Introduction

Colorectal cancer (CRC) is the third most common malignancy in the USA with an incidence of 1 million new cases annually. Furthermore, it accounts for the second cause of death related to cancer worldwide [1].

Total mesorectal excision (TME), first introduced by Heald [2], is the cornerstone surgical treatment of rectal cancer improving local control with a 3-year local recurrence rate of 3–6% [3]. TME consists of rectum and mesorectum resection in an intact envelope which covers tumor, blood and lymphatic vessels, and regional lymph nodes. The same principles of TME have been proposed in 2009 by Hohenberger [4] who described complete mesocolic excision (CME) for the treatment of colon cancer. As a result, CME has gained increased notoriety over recent years and has become the technique of choice among colorectal surgical centers [4, 5]. Moreover, the number of studies investigating the efficacy of CME is growing steadily [6, 7]. CME is performed by sharp dissection of the embryological mesocolic plane to create an intact envelope with high tie of colonic arteries and veins called central vascular ligation (CVL), ensuring maximum removal of lymphatic vessels and lymph nodes [8]. Oncological results are promising after CME compared to conventional right hemicolectomy (CRH), improving 4-year disease-free survival (DFS) from 75.9 to 85.8% [5]. Although the principle behind mesocolic plane surgery has been widely recognized, high vascular ligation remains a controversial concept because of technical difficulties and concern of increased postoperative morbidity [9]. Additionally, data about CME are based on retrospective studies and long-term outcomes are still a matter of debate, especially compared to CRH. Lastly, recent studies [10,11,12,13,14,15,16] were not included in previous published reviews [17].

The aim of this study was to perform a systematic review and meta-analysis to investigate safety and long-term outcomes of CME compared to CRH in patients with right colon cancer.

Materials and methods

Study design

This study is a systematic review and meta-analysis. Literature search, study design, and data analysis were performed following PRISMA (preferred reporting items for systematic reviews and meta-analyses) guidelines [18]. The protocol of this meta-analysis was registered with the prospective register of systematic reviews, PROSPERO (identification code: CRD42020189023).

Search strategy

Five medical databases were used in this research: MEDLINE, Cochrane Database of Systematic Reviews, Scopus, Web of Science, and Embase. The keyword was as follows: “complete mesocolic excision.” Two researchers (O.D. and A.B.) independently selected studies published up to 15 January 2020. Any disagreements between the two authors were resolved by discussion. We selected only articles written in English and we did not include abstracts or unpublished data.

Selection criteria and outcome measures

Inclusion criteria were cohort studies investigating patients with right colon cancer (included proximal transverse location) and assessing an intervention group (CME) and a control group (CRH).

The main outcomes measured and meta-analyzed were as follows: postoperative complications, anastomotic leakage, intraoperative bleeding, operation time, postoperative length of stay, number of lymph node yields, overall survival (OS), and DFS. We considered for quantitative analysis studies that described at least one of the outcomes of interest. We analyzed and subdivided postoperative complications in surgical and non-surgical complications, when reported. Patients with UICC stage III were considered for sub-group analysis of survival outcomes.

Exclusion criteria were as follows: < 15 total patients. In case of duplicate articles reporting analogous patient data, we considered only the most recent records.

All relevant text, tables, and figures were reviewed for data extraction.

Quality assessment of retrieved articles

Two researchers (O.D. and A.B.) independently assessed the quality of the articles using a quality evaluation list created with predefined parameters including Newcastle-Ottawa Quality Assessment Scale (NOS), as shown in Table 1, and a list of items assessing the quality of CME and cohorts’ characteristics, as shown in Table 2.

Table 1 Characteristics of the included studies
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Table 2 Quality and accuracy description of CME and CRH
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Data extraction

Data of the articles selected were extracted using a set of specified and predetermined parameters: first author, publication year, study design, number of patients and rate of male patients, body mass index (BMI), proximal transverse tumor rates, median age, Union for International Cancer Control (UICC) TNM classification, laparoscopic resection rates, postoperative complications (surgical and non-surgical), anastomotic leakage, intraoperative bleeding, operation time, postoperative length of stay, number of lymph node yield, DFS, and OS.

Statistical analysis

Review Manager 5.3 (Cochrane Collaboration, Nordic Cochrane Centre, Copenhagen, Denmark) was utilized to perform and review meta-analyses. We used mean difference (MD) and log of odds ratio (OR), when appropriate. A p value of 0.05 or less has been considered significant. The heterogeneity of the included studies was determined by the I2 statistic. Low, moderate, and high heterogeneity was considered for levels of I2 values, respectively, of 25–49%, 50–74%, and above 75% [20]. We applied random effects model, while if I2 statistic was lower than 50%; we applied fixed effect model to get pooled HR and 95% CI. Moreover, we used mean difference analysis, when appropriate. The graphical description of the outcomes was illustrated with forest and funnel plots. Evaluation of publication bias was determined with funnel plot analyses.

Analysis of pathological variables (pT, pN, and UICC staging) among CME and CRH groups has been performed using chi-square, Student t, and Fisher’s exact test, when appropriate.

Results

Studies and patient characteristics

After literature search, 1203 studies have been recorded. Screening by titles and abstracts led to the identification of 17 possibly relevant articles. Of these records, 6 studies [21,22,23,24,25,26] were excluded because patients with distal transverse and/or left colon cancer were also evaluated. Moreover, in 3 studies [5, 9, 27], only the most recently record was selected [15]. Lastly, 8 studies [10,11,12,13,14,15,16, 19], published between 2010 and 2019, met inclusion criteria (Fig. 1). All selected studies were observational; 2 of them were prospective [15, 19]. Overall, 1871 patients were enrolled in qualitative and quantitative analysis, 649 in the CME group and 1222 in the CRH group. Description of pathological N stage between groups was found in 7 studies. Laparoscopic resections were 284 (44%) and 687 (56%) in the CME group and in the CRH group, respectively. The characteristics of the selected studies are summarized in Table 1.

Fig. 1
figure 1

Flow chart of the literature search and selection process

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In 3 studies [12, 13, 19], CME surgery was introduced after CRH; therefore, cohorts were investigated consecutively. Among 3 studies [11, 14, 16], there were no indications about temporal sequence of CME or CRH. In 2 studies [10, 13], there was no description of CRH technique (Table 2). Quality description of accuracy of CME and CRH is reported in Table 2.

T and N status were not different among CME and CRH groups, with the exception of T2 patients that were almost the double in CME group (23 versus 11.9%, p = 0.05). There was no difference in terms of nodal status (pN) and staging (p = 0.57 and p = 0.44, respectively) according to UICC (Table 3).

Table 3 Comparison of CME and CRH groups according to pT, pN categories and UICC stage
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Intraoperative and postoperative outcomes

Postoperative complications were reported in 7 studies [11,12,13,14,15,16, 19] showing that no difference was observed between techniques (OR 1.13, 95% CI 0.88–1.46, p = 0.34). Six studies [10,11,12,13, 16, 19] separately analyzed surgical and non-surgical postoperative complications. No significant variation was reported between the 2 groups in the 2 different types of complications (surgical complications OR 1.09, 95% CI 0.72–1.63, p = 0.69, no surgical complications OR 1.37, 95% CI 0.79–2.36, p = 0.26, respectively). No significant difference was also observed between the two groups in terms of anastomotic leakage (OR 0.89, 95% CI 0.35–2.27, p = 0.81), while a significant negative median was reported for intraoperative bleeding in favor of CME group (MD − 109.36, 95% CI − 198.19 to − 20.54, p = 0.02). Five studies [11, 12, 14, 16, 19] evaluated the procedure time which was significantly shorter for CRH (MD 27.61, 95% CI 3.64–51.58, p = 0.02), although heterogeneity levels among studies was high (I2 = 94%, p < 0.00001). The analysis of postoperative length of stay showed no difference between the two groups of patients (MD − 0.89, 95% CI − 2.12 to 0.33, p = 0.15). Meta-analysis of intra and postoperative outcomes is shown in Fig. 2.

Fig. 2
figure 2

Meta-analysis of study of safety outcomes

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Lymph node yield

Number of lymph node yield was reported in 7 studies [10, 11, 13,14,15,16, 19]. The pooled analysis of 1726 patients found a positive median retrieval of 9.17 in CME group (MD 9.17, 95% CI 4.67–13.68, p < 0.001). High heterogeneity among the included studies was detected (I2 = 96%, p < 0.00001). Lymph node yield meta-analysis is shown in Fig. 3.

Fig. 3
figure 3

Meta-analysis of study of lymph node yield

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Survival outcomes

Five studies [11, 13, 15, 16, 19] reported data of 3-year OS with a significant OS benefit in CME group (OR 1.57, 95% CI 1.17–2.11, p = 0.003). This data was characterized by moderate between-study heterogeneity (I2 = 37%). Furthermore, 76.4% of patients undergoing CME surgery were alive at 5 years, compared with 68.2% of CRH (OR 1.41, 95% CI 1.06–1.89, p = 0.02).

Two studies [11, 16] reported data of 3-year DFS without a significant difference between the 2 groups (OR 2.16, CI 0.95–4.94, p = 0.06). Meta-analysis of the 3 studies [11, 15, 19] reporting 5-year DFS confirmed the significant DFS benefit for patients undergoing CME (OR 1.99, 95% CI 1.29–3.07, p = 0.002). No significant heterogeneity was observed between the 3 studies (I2 = 0%, p = 0.89).

A sub-group analysis in patients with UICC stage III colon cancer did not demonstrate difference for 3-year OS (OR 2.47, 95% CI 0.86–7.06, p = 0.09) and for 5-year OS (OR 1.23, 95% CI 0.78–1.94, p = 0.38). Meta-analysis of survival outcomes is reported in Fig. 4.

Fig. 4
figure 4

Meta-analysis of study of long-term outcomes

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Funnel plot analyses of postoperative complications, anastomotic leakage, and survival outcomes are reported in Fig. 5.

Fig. 5
figure 5

Funnel plots of the analyzed outcomes

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Discussion

CME is a technique in which dissection is performed along the root of mesocolon with high tie and division of the feeding vessels [28]. Currently, matter of debate is the potential oncologic impact and the risk-benefit ratio of CME compared with CRH. Objective of this systematic review and meta-analysis was to investigate safety and long-term outcomes of CME compared to CRH in patients with right colon cancer.

Although CME is currently a standardized technique that has been described in detail for open [4, 29], laparoscopic [30,31,32] and robotic approach [33,34,35], the terminology CME and D3 lymphadenectomy are still often mutually used in literature. CME, by definition, focuses on the complete excision of the mesocolon, whereas D3 dissection is defined as lymphadenectomy at the root of the tumor-feeding vessels. Moreover, for the latter, the extension of colon resection is determined with the 5–10-cm rule by D3 Japanese guidelines, whereas CME follows vascular territory to define the length of bowel resected [28]. In fact, in CME, location of the tumor and its relationship to the supplying vascularization are essential to determine the tract of colon to be resected [36]. However, in the common clinical practice, CME includes equivalent lymphadenectomy and high ligation of supplying vessels, as described in D3 resection [37]. Therefore, although these two techniques have different concepts, both approaches maintain the same surgical purpose [5, 38, 39].

Commonly, the number of lymph node yield represents the oncological quality mark of surgery [40] and is also considered the cornerstone concept of CME. Data obtained in this meta-analysis confirmed that CME was associated with higher median of lymph nodes removed, although with high heterogeneity level between studies (I2 = 95%). The number of lymph nodes harvested has been shown to be an independent prognostic factor for survival [15, 41, 42] and may affect the control of local recurrence. Due to this theory, the risk of leaving residual disease may be minimize recommending CVL and extended lymphadenectomy [43, 44]. Kanemitsu et al. [45] reported a series on 370 consecutive patients who underwent D3 lymphadenectomy for right colon cancer showing a pN3 incidence rate of 1.8%, suggesting that a positive impact of D3 dissection likely occurred in only 1.1% of patients. In literature, central lymph node metastases are present in up to 8% of patients with T3 and T4 tumors [46, 47]; actually, the indication of performing D3 lymphadenectomy is still unclear based on T stage. Nevertheless, Hashiguchi showed that up to 25% of patients with UICC stages I and II will likely have recurrent disease [48]. One possible reason might be lymph node skip metastasis, even though the incidence ranges from 1.8 to 18.6% [43, 49]. Recently, Luo et al. [50] proposed the concept of isolated cancer cells into mesentery of colon and rectum, defined as “V metastasis,” showing a V metastasis rate of 22% in patients undergone either CME or TME. According to these evidences, CME may minimize the risk of local recurrence, skip metastasis, and V metastasis, explaining better oncological results (Fig. 3), particularly when the mesocolic fascia is completely removed.

When evaluating survival outcomes, CME was correlated with better 3-year OS and this positive survival trend was also shown for 5-year OS. However, the efficacy and quality of CME may be better assessed by DFS and disease-specific survival (DSS) because CME is expected to reduce local recurrence, especially for patients with UICC stage III tumors with proximal lymph nodes metastases [5, 17, 24]. Unfortunately, evaluation of DFS has been affected by scarcity of data in this review. Therefore, we can observe a positive survival trend in term of DFS in CME group, without being able to draw a significant conclusion. It would have been interesting to perform meta-analysis on survival outcomes, in particular DFS and DSS, differentiating for UICC stages I, II, and III. This was not possible due to lack of data. Nevertheless, a sub-group analysis in patients with UICC stage III did not demonstrate significant difference in terms of OS. The role of adjuvant therapy could have positively affected both CME and CRH patients, since introduction of CME in relation to CRH was not adequately described, as shown in Table 2. Despite our results, an unanswered question is if improvement in cancer-related survival in CME group can be explained solely by a loco-regional treatment like surgery [24]. Growing surgical experience, patient centralization in high-volume centers and evolution in adjuvant chemotherapy as well as screening tools detecting early tumors certainly contributed to improve colon cancer prognosis and they may have played as confounding factors [5, 51]. Thus far, relationship between CME and increased survival is supported by limited evidence. Probably, CME is integrated in a context of high-level oncological care where surgical technique is one of the factors which contribute to improve survival.

Similar to TME excision, West et al. [52], inspired by the classification used in the MRC CR07 trial [3], suggested a grading of the integrity of mesocolon, as good, moderate, or poor. Good (intact) colonic mesentery or proper muscular layer was significantly associated with longer 5-year OS. Qualitative analysis (Table 2) showed that there was no unique method for evaluating the completeness and quality of CME. To overcome these limitations, Strey et al. [53] proposed the “critical view” concept for surgical aspect of CME describing a procedure based on eight well-defined steps. In addition, Benz et al. [54] introduced a new classification system based on four categories for completeness and integrity of mesocolon, differently to West classification [52], which was based on specimen photography. However, as shown in Table 2, the quality of specimen was not univocally reported as well as CRH was not easily reproducible highlighting the disparity between CME and CRH descriptions.

Moreover, considerable anatomical variability is present in right colon. Vascular and mesenteric configurations are extremely variable: different lengths of the gastrocolic trunk of Henle, multiple middle colic arteries, several compositions of venous drainage of the middle colic vein [55]. All these variables can become pitfalls, particularly during vascular dissection.

Interestingly, the meta-analysis showed that CME was not associated with higher risk of postoperative complications. No significant difference was also found when complications were subdivided into surgical and non-surgical and also the rate of anastomotic leak was similar between the two groups. It was not possible to assess the clinical relevance of complication rate according to Clavien-Dindo classification [56] due to lack of data. Besides, CME showed a lower risk of intraoperative bleeding. These data suggest that CME is a safe procedure, probably also due to increased surgical experience in high-volume centers. However, as underlined in literature, the amount of mesocolic resection, especially when performing CVL in the region of superior mesenteric vessels, can increase the risk of vessel damage and sympathetic nerve plexus [9, 57, 58].

To our knowledge, this is the first systematic review and meta-analysis investigating CME solely for right colon cancer. However, there are several limitations that need to be considered when interpreting our data. Firstly, included studies are mainly retrospective and with mono-institutional cohorts, increasing selection bias. As stated before, assessment of the completeness and quality of CME is still heterogeneous and definition of CRH is lacking and this leads to a variable control group to compare. We could not have evaluated the influence of adjuvant chemotherapy in terms of survival and this probably increased selection bias. Additionally, if CME patients were more likely to receive adjuvant chemotherapy compared to CRH patients, it was not possible to address. Making any comparison between open and laparoscopic CME was not possible and mini-invasive approach could have played as confounding factor.

Prospective randomized trials results are needed to verify if CME could be considered standard surgery for right colon cancer. Two prospective randomized studies, RELARC and COLD, are ongoing and results are awaited [59, 60].

Our results, considering the limitations correlated with the included studies, suggest that CME for right colon cancer is safe and improves 5-year DFS, 3-year, and 5-year OS compared to CRH with a low level of evidence. High-quality studies, such as prospective randomized studies, are required to increase evidence in support of CME.