-up of 26 months (range 8-77), the 1-year, 3-year, and 5-year OS were 72% (range 66-77%), 37% (range 31-43%), and 26% (range 21-30%), respectively ( Figure 3). The analysis of the funnel plots showed the presence of a slight asymmetry. However, even if the presence of a small study bias cannot be excluded at all, the data suggest that it seems unlikely.
Heterogeneity was significant, so the variability cannot be related only to ethnicity.

Analysis of Prognostic Factors
The results of the meta-analysis of prognostic factors are shown in Tables 4 and 5.  The analysis of the funnel plots showed the presence of a slight asymmetry. However, even if the presence of a small study bias cannot be excluded at all, the data suggest that it seems unlikely.
Heterogeneity was significant, so the variability cannot be related only to ethnicity. Nevertheless, we could not include all the studies due to missing data. The analysis demonstrated that the primary cancer factors associated with higher OS were wellmoderately differentiated tumors, pT1-2 and pN0-1 adenocarcinoma. Chemotherapy was also a strong prognostic factor as well as R0 resections. Considering the burden of the disease, the presence of solitary metastasis, unilobar and metachronous metastases were all strongly positively associated with OS. On the contrary, older age, sex, size of primary tumor or metastasis, and the presence of lymphatic or venous invasion by the primary tumor were not significantly associated with OS.
The factors associated with a higher DFS were pT1-pT2 primary cancers, the absence of lymphatic invasion by the primary tumors, metachronous liver metastases, solitary metastasis, and the size of liver metastasis <3 cm. However, for the analysis of the prognostic factors related to DFS, less than 5 studies reported the results for each outcome.
The majority of the analyses had mild or low levels of heterogeneity, suggesting that the impact of those prognostic factors on OS and DFS is quite similar despite the well-known differences in the studies.

Discussion
This systematic review and meta-analysis demonstrate that surgical resection of GCLM, in the absence of peritoneal disease, is a safe procedure, with a 1.6% risk of mortality. It can achieve a 5-year OS of 26%. Those results are in line with the results of recent studies. Long et al., in a meta-analysis [61] of 39 studies, showed a 5-year OS rate of 27%. Similarly, Liao et al. [62], in a comparative analysis of 8 retrospective studies between hepatectomy and chemotherapy only, showed better OS in the surgical group with an odds ratio of 0.17 and 0.15 at 1 and 2 years. Up to now, no other meta-analysis has investigated DFS and prognostic factors related to DFS. We found that liver resection was associated with 5-year DFS of 22%.
Those positive results were particularly highlighted in the Asian studies. Historically, GC survival has always been substantially different in Asian and Western countries. However, results from recent systematic review and meta-analysis are discordant. While Gavriilidis et al. [63] showed no significant difference between Eastern and Western countries in terms of OS, Markar et al. [64] reported a better survival rate for the Eastern studies compared to Western. Furthermore, the results on this topic should be interpreted carefully due to differences between populations in terms of characteristics related to primary cancer, population screening, and dietary habits [65].
In clinical practice, patient selection is crucial in order to achieve acceptable mortality and morbidity. However, in addition to the importance of precision medicine, the role of a careful evaluation of each patient by multidisciplinary teams is improving. In fact, a multidisciplinary approach could increase the proportion of patients' candidates to curative treatment also in the metastatic setting. In this context, tools to perform a better selection of candidates for hepatectomy, such as the assessment of patients' performance status, hepatic invasiveness, and the feasibility of obtaining R0 resection, play a central role. Although there are still discordant results in the literature, we believe that radical resection of primary tumor and metastases is vital to achieve good outcomes.
Beom et al. demonstrated in a retrospective study the central role of conversion surgery following chemotherapy for 101 patients with metastatic GC [66]. In the trial, 65 patients (64.4%) had a major response and 11 patients (10.9%) received metastasectomy. Fifty-seven patients (56.4%) had a complete macroscopic resection, with a median survival of 26 months. The importance of R0 resection clearly emerged also in the study of Morgagni et al. [67], in which 11/54 metastatic GC underwent R0 resection. The authors concluded that conversion surgery in metastatic GC could be beneficial only if R0 resection could be achieved. We showed the same results in our analysis, with R1 resection strongly associated with poor OS and DFS. On the other hand, Cheon et al. [68] observed a similar survival rate after R0 or R1 resection, in contrast with our findings. However, the fact that a higher percentage of patients in the Korean series (88% vs. 27.6% in our series) received chemotherapy could be responsible for the differences in the outcomes, due to the positive impact of active treatment on survival. In general, in the case of synchronous disease, achieving an R0 resection both for primary tumor and for the hepatic metastases is recommend. Median survival exceeds 16 months after radical resections and drops to 6 months in case of R1 resections [8]. In our meta-analysis, R0 resection was found strongly associated with a better outcome, in terms of both OS and DFS. In addition to radical resection, other factors have been demonstrated to have a huge impact on prognosis.
In the study of Kinoshita et al. [35], a significant association with poor OS was found in the case of lymphatic and serosal invasion, when the liver metastases were more than 3, the maximum liver metastasis diameter was > 5 cm, or when there was high baseline CEA and CA19.9. Tiberio et al. [8], in an Italian cohort of 105 patients, showed that T-stage, R0 resection, and use of adjuvant chemotherapy were prognostic factors. Montangini et al. [69] showed that T and N staging, lymphovascular invasion of the primary tumor, and the burden of liver disease (i.e., number and diameter of the metastases) were strongly linked with survival. In particular, patients with involvement of the serosa or lymph nodes as well as with lymphovascular invasion had a poor prognosis. Otherwise, ≤3 liver metastases, tumor maximum diameter <5 cm, metachronous presentation, and R0 resections were linked to a better prognosis.
Other authors showed that some clinical and pathologic parameters, such as nodal status and histologic grade of the primary tumor, could impact the prognosis [48]. In this context, the lymph node ratio (number of metastatic lymph nodes on the number of the lymph nodes removed by surgery) is recognized to be an important factor linked to a poor prognosis among patients with GCLM who received combined surgical resection [70,71]. In fact, high lymph node ratio was significantly related to the more advanced pN stage, larger primary tumor dimension, microvascular invasion, and neoadjuvant chemotherapy.
In case of peritoneal involvement from GC, the survival is extremely poor. In those patients, hepatic resection does not add any benefit to survival [72,73]. For this reason, we excluded from the analysis the studies that included patients with peritoneal metastases.
Previous studies [22,56,74] have shown that the presence of multiple or synchronous liver metastases [74] were significant negative prognostic factors. However, in a recent metaanalysis, Cui et al. [75] showed that only the presence of synchronous GCLM was a negative prognostic factor, but they concluded that synchronous or multiple liver metastases should not be considered absolute contraindications for surgery.
Better survival could be obtained in presence of multiple scattered metastases in both lobes if R0 resection can be obtained [8]. In our study, the size of primary tumor and liver metastases were not unfavorable prognostic factors, as well as the presence of lymphatic or venous invasion by the primary tumor. However, we found that the best candidate for aggressive treatment is the patient with a well-moderately differentiated, pT1-2 and pN0-1 primary tumor and solitary, unilobar, and metachronous metastasis. Of course, R0 resection is vital in all cases.
Thus, three main treatment options have been identified for resectable GCLM: chemotherapy, upfront surgery, and preoperative chemotherapy followed by surgery [76]. In Western countries, there is no difference in the treatment strategy in case of synchronous or metachronous GCLM, whereas in Japan, upfront surgery is the preferred treatment option for the synchronous disease. According to international guidelines [5,77], a multimodality approach based on preoperative chemotherapy followed by surgery is considered the best treatment for both synchronous and metachronous resectable GCLM.
Although the REGATTA trial [77] is often cited in support of those guidelines, nowadays many oncologists still do not take the surgical approach into consideration in stage IV GC based on those results. In this phase 3 trial, 175 patients with GC and a single metastatic site confined to liver, peritoneum, or para-aortic lymph nodes were randomized to receive chemotherapy alone or gastrectomy followed by chemotherapy. The study failed to show an improvement in the survival of the experimental arm; additionally, it showed a detrimental effect of gastrectomy in this setting (median OS: 14.3 versus 16.6 months in the chemotherapy arm). However, those results should be interpreted with caution since two main concerns, at least, emerged: first, patients in the REGATTA trial did not receive neoadjuvant chemotherapy; second, the trial was designed to assess only the role of primary tumor site resection (gastrectomy with D1 lymphadenectomy) without any resection of metastatic lesions. That said, it is clear that the surgical treatment in the trial cannot be considered curative but only palliative. Additionally, in the trial, only 9% of the metastatic GC patients had a liver limited disease. Therefore, for all these reasons, the REGATTA trial should not be considered as strong evidence to discharge a multimodality strategy for patients with GCLM.
We believe that for surgeons a new era started since FLOT regimen (5FU, Folinic acid, Oxaliplatin, Docetaxel) was widely approved as the standard of care for advanced GC [78]. The neoadjuvant strategy was widely accepted for >T1N+, and oligometastatic GC has been increasingly recognized as a distinct clinical entity. It is characterized by limited metastatic spread and benefits from a multimodality strategy including chemotherapy and surgery [79]. Despite some limitations due to a non-randomized trial and a relatively small sample size, the phase 2 AIO/FLOT3 [58] showed an increased OS in oligometastatic GC patients treated with neoadjuvant chemotherapy (FLOT schedule) followed surgery. The trial underlined the concept that a more aggressive treatment strategy including preoperative chemotherapy and surgical resection of metastases might have better results in terms of survival in this setting.
Still, open questions are unsolved on which sub-population could really benefit from this strategy. In this regard, the results of the ongoing phase 3 RENAISSANCE/AIO-FLOT5 trial (NCT02578368) [80] are awaited.
In general, our study showed some interesting results that support the new surgical trend of approaching GCLM. However, the importance of neoadjuvant chemotherapy and the number of cycles of adjuvant chemotherapy should be taken into account. In our study, poor data were found for neoadjuvant CT to draw any firm conclusion, although, in our forest plot analysis regarding chemotherapy, including adjuvant and neoadjuvant, HR was 1.49 (p = 0.008). If we analyze separately, adjuvant chemotherapy had HR 1.5 (p = 0.01) instead of neoadjuvant CT with HR 1.39 (p = 0.34), therefore not significant (Figure 7, supplementary Figures S1-S25).
trend of approaching GCLM. However, the importance of neoadjuvant chemotherapy and the number of cycles of adjuvant chemotherapy should be taken into account. In our study, poor data were found for neoadjuvant CT to draw any firm conclusion, although, in our forest plot analysis regarding chemotherapy, including adjuvant and neoadjuvant, HR was 1.49 (p = 0.008). If we analyze separately, adjuvant chemotherapy had HR 1.5 (p = 0.01) instead of neoadjuvant CT with HR 1.39 (p = 0.34), therefore not significant (Figure 7, supplementary Figures S1-S25). Systemic chemotherapy remains the mainstay for the treatment of metastatic GC and progression during chemotherapy is probably the most relevant contraindication for any surgical approach.
In a study focusing on GCLM responder to induction chemotherapy, an R0 resection rate of 100% was obtained in all patients who underwent radical gastric resection plus liver metastasectomy after Docetaxel-Cisplatin-5-FU (DCF) chemotherapy [81]. Kinoshita et al. [82] reported a case series of 18 patients with liver metastases from GC and treated with DCF. In this experience, the majority of patients underwent conversion gastrectomy after chemotherapy (11 patients; 5 patients received also liver metastasectomy), showing an improvement in MST and 3-years OS rate if compared to patients who did not receive surgery (MST: 18.9 vs. 15.6 months; 3-year OS rate: 40.4% vs. 27.5%) Another retrospective case series including 29 patients with GCLM reported that six patients underwent conversion surgery after DCF chemotherapy (complete response in two patients), two patients received partial hepatectomies with a complete pathological response and two were treated with radiofrequency ablation (RFA) [83]. Additionally, Yamaguchi et al. [84] showed a conversion rate of 21.5% in patients with GCLM liver treated with chemotherapy and subsequent metastasectomy. Same results regarding the Systemic chemotherapy remains the mainstay for the treatment of metastatic GC and progression during chemotherapy is probably the most relevant contraindication for any surgical approach.
In a study focusing on GCLM responder to induction chemotherapy, an R0 resection rate of 100% was obtained in all patients who underwent radical gastric resection plus liver metastasectomy after Docetaxel-Cisplatin-5-FU (DCF) chemotherapy [81]. Kinoshita et al. [82] reported a case series of 18 patients with liver metastases from GC and treated with DCF. In this experience, the majority of patients underwent conversion gastrectomy after chemotherapy (11 patients; 5 patients received also liver metastasectomy), showing an improvement in MST and 3-years OS rate if compared to patients who did not receive surgery (MST: 18.9 vs. 15.6 months; 3-year OS rate: 40.4% vs. 27.5%) Another retrospective case series including 29 patients with GCLM reported that six patients underwent conversion surgery after DCF chemotherapy (complete response in two patients), two patients received partial hepatectomies with a complete pathological response and two were treated with radiofrequency ablation (RFA) [83]. Additionally, Yamaguchi et al. [84] showed a conversion rate of 21.5% in patients with GCLM liver treated with chemotherapy and subsequent metastasectomy. Same results regarding the good impact of surgery on the survival of those patients were reported in different analyses [66].
Regarding morbidity, most of the studies included in our analysis did not specify if the complications were major or minor. The 30-day morbidity and mortality were 24.7% and 1.6%, respectively, in our study.
Low mortality rate and a limited morbidity rate are not requisites to push patients with GCLM towards a surgical strategy, but certainly these data, in agreement with our results in terms of OS and DFS, reinforce the importance of future randomized prospective studies, needed to validate this strategy and recognize subgroups of patients who can really benefit from it.
Like previous works available in the literature, our study has some limitations. First, all the studies included in the analysis are retrospective and characterized by heterogeneous patient groups. Then, the results may have been affected by selection, institutional and national bias, underpowered sample size, and smaller oncological burden.

Conclusions
Japanese guidelines have begun to change attitudes towards GCLM, reporting surgical resection as recommended for cases with small number of metastases with no other incurable factor even though with a weak level of evidence [7,85]. Our findings suggest the possibility of expanding surgical indications for patients with GCLM if R0 can be achieved, always in a multidisciplinary setting.
Resection of GCLM is feasible, and a benefit in terms of long-term survival emerged despite the current guidelines. Identification of patient subgroups that would benefit from surgery is mandatory and in a multidisciplinary setting, we should take into consideration the stage of primary cancer, mainly with regard to serosal infiltration and lymph node ratio, and the characteristics of the liver metastases. The presence of solitary or unilobar metastases are positive prognostic factors, whereas size does not matter if GCLM are resectable and R0 could be achieved. Pre-and postoperative chemotherapy plays a key role in the treatment of these patients, even though the role of neoadjuvant CT should be better investigated. The ongoing FLOT 5 trial and a prospective register in the coming years will specify these findings and probably will change the current guidelines. A European registry from which a randomized controlled trial could be developed is necessary in the near future. Author Contributions: G.M. and F.S. contributed to the initial literature search for the content of the manuscript, filling the database, and design of the manuscript. A.T. and E.M. contributed significantly to the drafting of the manuscript, providing materials, and reviewing the English language. A.T. independently analyzed all the data and extracted the results. P.F., A.P., and P.M. gave a critical review of the content and were involved in the design of the manuscript. All authors contributed to the final manuscript drafting. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Ethics approval was not required due to the retrospective nature of the analysis and quality of the article design.

Informed Consent Statement:
The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by Ethics Committee of our Hospital.

Conflicts of Interest:
A.P. reported fees from Eli-Lilly, MSD, and Servier outside the submitted work. The other authors have no conflict of interest.