*2.4. Statistical Analysis and Data Synthesis*

The primary outcome was the spleen preservation failure rate. Secondary outcomes included intraoperative blood loss, operative time, prevalence of clinically relevant POPF (grade B/C), prevalence of postoperative complications (Clavien–Dindo [8] grades ≥3), hospital LOS, and mortality. For the analysis, values expressed as median (range) were converted to average ± standard deviation using Wan's method [11]. To pool proportions, we used random-effects or fixed-effect modelling according to the DerSimonian and Laird method [12,13] to take into account heterogeneity. The presence of heterogeneity among the studies was assessed using Cochran's Q test and quantified with the I<sup>2</sup> inconsistency index, with 25, 50, and 75% considered as thresholds for low, moderate, and high statistical heterogeneity, respectively. Heterogeneity was evaluated by sensitivity analysis [14]. Statistical analyses were performed using Review Manager version 5.3.

### **3. Results**

#### *3.1. Studies Selection 3.1. Studies Selection*

**3. Results** 

Eleven studies met the inclusion criteria and were included in the systematic review and meta-analysis [15–25] (Figure 1). Eleven studies met the inclusion criteria and were included in the systematic review and meta-analysis [15–25] (Figure 1).

**Figure 1.** PRISMA flow diagram. ITT: intention-to-treat. **Figure 1.** PRISMA flow diagram. ITT: intention-to-treat.

and 17 SP-LADP.

#### *3.2. Studies Characteristics 3.2. Studies Characteristics*

The characteristics of the selected studies are reported in Table 1. A total of 323 patients undergoing SP-RADP and 362 patients undergoing SP-LADP were included in this meta-analysis. Eight included series (72.7%) were retrospective cohort studies [16–18,21– 25], two were matched cohort studies (18.2%) [15,19], and one was a case-control study (9.1%) [20]. The reported median follow-up was 27 months (range 6.5–47) for SP-RADP and 33.5 months (range 32–75.5) for SP-LADP. The most frequent indications for surgery were neuroendocrine tumors (NET) in 61 SP-RADP and 52 SP-LADP, mucinous cystic neoplasms in 37 SP-RADP and 28 SP-LADP, intraductal papillary mucinous neoplasms (IPMN) in 15 SP-RADP and 28 SP-LADP, and pseudopapillary tumors in 18 SP-RADP The characteristics of the selected studies are reported in Table 1. A total of 323 patients undergoing SP-RADP and 362 patients undergoing SP-LADP were included in this metaanalysis. Eight included series (72.7%) were retrospective cohort studies [16–18,21–25], two were matched cohort studies (18.2%) [15,19], and one was a case-control study (9.1%) [20]. The reported median follow-up was 27 months (range 6.5–47) for SP-RADP and 33.5 months (range 32–75.5) for SP-LADP. The most frequent indications for surgery were neuroendocrine tumors (NET) in 61 SP-RADP and 52 SP-LADP, mucinous cystic neoplasms in 37 SP-RADP and 28 SP-LADP, intraductal papillary mucinous neoplasms (IPMN) in 15 SP-RADP and 28 SP-LADP, and pseudopapillary tumors in 18 SP-RADP and 17 SP-LADP.

*J. Pers. Med.* **2021**, *11*, 552



**Author and** 

Eckhardt et al.

Morelli et al.

Najafi et al.

Souche et al.

Chen et al. 2015 Matched

Liu et al. 2017 Matched

Ottawa scale (NOS). NA: not available.

**Rob/Lap**

2016 Cohort 12/29 50.5 ± 14.4–55 ±

2016 Case-control 15/15 58.2 ± 13.7–49.3 ±

Kang et al. 2011 Cohort 20/25 44.5 ± 15.9–56.5 ±

Yang et al. 2020 Cohort 37/41 42.9 ± 14–51.3 ±

cohort 47/33 55.6 ± 14.3–55.8 ±

Hong et al. 2020 Cohort 31/57 NA NA 36.5 ± 17.4–29.8 ±

**Age, Years Rob–Lap**

**Sex (F) Rob/Lap**

16.2 31/21 31.25 ± 3.4–29 ±

17.1 9/13 29.9 ± 16.5–26.9 ±

**Year Study Type <sup>N</sup>**

#### *3.3. Quality Assessment and Publication Bias 3.3. Quality Assessment and Publication Bias*

12.3 23/19 17.5 ± 2.7–16.5 ±

*J. Pers. Med.* **2021**, *11*, x FOR PEER REVIEW 4 of 11

**Table 1.** Summary of the selected studies with patients' characteristics and quality assessment according to the Newcastle–

**Lesion Size, mm** 

3.4

16.8 8/17 22 ± 10.4–38 ± 3 24.00 ± 3.4–27.3

13.9 12/14 35 ± 13–30 ± 14 24.2 ± 2.9–23.4 ±

13.5

<sup>2020</sup>Cohort 24/32 NA NA NA NA NA 3 \* 1 \* 3 \*

<sup>2018</sup>Cohort 13/13 NA NA NA NA NA 3 \* 1 \* 3 \*

2.4

Nell et al. 2016 Cohort 5/9 NA NA NA NA NA 3 \* 1 \* 3 \*

14.6 23/27 27 ± 12–42 ± 33 23.5 ± 3.2–24.1 ±

cohort 76/77 NA NA NA NA NA 3 \* 2 \* 3 \*

The results of the quality assessment of the 11 included studies according to the guidelines of the Newcastle–Ottawa Scale are reported in Table 1. The results of the quality assessment of the 11 included studies according to the guidelines of the Newcastle–Ottawa Scale are reported in Table 1.

3.4

23.3 ± 2.7–23.9 ± 3.2

**Rob–Lap BMI Rob–Lap ASA Rob–Lap**

24.4 ± 2.9–24.8 ± 2.7

26.4 ± 3.1–26.1 ± 1.9

**NOS Assessment**

**Comparability** 

**Outcome** 

**Selection** 

± 4.3 NA 3 \* 1 \* 3 \*

2.6 NA 3 \* 1 \* 3 \*

0.3 3 \* 2 \* 3 \*

0.5 2 \* 2 \* 3 \*

0.8 3 \* 1 \* 3 \*

0.5 3 \* 1 \* 3 \*

2.5 ± 0.7–1.91 ±

19.5 NA NA 3 \* 1 \* 3 \*

2.40 ± 0.5–2.30 ±

1.41 ± 0.6–1.58 ±

1.26 ± 0.4–1.39 ±

#### *3.4. Spleen Preservation Rate 3.4. Spleen Preservation Rate*

All selected studies reported the number of procedures intended to be spleen preserving and the spleen preservation failure rate for both the robotic and laparoscopic techniques. The risk difference (RD) of spleen preservation failures was 0.24 (95% CI 0.15, 0.33), favoring the robotic approach and with moderate heterogeneity (I<sup>2</sup> = 63%) (Figure 2). Heterogeneity was evaluated by sensitivity analysis, and the results are summarized in Table 2. All selected studies reported the number of procedures intended to be spleen preserving and the spleen preservation failure rate for both the robotic and laparoscopic techniques. The risk difference (RD) of spleen preservation failures was 0.24 (95% CI 0.15, 0.33), favoring the robotic approach and with moderate heterogeneity (I2 = 63%) (Figure 2). Heterogeneity was evaluated by sensitivity analysis, and the results are summarized in Table 2.


**Figure 2. Figure 2.**  Spleen preservation rate forest plot. Spleen preservation rate forest plot.

**Table 2.** Sensitivity analysis by sequential omission of each individual study. Meta-analysis estimates, given the named study is omitted. CI: confidence interval.


#### *3.5. Patient Characteristics and Operative Details*

Only four series [16,21,25,26] reported the average ASA score (median value of 1.9, range 1.3–2.5 for SP-RADP; 1.7, range 1.4–2.3 for SP-LADP), while preoperative BMI was described in six series [16,17,19,21,25,26] (median value of 24.1, range 23.3–26.4 for SP-RADP; 24.4, range 23.4–27.3 for SP-LADP). Of the groups reporting the incidence of previous abdominal surgery [16,17,21], 5 out of 15 patients in both groups had had previous surgery in one study [20], with no patients undergoing previous surgery in the other two reports. All other patients' characteristics are summarized in Table 1.

Eight of the included studies [15,16,18,20,21,23–25] reported the conversion rate, with an RD of <sup>−</sup>0.05 (95% CI <sup>−</sup>0.09, <sup>−</sup>0.01) and moderate heterogeneity (I<sup>2</sup> = 26%) of being converted to "open" technique favoring the robotic approach. Unfortunately, no study described the reason for conversion. The intraoperative blood loss (Figure 3), as reported in seven series [16,17,19,21,22,25,26], was significantly lower for the robotic group, with a mean difference of <sup>−</sup>138 mL (95% CI <sup>−</sup>205, <sup>−</sup>71) and high heterogeneity (I<sup>2</sup> = 97%). There was no statistical difference in the operative time between the two groups (Figure 3), reported by nine series [15–18,20,21,23–25], with a mean difference of 6.1 min (95% CI <sup>−</sup>40, 52) and high heterogeneity (I<sup>2</sup> = 97%). Four studies [17,23–25] reported the distal pancreatic stump closure technique, which was with an endo-GIA stapler in all cases in both groups. Eight studies [15,16,18,20,21,23–25] reported data on spleen preservation techniques, including a total of 211 robotic and 219 laparoscopic procedures. The Kimura technique [26] was adopted in 159 out of the 196 patients (81.1%) undergoing SP-RADP (the remaining 18.9% of patients had the pancreatic resection performed according to the technique described by Warshaw [27]) and in 84 out of the 154 SP-LADP (54.5%), with the Warshaw technique being adopted for the remaining 45.5%. *J. Pers. Med.* **2021**, *11*, x FOR PEER REVIEW 6 of 11


**Figure 3.** Secondary outcomes forest plots: (**A**) intraoperative blood loss (mL); (**B**) operative time (min); (**C**) perioperative blood transfusions; (**D**) Clavien–Dindo grade ≥3 complications; (**E**) postoperative pancreatic fistula grade B/C; (**F**) hospital length of stay (days). **Figure 3.** Secondary outcomes forest plots: (**A**) intraoperative blood loss (mL); (**B**) operative time (min); (**C**) perioperative blood transfusions; (**D**) Clavien–Dindo grade ≥3 complications; (**E**) postoperative pancreatic fistula grade B/C; (**F**) hospital length of stay (days).

30-day deaths. Seven studies [15–17,20,21,24,27] described the prevalence of POPF. The RD of clinically relevant POPF (ISGPS grade B/C) was 0.00 (95% CI −0.06, 0.07) with no heterogeneity (I2 = 0%). The RD of Clavien–Dindo grade ≥3 postoperative complications, as reported in six series [16,18,21,22,25,26], was −0.04 (95% CI −0.11, 0.03) with no heterogeneity (I2 = 0%). The mean hospital LOS difference was −1.5 days (95% CI −2.8, −0.2) in favor of SP-RADP and with high heterogeneity (I2 = 0%). Data on overall postoperative complications, Clavien–Dindo grade 1–2 postoperative complications, biochemical leaks,

and postoperative bleeding episodes are reported in Table 3.

*3.6. Postoperative Morbidity and Outcomes* 

### *3.6. Postoperative Morbidity and Outcomes*

Eight series [15–18,20,21,24,25] reported the perioperative mortality, with no cases of 30-day deaths. Seven studies [15–17,20,21,24,27] described the prevalence of POPF. The RD of clinically relevant POPF (ISGPS grade B/C) was 0.00 (95% CI −0.06, 0.07) with no heterogeneity (I<sup>2</sup> = 0%). The RD of Clavien–Dindo grade <sup>≥</sup>3 postoperative complications, as reported in six series [16,18,21,22,25,26], was −0.04 (95% CI −0.11, 0.03) with no heterogeneity (I<sup>2</sup> = 0%). The mean hospital LOS difference was <sup>−</sup>1.5 days (95% CI <sup>−</sup>2.8, <sup>−</sup>0.2) in favor of SP-RADP and with high heterogeneity (I<sup>2</sup> = 0%). Data on overall postoperative complications, Clavien–Dindo grade 1–2 postoperative complications, biochemical leaks, and postoperative bleeding episodes are reported in Table 3.



### *3.7. Quality of Evidence*

The level of evidence was rated according to GRADE and is summarized in Table 4.

**Table 4.** Robotic versus laparoscopic surgery for spleen-preserving distal pancreatectomies. \* The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio; MD: Mean difference.


### **4. Discussion**

To the best of our knowledge, this systematic review and meta-analysis is the first report summarizing all the available evidence on patients undergoing spleen-preserving distal pancreatectomy with robotic and laparoscopic techniques. All published studies comparing these two minimally invasive surgical approaches were screened in order to analyze the intention-to-treat population of patients undergoing DP where the spleen was intended to be preserved and to evaluate whether the surgical technique would have an impact on the spleen preservation success rate.

The spleen holds the largest lymphoid tissue mass in the body, producing early immunoglobulins M and containing macrophages that act as barriers against encapsulated pathogens. Avoiding unnecessary splenectomies prevents those patients undergoing DP from facing significant thromboembolic [28] and infective risks [29]. The most serious post-splenectomy complication is overwhelming post-splenectomy infection (OPSI), which can start with flu-like symptoms but can rapidly progress to septic shock, coma, and disseminated intravascular coagulation [30]. OPSI can represent a major medical emergency, with a mortality rate that can be up to 50–70% [31,32], a yearly incidence of 0.23%, and a lifetime risk of approximately 5%. The risk is greater within the first two years postoperatively but can vary depending on patient risk factors, such as age, immunological status, and indication for splenectomy [33,34]. In order to protect splenectomized individuals from such complications, prophylactic pneumococcal, Haemophilus influenzae type b, meningococcal, and annual influenza vaccinations are usually performed. Despite these risks, splenectomy is routinely performed alongside DP for pancreatic adenocarcinoma in order to achieve an adequate oncological clearance, given the high risk of lymph node involvement [35]. Spleen preservation should be considered in all patients undergoing DP for benign indications or pre-malignant/low-grade tumors, as it has been shown to be a safe procedure that can reduce perioperative morbidity and enable better long-term outcomes [36–39]. The spleen can be preserved despite the excision of the splenic vessels, as firstly described by Warshaw in 1988 [27], or with splenic vessel preservation, as demonstrated by Kimura et al. almost a decade later [26]. Both approaches have been shown to have comparable short- and long-term results in a recent international multicentric retrospective study [40] and carry fewer complications when performed with a minimally invasive technique. After early experiences of laparoscopic DP [1,2], the minimally invasive approach to pancreatic surgery has progressively gained popularity, with safety and efficacy profiles comparable to open surgery, together with reduced blood loss and a faster recovery time [41–45]. According to the most recent evidence-based guidelines, minimally invasive DP should be considered over open DP for all patients with benign and low-grade malignant tumors [46]. The robotic technique, with its superior accuracy, 3D vision, greater range of motion and precision [47], and excellent safety and efficacy profile in complex oncological surgery [48,49], has been utilized by several surgeons when performing pancreatic procedures [5,50,51].

This meta-analysis showed that the robotic approach is more effective than laparoscopy in allowing spleen preservation during DP, with an RD of spleen preservation failures of 0.24 (95% CI 0.15, 0.33), with reduced intraoperative blood loss (mean difference of −138 mL (95% CI −205, −71)) and similar operative time (mean difference of 6.1 min (95% CI −40, 52)). Patients undergoing SP-RADP were also less likely to experience intraoperative conversion to the "open" technique, with 3/201 open conversions (1.5%) in the robotic group and 15/219 (6.8%) in the laparoscopic group, with an RD of −0.05 (95% CI −0.09, −0.01) [15,16,18,20,21,23–25]. It was not possible to identify the proportion of patients where splenic vessel excision (Warshaw technique) was planned preoperatively, but a higher proportion of splenic vessel preservation was observed in patients undergoing SP-RADP (159/196 patients (81.1%)) versus SP-LADP (84/154 (54.5%)). With the exception of cases of tumor proximity or vascular involvement of the splenic vessels, when splenectomy or the Warshaw technique are usually the preferred choices, the Kimura technique is generally the preferred approach. The higher proportion of successful splenic vessel

preservations in the robotic group, coupled with the superior spleen preservation rate, could reflect the more precise vascular dissection of the small tributaries of the splenic artery and vein that can be performed robotically. No differences in overall, clinically significant complications (Clavien–Dindo grade ≥3) and POPF were observed between the two groups, but patients undergoing SP-RADP had a significantly shorter hospital LOS, with a mean difference of −1.5 days (95% CI −2.8, −0.2).

Due to the lack of long-term follow-up data, the postoperative morbidity results of the present meta-analysis could underestimate the possible beneficial effects of the robotic approach in terms of expected lower incidence of complications related to the occurrence of splenic infarctions and asplenia-related infections due to the significantly higher proportion of successful splenic and splenic vessel preservation in patients undergoing SP-RADP. Prevalence of overall complications, of Clavien–Dindo grade ≥3 complications, and of clinically relevant POPF were similar to those reported in the literature following minimally invasive DP and open DP [40], with overall complications reported in 31.5% and 45.4%, Clavien–Dindo grade ≥3 complications in 14.7% and 16.7%, and clinically relevant POPF in 14.8% and 15.1% of patients undergoing SP-RADP and SP-LADP, respectively.

Unfortunately, there was no randomized controlled trial directly comparing SP-RADP and SP-LADP that could be included in the present analysis. We performed a sensitivity analysis in order to further investigate the moderate heterogeneity (I<sup>2</sup> = 63%) of the main outcome.

In conclusion, both SP-RADP and SP-LADP proved to be safe and effective procedures, with minimal perioperative mortality and low postoperative morbidity. The robotic approach proved to be superior to the laparoscopic approach in terms of spleen preservation rate, intraoperative blood loss, and hospital length of stay. Future prospective and randomized studies with a longer follow-up could better evaluate the possible differences between these two techniques in terms of mid- to long-term complications and outcomes.

**Author Contributions:** Conceptualization, R.M. and G.R.; methodology, G.R.; software, R.M.; validation, R.I.T.; formal analysis, L.A.; resources, L.A.; writing—original draft preparation, G.R.; writing—review and editing, R.M. and R.I.T. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Data Availability Statement:** The data used for this manuscript are available upon request of the reviewers.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **Abbreviations**


### **References**


**Wanda Petz \*, Simona Borin and Uberto Fumagalli Romario**

Division of Digestive Surgery, IEO European Institute of Oncology IRCCS, 20141 Milano, Italy; simona.borin@ieo.it (S.B.); uberto.fumagalliromario@ieo.it (U.F.R.)

**\*** Correspondence: wanda.petz@ieo.it

**Abstract:** Background. Complete mesocolic excision (CME) is a surgical technique introduced with the aim of ameliorating the oncologic results of colectomy. Various experiences have demonstrated favorable oncologic results of CME in comparison with standard colectomy, in which the principles of CME are not respected. The majority of the literature refers to open or laparoscopic CME. This review analyses current evidence regarding robotic CME for right colectomy. Methods. An extensive Medline (Pub Med) search for relevant case series, restricted to papers published in English, was performed, censoring video vignettes and case reports. Results. Fourteen studies (ten retrospective, four comparative series of robotic versus laparoscopic CME) were included, with patient numbers ranging from 20 to 202. Four different approaches to CME are described, which also depend on the robotic platform utilized. Intraoperative and early clinical results were good, with a low conversion and anastomotic leak rate and a majority of Clavien–Dindo complications being Grades I and II. Oncologic adequacy of the surgical specimens was found to be good, although a homogeneous histopathologic evaluation was not provided. Conclusions. Further large studies are warranted to define long-term oncologic results of robotic right colectomy with CME and its eventual benefits in comparison to laparoscopy.

**Keywords:** complete mesocolic excision; robotic surgery; right colectomy

### **1. Background**

Complete mesocolic excision (CME) with central vessel ligation (CVL) is a surgical technique first described by West [1] in 2008 and Hohenberger [2] in 2009.

By analogy with the concept of total mesorectal excision (TME) for rectal cancer, and with the aim of improving the radicality of surgery and, therefore, of ameliorating the oncologic results of colectomy for cancer, it involves the complete removal of an intact mesocolic envelope surrounding the colon.

In addition, the technique implies ligature of the supplying vessels at their origin from mesenteric artery and vein, and an extended lymphadenectomy, superimposable to the D3 dissection described by Japanese authors [3].

The surgical community has shown a growing interest in this more radical approach to colon cancer, suggesting that it could play a role in ameliorating the oncologic results of right colectomy [4–14]; however, large randomized clinical trials providing a high level of evidence are lacking.

Therefore, the guidelines of the major international scientific societies still do not mention the need to perform a CME when approaching a colonic cancer [15,16], while the same guidelines make TME for rectal cancer mandatory [17,18].

Regarding the surgical approach to CME, the techniques most used are the open and the laparoscopic techniques, although the latter has been recognized as being technically more challenging, especially with regard to vascular dissection [19].

In this paper, we shall focus on the robotic approach to CME for surgery of right colon cancer, analyzing current evidence and providing a summary of its eventual benefits.

**Citation:** Petz, W.; Borin, S.; Fumagalli Romario, U. Updates on Robotic CME for Right Colon Cancer: A Qualitative Systematic Review. *J. Pers. Med.* **2021**, *11*, 550. https:// doi.org/10.3390/jpm11060550

Academic Editors: Marco Milone and Paolo Pietro Bianchi

Received: 19 April 2021 Accepted: 9 June 2021 Published: 12 June 2021

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

#### **2. Methods**

The Preferred Reporting Outcomes for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed [20] and an extensive Medline (Pub Med) search for relevant case series was performed. The search strategy included "complete mesocolic excision" AND "robotic" AND "right colon" OR "right colectomy" OR "right hemicolectomy".

Inclusion criteria were English language and detailed description of the surgical technique, including all the particular technical aspects of CME with CVL. Exclusion criteria were case reports, video vignettes and case series in which the CME technique was employed for colonic resections different from right or extended right colectomy; if a single centre published more than a paper, only the one including the greater number of patients was included.

The quality of each included study was assessed using the Newcastle–Ottawa Scale (NOS) [21] and the risk of bias was considered high if NOS total score was <7 or low if NOS total score was 7 or more.

A single reviewer (WP) screened each record retrieved and collected data from each report. Outcomes for which data were sought were: number of patients included in the study, type of robotic platform utilized, details of surgical technique (patient and trocar position, sequence of surgical steps, technique of anastomosis), conversion rate, operative time, intra and postoperative complications, number of retrieved lymph nodes, overall and disease-free survival.

Continuous data are presented as median and range, while categorical data are presented as percentages.

#### **3. Results**

After duplicate censoring, fourteen studies were included in this review [22–35], and the publication dates ranged from 2013 to 2021.

There are ten retrospective non comparative case series [22,23,27–31,33–35] and four comparative studies (three retrospective and one prospective) of robotic versus laparoscopic CME for right colectomy [24–26,32]; the patient number ranges from 20 to 202.

Characteristics and principal results of the included studies are reported in Table 1.

According to the NOS score obtained, the risk of bias was high in 4 studies and low in the remaining 10 (Table 2).

*J. Pers. Med.* **2021**, *11*, 550



**Table 2.** Risk of bias.

NOS: Newcastle–Ottawa Scale; S: selection; C: comparison; O: outcomes; E: exposure.

#### **4. Technical Considerations**

The da Vinci Xi robotic platform has been utilized in nine of the fourteen studies [23,25,28,30,31,33,35], the Si platform in two [22,24], the X platform in one [35] and both the Si and the Xi in the remaining two [29,32].

Four different approaches to colonic dissection, CME and lymphadenectomy are reported, the difference essentially residing in the sequence of surgical steps and the direction of detachment of the mesocolon from the retroperitoneum: a "medial-to-lateral" approach [22,24,30,32], a "bottom-to-up" approach [23,25,28,29,31,35], a "top-to-down" approach [26] and a "superior mesenteric vein first" approach [27,33,34].

Patient position on the operative table is similar for the "medial-to-lateral", the "bottom-to-up" and the "superior mesenteric vein first" approaches: the patient is supine and the operative table is in a slight Trendelenburg position and rotated to the left, in order to expose the surgical field by moving the small bowel in the left abdominal quadrants.

In the "top-to-down" approach, conversely, the patient is in a 30◦ reverse Trendelenburg position in the first phase of surgery, to facilitate entrance in the lesser sac through the gastrocolic ligament; a different docking is performed in the second part of the procedure.

In the "medial-to lateral" approach, when using the da Vinci Si® platform, trocars are positioned in the left abdomen with the camera in the left flank (Figure 1a,b); while using the da Vinci Xi® system, all the trocars are along the same line with an oblique costofemoral layout (Figure 2).

With the third robotic arm suspending cranially the transverse mesocolon, the procedure starts with opening of the peritoneum just below the prominence of ileocolic vessels and along the left side of superior mesenteric vein (SMV); the ileocolic artery and vein are then easily identified, dissected and ligated. Subsequently, vascular dissection proceeds cranially with ligature of right colic vessels, middle colic vein and right branch of middle colic artery.

CME is performed once vascular dissection is completed, by sharp separation of posterior mesocolic fascia from retroperitoneum.

*J. Pers. Med.* **2021**, *11*, x FOR PEER REVIEW 5 of 12

**Figure 1.** (**a**,**b**): trocars position for "medial-to-lateral" approach with the da Vinci Si® system. **Figure 1.** (**a**,**b**): trocars position for "medial-to-lateral" approach with the da Vinci Si® system.

**Figure 2.** Trocars position for "medial-to-lateral", "SMV first" and "top-to-down" approach with the da Vinci Xi® system. **Figure 2.** Trocars position for "medial-to-lateral", "SMV first" and "top-to-down" approach with the da Vinci Xi® system.

**Figure 2.** Trocars position for "medial-to-lateral", "SMV first" and "top-to-down" approach with the da Vinci Xi® system. This is similar to the "superior mesenteric vein first" approach described by Yang [27] and adopted by other authors [33,34]; the vascular dissection is performed first, exposing the anterior aspect of the SMV by removing the lymphatic tissue covering it, and sequentially ligating the right colic and right branches of middle colic vessels; afterwards This is similar to the "superior mesenteric vein first" approach described by Yang [27] and adopted by other authors [33,34]; the vascular dissection is performed first, exposing the anterior aspect of the SMV by removing the lymphatic tissue covering it, and sequentially ligating the right colic and right branches of middle colic vessels; afterwards the CME is performed by sharp dissection of the ascending and transverse mesocolon from retroperitoneum, exposing the duodenum and the head of the pancreas, and pro-This is similar to the "superior mesenteric vein first" approach described by Yang [27] and adopted by other authors [33,34]; the vascular dissection is performed first, exposing the anterior aspect of the SMV by removing the lymphatic tissue covering it, and sequentially ligating the right colic and right branches of middle colic vessels; afterwards the CME is performed by sharp dissection of the ascending and transverse mesocolon from retroperitoneum, exposing the duodenum and the head of the pancreas, and proceeding from medial to lateral until the right colo-parietal area.

the CME is performed by sharp dissection of the ascending and transverse mesocolon from retroperitoneum, exposing the duodenum and the head of the pancreas, and proceeding from medial to lateral until the right colo-parietal area. ceeding from medial to lateral until the right colo-parietal area. The "bottom-to-up" approach has been introduced with the da Vinci Xi® platform, which allows the thinner robotic arms to be positioned on the same suprapubic line (Figure 3): with this different vision, frontal to the axis of superior mesenteric vessels, the dissection starts with the incision of the root of mesentery and proceeds cranially developing the retro-mesocolic plane, separating ascending and right mesocolon from the

retroperitoneum and joining the ventral aspect of the duodenum and the pancreatic head. Once the is CME completed, vascular dissection is performed, exposing the ventral aspect of SMV and ligating the ileocolic, right colic and right branches of the middle colic vessels. the is CME completed, vascular dissection is performed, exposing the ventral aspect of SMV and ligating the ileocolic, right colic and right branches of the middle colic vessels.

The "bottom-to-up" approach has been introduced with the da Vinci Xi® platform, which allows the thinner robotic arms to be positioned on the same suprapubic line (Figure 3): with this different vision, frontal to the axis of superior mesenteric vessels, the dissection starts with the incision of the root of mesentery and proceeds cranially developing the retro-mesocolic plane, separating ascending and right mesocolon from the retroperitoneum and joining the ventral aspect of the duodenum and the pancreatic head. Once

*J. Pers. Med.* **2021**, *11*, x FOR PEER REVIEW 6 of 12

**Figure 3.** Trocars position for "bottom-to-up" approach with the da Vinci Xi® system. **Figure 3.** Trocars position for "bottom-to-up" approach with the da Vinci Xi® system.

The "top-to-down" technique has been proposed [26] for the surgical approach to cancer of the distal ascending colon, hepatic flexure or proximal transverse colon: with an oblique offset costofemoral trocars layout (Figure 2), the procedure starts with opening of the gastrocolic ligament and the identification and section of gastroepiploic vessels; the gastro-epiploic vein is then used as a guide to identify and dissect the gastro-colic trunk and, subsequently, the SMV, with removal of the lymphatic and fatty tissue of its anterior aspect. The second phase of the surgical procedure entails a robot redocking with a change of patient position to a 30° Trendelenburg; with the same trocars layout, the vascular dis-The "top-to-down" technique has been proposed [26] for the surgical approach to cancer of the distal ascending colon, hepatic flexure or proximal transverse colon: with an oblique offset costofemoral trocars layout (Figure 2), the procedure starts with opening of the gastrocolic ligament and the identification and section of gastroepiploic vessels; the gastro-epiploic vein is then used as a guide to identify and dissect the gastro-colic trunk and, subsequently, the SMV, with removal of the lymphatic and fatty tissue of its anterior aspect. The second phase of the surgical procedure entails a robot redocking with a change of patient position to a 30◦ Trendelenburg; with the same trocars layout, the vascular dissection is performed and then the CME is realized with a medial-to-lateral direction.

section is performed and then the CME is realized with a medial-to-lateral direction. The ileo-colic anastomosis was performed intracorporeally in ten out of the fourteen studies [22–25,29,31–35] and extracorporeally in two [28,30]; both the techniques have been utilized in two studies [26,27], in which, however, the number of patients receiving intracorporeal or extracorporeal anastomosis is not specified. The ileo-colic anastomosis was performed intracorporeally in ten out of the fourteen studies [22–25,29,31–35] and extracorporeally in two [28,30]; both the techniques have been utilized in two studies [26,27], in which, however, the number of patients receiving intracorporeal or extracorporeal anastomosis is not specified.

#### **5. Clinical Outcomes**

#### **5. Clinical Outcomes**  *5.1. Operative Results*

*5.1. Operative Results*  Conversion rate was reported in all the studies and ranged from 0 to 3.8%; among the four comparative series of robotic versus laparoscopic CME, only Spinoglio [24] re-Conversion rate was reported in all the studies and ranged from 0 to 3.8%; among the four comparative series of robotic versus laparoscopic CME, only Spinoglio [24] reported a significantly higher conversion rate in the laparoscopic than in the robotic group (7% vs. 0).

ported a significantly higher conversion rate in the laparoscopic than in the robotic group (7% vs. 0). The mean reported operative time was 236 min; in all the four comparative studies, operative time in the robotic group was significantly higher than in the laparoscopic group.

Intraoperative complications were only reported by Yozgatli [26], who described two cases of minor vascular injuries that were repaired robotically and did not require conversion to open surgery. In the comparative series from Spinoglio [24], a patient in the laparoscopic group had an intraoperative lesion of SMV.

#### *5.2. Early Clinical Results*

Postoperative complications were detailed in all the studies, with a mean incidence of 22% and no significant differences found in the four comparative studies of robotic versus laparoscopic CME.

The majority of complications were Clavien–Dindo Grade I–II, while median incidence of Clavien–Dindo Grade III–IV complications was 2.8% (range 0–11.5%).

Anastomotic leak rate was very low (0–2%) with the majority of the studies (ten out of fourteen) [22,23,26–28,32–34] reporting no leaks in the study population.

Early postoperative mortality was declared in only one study [24] and related to a sudden cardiac death.

#### **6. Oncologic Outcomes**

Adequacy of resection was mainly evaluated by reporting the median number of harvested lymph nodes, which totalled 32 (range 19–41) considering all the studies; in the comparative series published by Ngu [25] and Yozgatli [26], significantly more lymph nodes were retrieved in the robotic group in comparison with the laparoscopic group (41 vs. 31 and 41 vs. 33, respectively), while differences were not significant in the remaining two comparative series.

The length of the specimen was only reported in four studies [22–24,31] and its median value was 38.5 cm.

The integrity of the mesocolon was reported in only one study [22].

Only three studies reported on long-term oncologic outcomes: Spinoglio [24], with a median follow up of 60 months, described a 5-year overall survival (OS) rate of 77% vs. 73%, a 5-year cancer specific survival (CSS) of 90% vs. 85% and a 5-year disease-free survival (DFS) of 85% vs. 83%, respectively, in the robotic versus the laparoscopic group; in the specific subgroup of stage III patients, 5-year DFS was 81% versus 68%. Although more noticeable, this, as the other oncologic outcomes, did not differ significantly among the two groups.

In the study from Bae [29], median follow up was 55 months, and OS and DFS were 93% and 81%, respectively.

Siddiqui [34] reported an OS and a DFS of 94%. However, follow up was shorter (3 years).

A summary of clinical and oncologic outcomes of the four different surgical approaches described ("medial to lateral", "bottom-up", "top-to-down" and "SMV first") is depicted in Table 3.


**Table 3.** Clinical and oncologic outcomes of robotic CME for right colectomy.

\*: one way ANOVA test; ◦ : Chi-square test; Pat.: patients; SMV: superior mesenteric vein; Op.: operative; min: minutes; Postop.: postoperative; compl.: complications; LN: lymph nodes.

#### **7. Discussion**

This review underlines the feasibility and safety of the robotic approach to CME with CVL for right colon cancer; in all the reported studies, operative, clinical and oncologic outcomes were good, with a very low rate of conversions to open surgery, a low rate of postoperative serious complications and anastomotic leaks, and satisfactory oncologic results.

Although laparoscopic surgery is considered the gold standard treatment for colon cancer owing to its better short-term outcomes in comparison to open surgery [36–38], laparoscopic right colectomy with CME is generally adopted by expert surgeons in high volume Centers [39–41].

One of the major concerns regarding the adoption of minimally invasive CME is its intrinsic technical challenge [42]. This is particularly the case when approaching right colectomy. In fact, the extensive dissection of the superior mesenteric vein and artery, to perform an extended lymphadenectomy, and the posterior approach to the transverse mesocolon to expose the second duodenum and the head of pancreas are undoubtedly more complex than the corresponding procedure for left colectomy. In the left colectomy, the dissection plane from the left Toldt's and Gerota's fascia is easier to approach, and only two major vessels (the inferior mesenteric artery and vein) have to be isolated and sectioned.

Vascular anatomy of the right colon is more complex [43]; right colonic vessels are not always constant, as the course of ICA after its emergence from SMA (anterior or posterior to SMV). Furthermore, the dissection of Henle's trunk and the preservation of its pancreatic and gastroepiploic afferents presents an added difficulty.

Surgeons performing a robotic approach to the vascular dissection of a right colectomy with CME are of the opinion that the robotic assistance can play a role in decreasing its technical difficulties; this concept has been widely reported by all the authors of the papers included in this review.

Similarly, some authors have raised concerns of a major risk of vascular injury when CME started to become surgically widespread [44]. This concern was confirmed by preliminary results of an ongoing randomized, controlled, phase 3 superiority trial on laparoscopic right colectomy with CME versus D2 lymphadenectomy [45]. However, it has not been confirmed in our present review of robotic series, as only one author described two cases of minor vascular injury, both of which were successfully repaired and did not require conversion to open surgery. Robotics would, therefore, seem to promise great potential in assuring the feasibility of complex and precise surgical maneuvers.

The operative feasibility of robotic CME is confirmed by the very low incidence of conversions to open surgery (0% in eleven out of the fourteen included studies); in the largest comparative series [24], a significant lower conversion rate in the robotic group is reported.

This is in accordance with evidence from the peer-reviewed published medical literature regarding robotic versus laparoscopic colorectal surgery, where the low conversion rate is accepted as one of the predominant advantages of robotics [46,47]

Finally, the dexterity of the robotic platform with the seven degrees of freedom of surgical instruments has been evoked as decisive in increasing the use of intracorporeal anastomosis (ICA) in comparison to laparoscopic surgery [48–51]; in all but two studies included in this review [28,30], an ICA was performed and the specimen was extracted through a Pfannenstiel incision. Although level 1 evidence from the literature concerning the advantages of ICA over extracorporeal anastomosis (ECA) after right colectomy is still lacking, [52,53] a recent systematic review and meta-analysis including more than 4400 patients [54] demonstrated that patients receiving an ICA had a significantly lower incidence of conversion to open surgery, total complications, anastomotic leakage, surgical site infection and incisional hernia compared to the ECA group.

If the surgical principles of CME are respected, patients' oncologic outcomes are likely to improve, as has been shown in previous series, although these are mainly retrospective and non-randomized [4–14].

Therefore, assessment of the adequacy of the surgical resection is mandatory when considering CME surgery; this has been evaluated by number of harvested lymph nodes, length of surgical specimen, distance of tumor from the vessels ligation site, integrity of the mesocolon and plane of surgery achieved. However, all these parameters are not always detailed in the studies reporting on CME, which makes it difficult to obtain definitive and homogeneous results.

Recently, Benz [55] proposed a new classification of surgical specimens of right colectomy with CME, with the aim of standardizing the histopathological evaluation. It takes into account two main parameters: the integrity of the mesocolon and the completeness of tissue removal. The focus, therefore, is on one of the key factors of CME, that is the clearance of the part of the mesocolon covering the anterior surface of SMV between the stumps of ileo-colic and middle colic vessels.

In new trials on CME for right colon cancer, a homogeneous adoption of this new classification is suggested, to standardize and, therefore, compare results.

Among the studies included in this review, only Trastulli [22] mentioned that the quality of mesocolic excision was assessed referring to the West classification of plane of resection, while in all the other studies the only evaluated histopathologic parameters were number of harvested lymph nodes and [22–24,31] the length of specimen.

It can, therefore, only be affirmed that the number of lymph nodes number was oncologically appropriate, and that in two of the comparative series, more lymph nodes were retrieved in the robotic group than in the laparoscopic group. However, in the majority of the reported series, principles of CME were declared by authors when describing the surgical technique but could not be verified on surgical specimens.

Regarding oncologic results, understood in terms of OS and DFS, these were very good but only reported in three papers.

The results of the four different approaches to robotic CME described in this review are shown in Table 2. Excluding the "top-to-down" approach reported only in one series [26], clinical and oncologic outcomes of the "medial-to-lateral", "bottom-to-up" and "SMV-first" approach do not show statistically significant differences.

Nevertheless, the number of harvested lymph nodes is greater in the "bottom-to up" and in the "SMV first" approaches in comparison with the "medial-to-lateral".

One of the advantages of the "bottom-to-up" approach is the frontal vision of superior mesenteric vascular axis, that can make extensive vascular dissection and D3 lymphadenectomy easier to perform in comparison with the "medial-to-lateral" approach.

Even the "SMV-first" approach is focused on the extensive vascular dissection prior to any other surgical manoeuvre; these technical details, if confirmed by larger scale randomized trials, could in part explain the greater lymph-nodes yield with these two approaches.

In conclusion, this review asserts the feasibility of the robotic approach to CME and CVL for right colectomy; this allows for a low conversion rate, the successful management of any intraoperative complications that might arise, and good clinical outcomes.

Oncologic results should be evaluated, in future trials, by a rigorous assessment of the surgical specimen [55] and by long-term survival rates.

**Author Contributions:** Conceptualization, W.P.; methodology, W.P.; software, W.P., S.B.; validation, W.P.; formal analysis, W.P.; investigation, W.P.; resources, W.P.; data curation, W.P.; writing—original draft prepewration, W.P.; writing—review and editing, W.P., U.F.R.; visualization, W.P., S.B., U.F.R.; supervision, W.P., U.F.R.; project administration, W.P., U.F.R. All authors have read and agreed to the published version of the manuscript.

**Funding:** This work was partially realized with the Italian Ministry of Health with Ricerca Corrente and 5 × 1000 funds.

**Institutional Review Board Statement:** Ethical review and approval were waived for this study, due to the fact that it represents a review of already published articles and no added data on patients were included.

**Informed Consent Statement:** Patient consent was waived as patient data were already published in the articles analyzed.

**Data Availability Statement:** All data were retrieved by PubMed search.

**Conflicts of Interest:** The authors declare no conflict of interests.
