Essential updates 2020/2021: Advancing precision medicine for comprehensive rectal cancer treatment

Abstract In the paradigm shift related to rectal cancer treatment, we have to understand a variety of new emerging topics to provide appropriate treatment for individual patients as precision medicine. However, information on surgery, genomic medicine, and pharmacotherapy is highly specialized and subdivided, creating a barrier to achieving thorough knowledge. In this review, we summarize the perspective for rectal cancer treatment and management from the current standard‐of‐care to the latest findings to help optimize treatment strategy.

reduce the surgical invasiveness compared to open surgery, mainly based on major randomized clinical trials (RCTs), including the COLOR, CLASICC, and JCOG0404 trials. [4][5][6][7][8] Although the efficacy of laparoscopic surgery for rectal cancer in phase II trials has led to its widespread adoption, the efficacy of laparoscopic surgery for LARC remains controversial. [9][10][11] Two large RCTs, the COLOR II and COREAN trials, have shown similar short-term pathological and 3-y survival outcomes between open surgery and laparoscopic surgery for LARC, whereas two other RCTs, ACOSOG Z6051 and ALaCaRT, failed to demonstrate noninferiority of laparoscopic surgery to open surgery with regard to composite pathological endpoints, including the quality of TME and circumferential resection margin (CRM). These results suggest that there may be a concern that manipulation in the deep pelvis with straight-shaped laparoscopic forceps surgery is too difficult to safely and securely dissect the correct plane around the tumor with sufficient margin. [12][13][14][15] On the other hand, increasing demand for patient satisfaction with surgery, including better cosmetic and functional outcomes, have raised the social need for minimally invasive surgery. [16][17][18][19] Robotic systems are a promising advanced technology that could overcome some of the inherent limitations of laparoscopic surgery for rectal cancer, providing high-quality three-dimensional images, articulating instruments, stable camera work, and motion scale function. 20,21 The ROLARR trial was performed in a multicenter setting to compare robotic-assisted and conventional laparoscopic rectal cancer surgery, indicating that robotic-assisted laparoscopic surgery did not significantly reduce the risk of conversion to open laparotomy (8.1% vs 12.2%). 22 However, a retrospective cohort study based on the National Clinical Database in Japan found a significantly lower conversion rate to open surgery in robot-assisted laparoscopic surgery than in conventional laparoscopic low anterior resection (0.7% vs 2.0%), less intraoperative blood loss (15 ml vs 20 ml), and a shorter postoperative hospital stay (13 d vs 14 d). 23 Regarding the long-term results of robot-assisted laparoscopic surgery, the oncological differences between robot-assisted and conventional laparoscopic rectal cancer surgery have not yet been reported in RCTs, although the REAL trial, an RCT comparing the two procedures, recently demonstrated that CRM, which is a surrogate marker of oncological outcome, was more favorable with the robotic approach. 24 We are also currently carrying out the VITRUVIANO trial, in which the results of CRM using the robotic approach in Japanese patients are being analyzed. According to the recent meta-analysis, the prognosis, including overall survival and local or distant recurrence rate, is comparable. 25,26 Although the outcomes of robot-assisted laparoscopic surgery remain controversial, a recent meta-analysis indicated that robot-assisted surgery with advanced visualization can improve autonomic nerve preservation, thereby providing better urinary and erectile function than conventional laparoscopic surgery for rectal cancer patients. 27 We consider that robotic surgery can meet patient demands for function preservation, especially in the era of minimally invasive surgery. However, the usefulness of robotic surgery has to be validated from multiple perspectives.

| Key surgical concepts for rectal cancer
Surgical treatment is the mainstay in multidisciplinary treatment for locally advanced rectal cancer, and the quality of surgery is directly associated with postoperative local recurrence. Thus, appropriate objective indicators are needed to assess the quality of surgery. In the 1980s, Heald et al proposed the importance of TME and reported that complete TME leads to a lower local recurrence rate and prolonged overall survival. 28 Adam et al also reported a significantly increased local recurrence rate in patients with a CRM ≤1 mm. 29 Since then, TME has become the standard procedure for rectal cancer, and its completion and assurance of CRM are considered the most important surgical factors and used as indicators of surgical quality. In general, CRM is judged as positive if the margin is ≤1 mm. Notably, if the tumor is in close proximity to or involves the mesorectal fascia, the CRM may be positive even if TME is completed, and accurate preoperative diagnosis is necessary to ensure a negative CRM.
In Western countries, CRM and TME, especially CRM are used as the most important indicators of the oncological quality of surgery but, in Japan, these indicators have not been regarded as important for a long time. According to Japanese practice, the resected specimen is opened longitudinally to assess the tumor morphology and distal resection margin, and the mesentery is removed from the specimen to ascertain the number and location of lymph node metastases (LNMs), making accurate assessment of the CRM difficult.
Therefore, it has long been difficult to compare the quality of surgery in Japan with the quality in Western countries using CRM. For the purpose of validating the results of Japanese MIS, the development of a method to assess CRM and TME in Japan has been desired. We previously developed the "semi-opened circular specimen processing method" for pathological CRM assessment that fits into Japanese practice (Figure 1), 30 which was verified by a multicenter validity study. 31 Using this method, the oncological validity of laparoscopic surgery for advanced rectal cancer in Japan was assessed in the PRODUCT study, which demonstrated that the positive CRM rate was 8.6%. 32 Table 1 compares the positive CRM rates between four representative RCTs and the PRODUCT study. Regarding robotic surgery, the VITRUVIANO trial, a prospective, multicenter, registry study of the oncological validity of robot-assisted surgery for advanced rectal cancer, is currently underway, in which the primary endpoint is CRM by the semiopened circular specimen processing method. For quality control, the operating surgeons are certified if the experience with robotic surgeries is more than at least 40 cases.
Enrollment is already completed and the positive CRM rate after robotic surgery in Japan is going to be clarified in the near future.

| Transanal minimally invasive surgery
During laparoscopic surgery for rectal cancer, the transabdominal manipulation in the deep pelvis is technically demanding due, in part, to limited maneuverability in the confined space far from the abdominal wall or the confliction between the forceps. Given that the noninferiority of laparoscopic surgery to open surgery was not demonstrated in the ALaCaRT or ACOSOG Z6051 trials, there may be a concern that this difficulty can deteriorate the quality of TME or jeopardize the acquisition of a clear CRM.
In 2010, Sylla et al reported the application of transanal TME (TaTME) for rectal cancer resection to address the abovementioned difficulties. 33,34 During TaTME, the operating surgeon can perform dissection near the access device placed at the anal canal and the forceps can easily be applied in the direction of the rectal axis, providing better accessibility to the deep pelvis ( Figure 2). The following evidence from advanced institutions in this field demonstrates the favorable results of TaTME, with a lower positive CRM rate, improved quality of the TME, or curtailed operative time compared to the conventional laparoscopic approach. [35][36][37] Compared to conventional surgery, TaTME has shown better oncological results with a definitive distal margin and lower positive CRM rate. 38 Furthermore, TaTME has been reported to improve safety and functional preservation, with lower conversion rates, fewer postoperative complications, and higher rates of anal preservation. [39][40][41] In abdominoperineal excision (APE), perineal dissection is conventionally carried out under direct view. However, the anatomical configurations of the pelvis are highly complicated, especially around the rectal anterior wall; thus, the surgeons are forced to deal with this complex area through a restricted wound. 42 Transperineal APE (TpAPE) has emerged as an advanced approach to TaTME, and it can address the technical difficulty encountered during a perineal procedure ( Figure 2). 43,44 In contrast to the advantages of TaTME, several concerns specific to TaTME should be noted. The first concern is urethral injury, which rarely occurs during the transabdominal approach.
Reportedly, urethral injury occurs in ~1% of procedures and is especially frequent during the first eight cases of implementation. 45,46 To avoid urethral injury, understanding of the pelvic anatomy from the perineal side is mandatory for the surgeons to dissect the rectal anterior wall correctly. The second concern is that TaTME has a possibility of increasing the local recurrence rate and promoting a multifocal pattern of recurrence. A Norwegian national audit estimated a rate of local recurrence at 2.4 y of 11.6%, with a multifocal or extensive pattern of local recurrence in two-thirds of patients. 47 Similarly, according to the Dutch study, multifocal recurrence was frequent during the implementation phase of TaTME. 48 Presumably, the unfavorable results were caused by leakage of gas or liquid containing malignant cells due to incomplete closure of the purse-string suture or rectal perforation. In advanced centers, the rate of local recurrence was low (2.0%-3.4%) and a multifocal pattern of recurrence was not found. 39,49,50 Thus, quality control of TaTME is crucial to securely perform rectal cancer surgery, and the training curriculum should be carried out to introduce TaTME. 51,52 Ongoing RCTs comparing laparoscopic TME and TaTME, such as COLOR III (NCT02736942) and GRECCAR 11 (NCT02584985), will clarify the validity of TaTME. 53,54 Furthermore, it is important to address the efficacy of TaTME for far advanced cases, such as combined resection of adjacent organs or total pelvic exenteration.

| Lateral lymph node dissection
In lower rectal cancer with a depth of cT3 or cT4, 15%-20% of patients have metastasis in the lateral lymph nodes. 55 The Japanese standard of care includes lateral lymph node dissection (LLND) in addition to TME, whereas preoperative chemoradiotherapy (CRT) is commonly used in Western countries, and the local recurrence rates for both are comparable. 56 JCOG0212 evaluated the noninferiority of mesorectal excision (ME) alone to ME + LLND in stages II and III lower rectal cancer patients without lateral LNM on preoperative imaging. The primary endpoint of 5-y recurrencefree survival was not proven to be noninferior to ME + LLND, and the local recurrence rate was significantly reduced from 12.6% to 7.4% after LLND, 57 indicating that LLND could be effective in preventing local recurrence. However, LLND is associated with longer operative times, increased blood loss, and risk of functional F I G U R E 1 Semiopened circular specimen processing method for pathological circumferential resection margin (CRM) assessment (a) anterior view of the resected rectal specimen. impairment. Furthermore, relapse-free survival did not differ whether LLND was or was not performed; therefore, more than a few Japanese surgeons even omit LLND for prophylactic purposes and restrict the indication of LLND to cases with evident metastasis. In contrast, in cases with enlarged lateral lymph nodes, even if neoadjuvant CRT is administered, the addition of LLND could prevent lateral local recurrence, suggesting that LLND is an important option in multimodal therapy and would be effective in select cases. 58,59 Autonomic nerve-preserving LLND, which was developed in Japan, is now being appreciated in the West, and the West meets East concept is attracting a lot of attention. 60 Given that intensified multimodal treatment combined with LLND can be effective at lowering the rate of local recurrence for a portion of patients, more accurate criteria are needed for predicting metastasis to lateral lymph nodes. Several studies have demonstrated the risk factors for metastasis, including the size or shape of the lateral lymph node, tumor location, or extramural venous invasion (EMVI). 61,62 EMVI is defined as the active invasion of malignant cells into veins beyond the muscularis propria in colorectal cancer that can be diagnosed on magnetic resonance imaging (MRI). 63 The combination of EMVI with the size of the lateral lymph node could differentiate high-risk cases, which may optimize the indication for LLND. 61,62 Concerning LLND techniques, the conventional procedure has been open surgery, although the indication for MIS has been gradually expanded to LLND. Several retrospective studies have demonstrated the safety and feasibility of laparoscopic LLND. 64,65 To enhance the precision of the operation in the deep and narrow cavity, application of robotic surgery for LLND is being attempted, demonstrating that it may decrease postoperative complications TA B L E 1 Comparison of the results of laparoscopic surgery in randomized controlled trials and the PRODUCT study analyzing the rate of CRM positivity compared to open or laparoscopic surgery 66,67 or significantly improve the 5-y local recurrence-free survival rate compared to open surgery. 68 The deepest lymph node station, 263, is reportedly the most frequently metastatic region, which is technically difficult to dissect. 69 We consider that robotic LLND can be efficacious to clear the lateral lymph nodes, including station 263.

| ME A SUREMENTS TO PRE VENT REC TAL C AN CER SURG ERY-REL ATED COMPLIC ATIONS
A variety of complications can occur after rectal cancer resection, including anastomotic leakage (AL), infection, bowel obstruction or ileus, and surgical site infection. In this chapter we discuss how we efficiently prevent AL or AL-related problems, considering its significance in clinical practice.

| ICG fluorescence angiography
Anastomotic leakage is one of the most detrimental complications of colorectal surgery, which is associated with elevated morbidity and mortality rates, as well as the risk of local recurrence in rectal cancer resection. [70][71][72][73] Various factors, including surgical, patient, and tumor factors, are associated with the occurrence of AL. [74][75][76] Adequate blood flow to the anastomotic intestinal stump is also essential to avoid AL, but it is not always easy to precisely evaluate blood flow. Conventionally, intestinal blood flow is evaluated by surgeons using several clinical signs, such as the color of the intestinal mucosa, peristaltic movement, bleeding from the marginal artery, and palpable arterial pulses in the mesentery. These signs are useful for judging the intestinal blood flow, but it may easily be surgeon-dependent and inconsistent. 77 Indocyanine green (ICG) fluorescence angiography allows surgeons to visualize intestinal perfusion in real time [78][79][80] and is anticipated to decrease the incidence of AL ( Figure 3). 81-84 A meta-analysis to assess the efficacy and safety of ICG in colorectal cancer surgery in 11 047 patients showed that ICG fluorescence angiography significantly reduces the rate of AL (3.7% with ICG vs 7.6% without ICG), but this metaanalysis was mostly comprised of retrospective studies and small studies. 85 In the interim analysis of the PILLAR-III trial, a randomized, controlled, parallel, multicenter study assessing perfusion outcomes in low anterior resection, the incidence of AL was 9.0% in the ICG group and 9.6% in the non-ICG group. This trial was terminated because the efficacy was not confirmed. 86 PILLAR-III was associated with several limitations: the criteria to assess intestinal blood flow was not standardized, whether the transection line was changed after administering ICG was not clear, and a detailed description of the sample size was lacking. Therefore, the results of PILLAR-III could not clearly conclude that ICG fluorescence angiography prevented the occurrence of AL. 86  with absorbable tissue reinforcement, the application of which has already been reported to be effective for gastrectomy or pancreatectomy. 91 Based on this background, its use in rectal transection can be considered efficacious in strengthening the intersection. We are currently conducting a multicenter, prospective, observational study (UMIN000030240) to evaluate the safety and efficacy of the reinforced linear stapler in rectal cancer resection. As AL is a multifactorial event, it will require various approaches, among which the use of novel devices for tissue reinforcement may play an important role.

| Closure of diverting stoma
Diverting stoma in rectal cancer resection may reduce symptomatic AL or the need for urgent abdominal reoperation for leakage. [92][93][94] As loop ileostomy is associated with fewer stoma-related complications than colostomy, loop ileostomy is more commonly constructed in Japan. According to the established guidelines, stomas should be placed away from skin folds, scars, bony prominences, and the belt line. 95 Moreover, they should be placed within the rectus abdominis muscle and should be visible to the patient. A long distance from the ileocecal valve to the ileostomy is associated with a low risk of stoma retraction and a high risk of ileus, and the height of the distal limb of the ileostomy significantly affects the incidence of parastomal dermatitis and mucocutaneous separation. 96 Surgical site infection (SSI) is the most common postoperative complication after ileostomy closure, with a reported rate of up to 40%, leading to longer hospital stays and higher medical costs. 97 Various measures have been taken to reduce the incidence of SSI, such as bowel preparation, the administration of appropriate perioperative antibiotics, wound protection, the use of absorbable sutures, wound irrigation with saline, 98 and purse-string skin closure. 97 We have reported a lower incidence of SSI with primary wound closure and preventive negative-pressure wound therapy, which may be effective as a preventive option. 99

| Fluorescence lymph navigation surgery for colorectal cancer
The intraoperative navigation surgery using near-infrared (NIR) fluorescence has become possible with improvements in laparoscopic surgical devices. In recent years, ICG fluorescence imaging has been applied clinically for real-time visualization of lymphatic flow to optimize lymph node dissection. [100][101][102] We reported the usefulness of ICG fluorescence imaging instead of India ink tattooing for tumor site marking in laparoscopic surgery. 103  in cases of LNM. 106 The metastatic lymph nodes that are completely occupied by cancer do not fluoresce on ICG fluorescence imaging, regardless of the lymph node size. 107 We investigated the associa-

| Near-infrared ureteral stent for preventing urethral injury
The urethra is difficult to detect during TaTME due to the view of the pelvic anatomy from the perineal side. Greater difficulty identifying the urethra in APE is a hurdle to applying the transanal approach. 109 Misidentification of the urethra as the rectourethral muscle during dissection of the rectal anterior plane can result in urethral injury.
An NIR spectroscopy ureteral stent, which was originally a medical device to fluorescently label the ureter, can also work as a marker to help identify the urethra in TaTME. 109,110 Such a novel device can be useful for implementing TaTME more safely. was compared to CRT in which CAPOX was used concomitantly. 121 Although overall survival was superior to CRT at 3 y, other longterm outcomes were not different, and the difference in overall survival disappeared at the 8-y follow-up. 122 The STELLAR trial investigated the noninferiority of TNT to CRT by assessing DFS, demonstrating that the DFS was similar between the two treatments, although the overall survival of TNT was significantly better than that of CRT. 123 In contrast, the RAPIDO and PRODIGE23 trials showed the better efficacy of TNT over CRT. 124 Surgery has been an essential part of multimodal therapy and has a great therapeutic effect; however, it concurrently comprises surgical invasion, risk to sphincter preservation, possibility of stoma creation, or impaired urinary or sexual function for patients. The watch and wait (W&W) strategy has received attention in recent years, as once cCR is achieved, more than half of patients likely avoid local regrowth. [126][127][128] It is possible that TNT can play a crucial role in the W&W strategy. Given that the local recurrence rate after surgery is comparable between TNT and CRT, 121-125 we cannot argue that TNT is able to offer better local control, but TNT may improve the pCR rate according to a meta-analysis, in which the odds of pCR are elevated ~40%. 120 Conversely, the prognosis of non-pCR cases is not necessarily favorable; therefore, it is also important not to assess the efficacy of TNT as a whole only with the pCR rate. Recently, the OPRA trial, which evaluated DFS as a primary endpoint between induction and consolidation chemotherapy with CRT, demonstrated that DFS is comparable between the two TNTs, whereas CRT followed by consolidation chemotherapy was associated with a higher rate of organ preservation. 129 If we intend to offer the W&W approach for a patient, it may be possible that TNT including consolidation chemotherapy is more efficacious.
It is also plausible that TNT may be effective for comparably earlystage tumors, such as the "good" risk group defined in the ESMO guidelines, with an aim to achieve CR, but no evidence is currently available regarding whether this hypothesis is correct, which should be validated in future trials. The future treatment strategy for LARC may change dramatically.  Surprisingly, pCR could be successfully achieved in all of the enrolled patients, indicating that ICI would also be an important part of multimodal therapy. In the future, the tumor indicated for omission of neoadjuvant RT may be clearly defined to promote precision medicine.

| Future perspectives
Some patients can be offered the possibility of a W&W approach and can be cured without surgery. Nevertheless, surgery remains an important part of therapy for most patients who fail to achieve pCR or suffer from local regrowth. The indication of LLND in multimodal therapy should also be discussed, in which risk assessment for lateral LNM is mandatory. 59,61,142,143 Establishment of criteria for risk stratification is essential to guide optimal treatment for each patient, and molecular or imaging technology may serve efficiently. The VEGA trial, a de-escalation trial, is a randomized phase III study for postoperative ctDNA-negative patients with high-risk stage II and lowrisk stage III to evaluate whether surgery alone is noninferior to the standard CAPOX therapy (ie, whether omitting postoperative adjuvant chemotherapy may be acceptable). Although the VEGA trial is targeted at colon cancer, it has the potential to be applied to rectal cancer as well. The ctDNA-positive group is a very high-risk group for recurrence, and early intervention may be expected to prolong survival. The additional intestinal resection to investigate the predictive ability of LNM using ctDNA analysis compared to standard pathological criteria. 158 As described above, the global standard treatment for locally advanced rectal cancer is neoadjuvant CRT followed by resection of the rectum, but there are currently no criteria for TNT. Considering adverse events and high medical costs, the application of TNT for all locally advanced rectal cancers can be excessive. Although preoperative ctDNA has been considered to have limited clinical relevance because it is not associated with progression or prognosis, preoperative the ctDNA results were recently shown to be strongly associated with subsequent distant metastatic recurrence when locally advanced rectal cancer is treated with neoadjuvant CRT. 159,160 Based on this finding, a new cohort was launched to optimize the indication for TNT using preoperative ctDNA after neoadjuvant CRT. The ctDNA assay is expected to provide new evidence for the establishment of a noninvasive personalized diagnosis and facilitate optimal treatment strategies for colorectal cancer patients. 161

| REC TAL C AN CER D IAG NOS IS
In Western guidelines, MRI is regarded as an essential exam to precisely diagnose malignant features of rectal cancer. 2,3 The protocol for image acquisition is strictly defined, and the structured reporting system for MRI is systematized. 162 Different from Japan, Western countries have emphasized precise baseline diagnosis to guide appropriate neoadjuvant treatment, although a surgery-first approach has long been used as the standard of care in Japan, which is partly reflected in the difference in attitudes toward MRI findings. In the MERCURY study, MRI-involved CRM was verified to be the only risk factor for long-term outcomes (not only local recurrence, but overall survival and DFS), which was a superior predictive marker to T or N factors. 164 In the MERCURY II study, the risk factors for pathologically positive CRM were analyzed to decrease the positive CRM rate for rectal cancers lower than 6 cm from the anal verge. 165 As a result, positive EMVI, MRI-involved CRM, anterior tumor site, and tumor height lower than 4 cm were significant risk factors, which enabled the assessment of pCRM positivity. This preoperative assessment is useful to judge indications for neoadjuvant treatment.
Neoadjuvant CRT was introduced into the Japanese guidelines in 2019 as a treatment option. Thus, diagnosis of the tumor on MRI has become mandatory before determining treatment in Japan. Precise diagnosis is increasingly demanded, but this is not necessarily an easy task. The accuracy of MRI diagnosis has room for improvement, even in the data from the MERCURY group. 166 In recent years, some attempts have been made to diagnose on MRI precisely. Artificial intelligence-based technology has been constructed to visualize the rectal cancer area, which can potentially be utilized to find the malignant features of rectal cancer. [167][168][169] In addition, according to a recent report, artificial intelligence can be utilized for preoperative simulation to visualize anatomical configuration individually, possibly improving operative safety. 170 If the diagnostic accuracy could be more sophisticated, the treatment strategy may be optimized based on the status of the individual tumor, which would be beneficial for the patient.  172 Therefore, meta-analyses and systemic reviews were not available, and even the prevalence of LARS was not clear. 173 The LARS score was developed by Emmertsen and Laurberg in 2012 as a scoring system that can easily evaluate multiple symptoms of LARS according to the level of QoL impairment. 174 The LARS score highly correlates with the EORTC QLQ-C30, 175,176 CR38,177 and SF36, 178 and its clinical usefulness has been described in several articles. The LARS score has been translated into more than 30 languages, and we reported the validation of the Japanese version of the LARS score through double translation in 2018. 179 The LARS score enables easy diagnosis and evaluation of LARS; furthermore, international comparison is possible by using the score created and validated in accordance with international standards.

| LOW ANTERI OR RE S EC TI ON SYNDROME
Assessment of the diagnosis and severity of LARS based on certain criteria has also revealed risk factors for severe LARS.

| UROG ENITAL DYS FUN C TION
Urinary dysfunction occurs after TME at a fixed frequency of 30%-50%, 186,187 which may cause deterioration of the patient's QoL or induce urinary tract infection. This postoperative complication is mainly due to disturbance of the nervous system, including the pelvic plexus and neurovascular bundle. 188,189 The addition of LLND to TME can reportedly increase the risk more, at an odds ratio of about 2,190,191 but JCOG0212 demonstrated that a difference in urinary dysfunction could not be found between TME alone and TME with nerve-preserving LLND. 187 These data suggest that difficult manipulation in the deep pelvis can result in inadvertent injury to surrounding autonomic nerves. Being male, having a low level of anastomosis, anterior tumor, or increased blood loss have been demonstrated to be risk factors for urinary dysfunction after TME in previous studies, all of which are possibly related to an elevated risk of nerve injury. 187,188,192,193 Sexual dysfunction is also likely to be compromised after rectal cancer resection in more than half of patients, although the definition of sexual dysfunction is not standardized. 186 This result is caused by multifactorial effects, including nerve injury and preoperative radiotherapy. 194 In recent years, the above-mentioned evolution in minimally invasive surgery has dramatically improved the visibility or maneuverability in the deep pelvis, and robot-assisted laparoscopic surgery would be efficacious for preserving autonomic nerves. [195][196][197] A meta-analysis investigating the effect on urinary and sexual dysfunction demonstrated that the function after robotic approach was favorable compared to the laparoscopic approach, especially in male patients. 27 In taking this evidence into consideration, robot-assisted laparoscopic surgery can be beneficial in terms of postoperative urinary and sexual dysfunction, but this should be validated in a prospective study. The current VITRUVIANO trial is investigating CRM, as well as urinary dysfunction, and we are going to demonstrate the significance of its use in light of the urinary function.

| SUMMARY
In