Robotic male and laparoscopic female sphincter-preserving total mesorectal excision of mid-low rectal cancer share similar specimen quality, complication rates and long-term oncological outcomes

The aim of this study was to compare perioperative and long-term oncological outcomes between laparoscopic sphincter-preserving total mesorectal excision in female patients (F-Lap-TME) and robotic sphincter-preserving total mesorectal excision in male patients (M-Rob-TME) with mid-low rectal cancer (RC). A retrospective analysis of a prospectively maintained database was performed. 170 cases (F-Lap-TME: 60 patients; M-Rob-TME: 110 patients) were performed by a single surgeon (January 2011–January 2020). Clinical characteristics did not differ significantly between the two groups. Operating time was longer in M-Rob-TME than in F-Lap-TME group (185.3 ± 28.4 vs 124.5 ± 35.8 min, p < 0.001). There was no conversion to open surgery in both groups. Quality of mesorectum was complete/near-complete in 58 (96.7%) and 107 (97.3%) patients of F-Lap-TME and M-Rob-TME (p = 0.508), respectively. Circumferential radial margin involvement was observed in 2 (3.3%) and 3 (2.9%) in F-Lap-TME and M-Rob-TME patients (p = 0.210), respectively. Median length of follow-up was 62 (24–108) months in the F-Lap-TME and 64 (24–108) months in the M-Rob-TME group. Five-year overall survival rates were 90.5% in the F-Lap-TME and 89.6% in the M-Rob-TME groups (p = 0.120). Disease-free survival rates in F-Lap-TME and M-Rob-TME groups were 87.5% and 86.5% (p = 0.145), respectively. Local recurrence rates were 5% (n = 3) and 5.5% (n = 6) (p = 0.210), in the F-Lap-TME and M-Rob-TME groups, respectively. The robotic technique can potentially overcome some technical challenges related to the pelvic anatomical difference between sex compared to laparoscopy. Laparoscopic and robotic approach, respectively in female and male patients provide similar surgical specimen quality, perioperative outcomes, and long-term oncological results.


Introduction
Total mesorectal excision (TME) has significantly decreased local recurrence rates (LRR) and improved overall survival (OS) becoming the cornerstone of rectal cancer (RC) surgery [1]. Additionally, the development of new chemoradiotherapy regimens and image modalities leaded to more favorable outcomes [2,3]. Precise pelvic dissection is essential to obtain acceptable circumferential resection margins (CRM), distal resection margins (DRM), and complete mesorectal excision, which benefit the oncological outcomes [4][5][6]. Comparative studies between male and female patients with colorectal cancer were previously described [7][8][9]. Female patients with RC have better oncological outcomes than male patients [10]. Different factors have been shown to be causative, however, it is still unclear the relationship between surgical approach for RC and sex [11][12][13]. For instance, male patients are generally characterized by a narrow pelvis which restricts the freedom of movement of laparoscopic instruments during TME [14]. The robotic platform (Intuitive Surgical Inc., Sunnyvale, CA, USA) is specifically designed to overcome the technical limitations of laparoscopy allowing and advantage especially for narrow spaces [15]. This technical improvement could result in a benefit for patients undergoing pelvic procedures both on oncological and functional outcomes [16]. Previously, we reported comparative results of laparoscopic TME (Lap-TME) versus robotic TME (Rob-TME) in male patients and demonstrated the superiority of the robotic approach on perioperative and long-term oncological results [17]. However, the technical advantage of the robotic platform may not be required for female patients who are generally characterized by a wider pelvis. Recent meta-analyses showed the advantage of the robotic over laparoscopic approach in male patients with no benefit in female patients in terms of genitourinary outcomes [18]. Nevertheless, there are no comparative studies between male and female patients with RC specifically on oncological outcomes between the robotic and laparoscopic approach.
Herein, we aimed to evaluate and compare the perioperative and oncological results between female Lap-TME (F-Lap-TME) and male Rob-TME (M-Rob-TME) for midlow RC patients.
Patients with clinical T3, T4, or node-positive disease (stage II and III) were initially treated with either neoadjuvant long-course chemoradiotherapy (5080 cGy administered in 28 fractions and 5-fluorouracil based chemotherapy). The waiting period was 8-to-12 weeks for long-course radiotherapy. The performed Lap-TME and Rob-TME technique was previously described [19,20]. Perioperative outcomes included operation time, conversion to an open procedure, time to first flatus, time to soft diet, and length of postoperative hospital stay. Conversion was defined as any unplanned laparotomy at any time during surgery, regardless of the incision length.
Pathological staging was modified according to the American Joint Committee on Cancer (AJCC) 8th edition staging system during data review [21]. All pathology specimens were examined to determine tumor size, number of lymph nodes harvested, microscopic proximal resection margin (PRM), DRM, CRM, and the integrity of the mesorectum. Quality of mesorectum was assessed according to Quirke et al. [22].
A positive CRM was defined as a direct tumor extension within 1 mm of the radial, non-peritonealized surface of the resection specimen [23].
Postoperative complications were defined as adverse events occurring within 30 days from surgery and were assessed according to Clavien-Dindo's classification [24].
Long-term oncological outcomes were compared between F-Lap-TME and M-Rob-TME groups. Follow-up included control of oncological markers (CEA, Carbohydrate antigen 19-9) every three months, evaluation with thoracoabdominal CT annually, and colonoscopy examination on the first, third, fifth, and tenth year from primary surgery.
Overall survival (OS) was measured from date of surgery to that of death/last follow-up, disease-free survival (DFS) to that of tumor recurrence. Recurrence was diagnosed through radiological detection of enlarging lesions or by histological confirmation. This study follows the STROBE statement for cohort studies [25].

Statistical analysis
Patient characteristics were summarized using basic descriptive statistics. Continuous variables were presented as median (interquartile range, IQR) or mean ± standard deviation accordingly, and compared using the Mann-Whitney U test. Categorical variables were expressed as proportions and analyzed using the Chi-squared or Fisher's exact test. Statistical analysis was performed using the STATA software package version 9.0 (StataCorp, College Station, TX, USA). Survival and recurrence rates were estimated through the Kaplan-Meier model, and compared by the log-rank test. p values < 0.05 were considered statistically significant.

Clinical outcomes
A total of 170 consecutive patients were selected for the study: 60 F-Lap-TME and 110 M-Rob-TME. Patient's demographic and clinical details are listed in Table 1. Both groups were comparable in demographics, BMI, ASA score, tumor location, clinical TNM stage, and neoadjuvant treatment. Perioperative outcomes are summarized in Table 2. There was no conversion to open surgery in both groups. Protective ileostomy was created in 48 (80%) patients from F-Lap-TME and 97 (94%) patients from the M-Rob-TME group (p = 0.494). The mean operation time was significantly longer in the M-Rob-TME group than in the F-Lap-TME group 185.3 ± 28.4 versus 124.5 ± 35.8 min (p < 0.001). There was no difference regarding blood loss, bowel activity, or postoperative hospital stay.

Histopathologic outcomes
The histopathological findings are shown in Table 3. The mean number of retrieved lymph nodes (F-Lap-TME vs. M-Rob-TME) were: 26.3 ± 10.4 versus 29.6 ± 8.2 nodes (p = 0.714). The mean length of DRM was 14.50 ± 1.8 mm and 15.7 ± 1.2 mm (p = 0.065), in F-Lap-TME and M-Rob-TME groups, respectively. CRM involvement was observed in two (3.3%) and three (2.9%) in F-Lap-TME and M-Rob-TME patients, respectively (p = 0.210). Incomplete mesorectum was observed in two (3.3%) and three (2.8%) patients of F-Lap-TME and M-Rob-TME groups, respectively (p = 0.508). Other histopathological outcomes, including tumor size, grade of tumor differentiation, and pathological T and N stage, were not significantly different between the two groups.

Postoperative complications
The overall complication rate was 21.7% (n = 13) for the F-Lap-TME group and 19.1% (n = 21) for the M-Rob-TME group (p = 0.420) Table 4). Postoperative morbidity based on a Clavien-Dindo classification was not significantly different between F-Lap-TME and M-Rob-TME groups (p = 0.650). Incidence of AL was 6.7% (n = 4) and 7.3% (n = 8) in F-Lap-TME and M-Rob-TME patients, respectively. All patients with leakage were treated conservatively by maintaining a pelvic drain until the existing collection was clinically resolved, and postponing the ileostomy closing time.
Rectovaginal fistula developed in two (3.3%) patients from the F-Lap-TME group, which further underwent a Martius labial flap interposition procedure. Rectourethral fistula occurred in one (0.9%) patient from the M-Rob-TME group,  which was managed with colostomy opening and fistula repairing, and closed after the no evidence of fistula.

Oncological outcomes
With a mean follow-up of 62 months (range 24-108) in F-Lap-TME and 64 months (range 24-108) in M-Rob-TME, the 5 years DFS was 87.5% and 86.5%, respectively. The 5 years OS rates for the F-Lap-TME and M-Rob-TME groups were 90.5% and 89.6%, respectively. Kaplan-Meier OS and DFS curves are reported in Fig. 2. LR occurred in three (5%) patient in the F-Lap-TME and six (5.5%) patients in the M-Rob-TME group. Distant metastasis developed in five (8.3%) and ten (9.1%) patients, respectively in the F-Lap-TME and M-Rob-TME groups.

Discussion
The adoption of minimally invasive surgery in patients with RC has gained tremendous popularity due to its benefits, especially for low lying rectal cancers [26]. Results of the two major randomized trials demonstrated non-inferiority of laparoscopic RC surgery compared to the open approach [27,28]. The ROLARR randomized clinical trial demonstrated no significant differences between the robotic and conventional laparoscopic TME in terms of conversion patients were prone to significantly higher conversion rates in the laparoscopic group [29]. Additionally, our recent study showed that obese and male patients with mid-low RC undergoing Lap-TME had a higher conversion rate and poorer specimen integrity and long-term local control compared to those undergoing Rob-TME [17]. The 10 years follow-up of 217 standardized Lap-TME cases performed by a single surgeon (O.A.) between 2005 and 2012, showed that oncological outcomes were adversely affected in open surgery converted patients [19]. In the conversion group (6.5%), DFS was 50.0%, whereas it was 78.3% in the laparoscopic group (p < 0.001). Chan et al. also reported higher rates of LR (9.8 vs. 2.8%; p < 0.001) and reduced cumulative DFS in colorectal cancer patients who had a conversion from laparoscopic to open procedures [30]. In contrast, compared to laparoscopy, robotic RC surgery provided lower conversion rates, better preservation of sexual function, and oncological outcomes [31,32]. Also, the robotic approach has a shorter learning curve [33] and provides higher camera navigation quality than laparoscopy [34]. If the robotic approach could be theoretically advantageous for male patients with mid-low RC, for female patients both robotic and laparoscopic approach could provide similar results. The aim of the present study was to compare the laparoscopic approach in anatomically easier patients (females) with the robotic approach in anatomically challenging patients (males). Sex differences in pelvic anatomy and reflection on surgical outcomes as well as pathological metrics in RC surgery were widely described previously [35][36][37][38].
A female-wide pelvis is beneficial for the maneuverability of laparoscopic instruments during TME for RC. In contrast, it is challenging to perform Lap-TME in male patients with mid-low RC without damaging the mesorectal envelope and obtaining negative DRM and CRM. This was confirmed in our previous study, comparing Lap-TME (n = 84) and Rob-TME (n = 103) techniques in male patients with mid-low RC [17]. Rob-TME provides improved mesorectum specimen compared to Lap-TME (complete mesorectum 93.2 vs. 44.1%) in male patients with mid-low RC. Additionally, we found differences in conversion rates in male patients with RC concerning laparoscopic and robotic approaches (Lap-TME 3.5% versus Rob-TME 0%) [17]. Also, Rob-TME decreases the local recurrence rate (LRR) and improves OS (LRR 3.8 vs. 7.1%, OS 87.0 vs. 85.7%) [17].
Multiple studies have been conducted on comparative analysis of laparoscopic and robotic approaches for RC surgery [17,20,29,39,40]. The effects of both techniques on perioperative (conversion to open surgery, amount of bleeding, operative time), postoperative (complication rates, length of postoperative hospital stay, pathological parameters), and oncologic outcomes (LRR, DFS, OS) were investigated. However, most of these studies included mixed-sex (male/female) patients. Due to the distinct difference in pelvic anatomy between male and female individuals, questions on superiority of laparoscopic or robotic approaches were made. The effects of these approaches on TME quality in both sex and its reflection on long-term oncological results have not been evaluated yet.
The adult male pelvis is more technically challenging during sphincter-preserving Lap-TME because of its anatomical features: narrow space, oval-shaped pelvic inlet, angle of the public arch less than 90°, and the insertion level of the levator ani muscle which is lower [35]. Limited space restricts maneuverability of laparoscopic instruments, which translates into a decreased quality of mesorectal dissection, associated with higher conversion rate, and particularly impaired local control. Additionally, it becomes challenging to perform division of the rectum, requiring multiple number of staples in the depths of the pelvis which can increase the AL rates [41].
Pathological evaluation is essential for predicting the prognosis of patients after TME. Therefore, CRM, DRM, and mesorectal integrity are pathological metrics that play a crucial role in assessing TME quality and local control [4][5][6]23]. Furthermore, the precise dissection provided through the robotic platform may be expected to improve the pathological metrics. Standardized TME procedures performed by experienced surgeons reduced the risk of obtaining CRMpositive specimens [19]. The high rate of CRM positivity reported in the Colorectal Cancer Laparoscopic or Open Resection (COLOR II) trial in the laparoscopic group has raised concerns regarding the feasibility of the laparoscopic approach for rectal cancer [27]. In the prospective study conducted by Baek et al., the CRM involvement was not statistically different between Lap-TME and Rob-TME groups [16].
A recent study showed that the rate of positive CRM was lower in the Rob-TME group than in the Lap-TME group [29]. Aliyev et al. found significant differences in CRMpositive rates between the Lap-TME (7.1%) and Rob-TME (3.0%) groups, including only male patients [17]. The authors concluded that Rob-TME allowed to achieve complete and oncological adequate resection of the specimen with lower CRM involvement than the Lap-TME in male patients [17].
On the contrary, the current study demonstrated that mesorectal integrity, CRM, and DRM results are similar if the TME is performed laparoscopically in females and robotically in male patients with mid-low rectal cancer. Moreover, long-term oncologic outcomes (OS, DFS, and LRR) are comparable in the two groups of patients. There was no conversion to open surgery in both groups of patients. Rob-TME in male patients provided more harvested lymph nodes than Lap-TME in female patients. M-Rob-TME was associated with a more extended operation time than the Lap-TME group. The postoperative complications rates were also comparable among the two groups of patients. Therefore, this study shows that performing Lap-TME in females is as good as Rob-TME in males on perioperative and oncological outcomes. This study could lead to a sexbased analysis between Lap-TME and Rob-TME on a wider scale in order to confirm these results. The possible outcome is to indicate Rob-TME especially to male patients, or generally complex pelvic anatomies, optimizing the implementation of the robotic platform for RC.
This study has several limitations. First of all, it was a retrospective analysis of prospectively collected data from a single surgeon's experience. Second, the number of Lap-TME procedures is lower than Rob-TME. A large prospective randomized study is needed to confirm our results. Third, side of the recurrences was not revealed in this study. Fourth, comparative functional outcomes (urinary, sexual, and overall quality of life) were not evaluated. Fifth, molecular and genetic data were unavailable in this study, and tumor behavioral biology may differ between the two sex, which may have affected the oncological outcomes. And finally, cost-effectiveness was not investigated in this study.

Conclusion
Patients' sex, relatively to the anatomical conformation of the pelvis, is a factor that affects sphincter-saving TME approach for mid-low RC. No difference in specimen quality (mesorectal integrity, CRM, and DRM), oncological outcomes (OS, DFS, and LRR), and postoperative complications rate was reported when comparing female patients undergoing Lap-TME and male patients undergoing Rob-TME. The adoption of the robotic approach to the male sex only could have normalized the technical differences between the two sex.