- Journal List
- BJS Open
- v.8(3); 2024 Jun
- PMC11126316
As a library, NLM provides access to scientific literature. Inclusion in an NLM database does not imply endorsem*nt of, or agreement with, the contents by NLM or the National Institutes of Health.
Learn more: PMC Disclaimer | PMC Copyright Notice
BJS Open. 2024 Jun; 8(3): zrae029.
Published online 2024 May 24. doi:10.1093/bjsopen/zrae029
PMCID: PMC11126316
PMID: 38788679
Marieke L Rutgers,
Thijs A Burghgraef, Jeroen C Hol, Rogier M Crolla, Nanette A van Geloven, Jeroen W Leijtens, Fatih Polat, Apollo Pronk, Anke B Smits, Jurriaan B Tuyman, Emiel G Verdaasdonk, Colin Sietses, Esther C Consten, and Roel Hompes
Author information Article notes Copyright and License information PMC Disclaimer
Associated Data
- Data Availability Statement
Abstract
Background
The routine use of MRI in rectal cancer treatment allows the use of a strict definition for low rectal cancer. This study aimed to compare minimally invasive total mesorectal excision in MRI-defined low rectal cancer in expert laparoscopic, transanal and robotic high-volume centres.
Methods
All MRI-defined low rectal cancer operated on between 2015 and 2017 in 11 Dutch centres were included. Primary outcomes were: R1 rate, total mesorectal excision quality and 3-year local recurrence and survivals (overall and disease free). Secondary outcomes included conversion rate, complications and whether there was a perioperative change in the preoperative treatment plan.
Results
Of 1071 eligible rectal cancers, 633 patients with low rectal cancer were identified. Quality of the total mesorectal excision specimen (P = 0.337), R1 rate (P = 0.107), conversion (P = 0.344), anastomotic leakage rate (P = 0.942), local recurrence (P = 0.809), overall survival (P = 0.436) and disease-free survival (P = 0.347) were comparable among the centres. The laparoscopic centre group had the highest rate of perioperative change in the preoperative treatment plan (10.4%), compared with robotic expert centres (5.2%) and transanal centres (2.1%), P = 0.004. The main reason for this change was stapling difficulty (43%), followed by low tumour location (29%). Multivariable analysis showed that laparoscopic surgery was the only independent risk factor for a change in the preoperative planned procedure, P = 0.024.
Conclusion
Centres with expertise in all three minimally invasive total mesorectal excision techniques can achieve good oncological resection in the treatment of MRI-defined low rectal cancer. However, compared with robotic expert centres and transanal centres, patients treated in laparoscopic centres have an increased risk of a change in the preoperative intended procedure due to technical limitations.
This multicentre, retrospective cohort study showed that with all three minimally invasive techniques (robot, transanal and laparoscopy) good oncological resection can be achieved in the treatment of MRI-defined low rectal cancer. However, patients treated in laparoscopic centres have an increased risk of a change in the preoperative intended procedure due to technical limitations.
Introduction
Surgical resection according to the total mesorectal excision (TME) principle remains one of the key elements in the treatment of rectal cancer1,2. Robot-assisted surgery (R-TME) and transanal surgery (TaTME) may overcome some of the challenges found in laparoscopic rectal cancer surgery (L-TME) due to enhanced visualization of and access to embryological planes deep in the pelvis. Especially in LOw REctal Cancer (LOREC), this could lead to a superior TME specimen with less positive resection margins (R1), lower conversion rates and more primary anastomoses3–7. Nevertheless, current literature does not usually describe outcomes for LOREC separately.
The most appropriate definition for LOREC is still debated, but is mainly based on tumour height from the anal verge or anal ring8. However, the use of tumour height may lack precision due to variations in individual anatomy9–12. An MRI-based definition of LOREC offers a more standardized approach and allows for the identification of technically challenging cases. According to the UK LOREC programme, a low rectal tumour can be identified through the anatomical landmark where the tapering of the mesorectum starts, which can be seen on sagittal MRI8,13–15. So far, this new definition of LOREC is only utilized in a handful of papers, with very little actual clinical data. Furthermore, most published data on R-TME and TaTME behold results of cases performed during the learning curve which may not fully represent the true potential of these techniques16,17. For TaTME, the learning curve is set at around 45–51 cases, followed with a minimum caseload of 25–30 cases per year to ensure expertise and procedural quality18,19. The learning curve for robotic TME appears to be similar20,21.
The present study aimed to compare the oncological outcomes of MRI-defined LOREC in centres that completed the learning curve in different minimally invasive techniques. Secondary outcome measures include conversion rates, perioperative complications and changes in the preoperative surgical plan.
Methods
A retrospective, multicentre cohort study was conducted in 11 centres in The Netherlands with large experience in one of the three minimally invasive techniques (three TaTME, three R-TME and five L-TME centres). The study protocol was approved by the Medical Research Ethics Committees United (MEC-U, AW 19.023/W18.100) and the local ethical boards of all participating centres.
Data extraction
Data were initially obtained from the Dutch Colorectal Audit (DCRA), which is a mandatory nationwide registry that collects information on all surgically resected primary colorectal cancer patients. Missing data and additional information not available in the DCRA data set were added by local investigators with use of the local electronic medical records. Data extracted consisted of outpatient visit notes, multidisciplinary team (MDT) notes, surgical notes, radiology reports and images, pathology reports, (neo)adjuvant therapy details and complications. All pseudonymized data were collected between January and April 2020 in the data management system CASTOR, a research data collector system22.
Patient selection
All patients 18 years and older, diagnosed with rectal cancer, adhering to the sigmoidal take-off definition14, for which they underwent rectal cancer surgery (open or minimally invasive) with curative intent between January 2015 and December 2017 in 1 of the 11 participating hospitals were included. The groups were divided according to the minimally invasive technique used in the respective centres. To participate, each centre had to perform a minimum of 30 procedures per year using the expert technique. Procedures performed in the year 2015 at two centres where the expert technique was introduced in 2014 (one robot and one TaTME centre respectively) were excluded because it was assumed that for those cases the learning curve had not fully run its course.
Subsequently all staging MRI scans were reviewed by trained local investigators to identify the cohort of patients with MRI-defined LOREC according to the defined criteria8,15,21. Excluded from analysis were patients with palliative treatment, synchronous colonic tumours, acute procedures, hyperthermic intraperitoneal chemotherapy (HIPEC), intraoperative radiotherapy (IORT) and non-TME surgery (including local excision, transanal endoscopic microsurgery (TEM) or transanal minimally invasive surgery (TAMIS)). Open surgery procedures were not excluded, but since seldom performed, were not analysed in depth for the outcomes of interest (see below). Each patient was discussed by a local MDT and indications for neoadjuvant treatment were given according to the current Dutch national guidelines for colorectal cancer.
Outcomes of interest and definitions
Outcomes of interest were compared among the centres (L-: laparoscopic TME centres, R-: robotics TME centres and Ta-: TaTME centres). The primary outcomes were the oncological outcomes, specifically the rate of positive resection margins (R1) and quality of the TME specimen, and 3-year local recurrence, distant recurrence, overall survival and disease-free survival. Secondary outcomes included conversion rate, intraoperative changes to the procedural plan, incidence of restorative procedures (with or without diverting stoma), and the intra- and postoperative outcomes (for example 30-day morbidity rate, anastomotic leakage rate (AL) and 30-day readmission rate).
A LOREC tumour was defined as a tumour with the lower border located distal to the point where the levator ani muscles insert on the pelvic bone, as identified on sagittal MRI8,15,21. The TaTME technique combines an endoscopic transanal approach with a laparoscopic abdominal approach. R-TME is a procedure where (at least) the pelvic dissection was performed with the da Vinci surgical system.
The type of procedure was categorized as either low anterior resection (LAR) with anastomosis, encompassing all sphincter-saving procedures with primary anastomosis with or without a temporary stoma. Non-restorative procedures included LAR with end colostomy (Hartmann’s procedure) or abdominoperineal resection (APR), which includes any procedure with perineal dissection with complete, intersphincteric, or extrasphincteric proctectomy and definitive end colostomy.
To avoid selection bias, other techniques used to treat low rectal tumours in a specific expert centre, such as the use of laparoscopy for APR in TaTME and R-TME centres, were not excluded from analysis.
A positive mesorectal fascia (MRF) was defined as a distance ≤1 mm from the resection margin on MRI. Circumferential and distal resection margin involvement (CRM+ and DRM+ respectively) were defined as a tumour or malignant lymph node ≤1 mm from the circumferential or distal resection margin, and were both regarded as R1 resections. A conversion to open surgery was defined as the use of a median laparotomy or any accessory incision for purposes other than specimen extraction. The 30-day morbidity rate was categorized according to the Clavien–Dindo classification23. Anastomotic leakage was defined as anastomotic dehiscence or intra-abdominal abscess adjacent to the anastomotic site, including those occurring beyond 30 days. The leakages were graded according to the International Study Group of Rectal Cancer (ISREC) classification for anastomotic leakage after anterior resection, where grade A can be managed without changing the management, grade B requires active therapeutic intervention but without reoperation on and grade C requires laparotomy24. Change in the preoperative treatment plan was defined as a change in the operative plan agreed by the MDT (i.e., from a restorative to a non-restorative procedure). Information was extracted from the surgical notes. A secondary stoma was defined as a second stoma formation after a first attempt of primary stoma reversal.
Statistical analysis
Descriptive statistics were used to describe baseline characteristics. Categorical variables were presented as numbers and percentages, while continuous variables were presented as mean(s.d.) or median (interquartile range) depending on the type of distribution. Univariable analysis was performed using the chi-square test for categorical data. The independent sample t-test or the Wilcoxon-rank sum test were used for continuous data. Multivariable logistic regression analysis, using backward selection, was conducted to evaluate independent factors associated with CRM positivity, anastomotic leakage and a change in procedural plan. Variables taken into account were: actual surgical technique (L-TME, R-TME and TaTME), age, BMI, sex, ASA score, surgical abdominal history, distance to the anorectal junction (ARJ), MRF, clinical tumour (cT) stage, clinical node (cN) stage, clinical metastasis (cM) stage and neoadjuvant therapy. The results were expressed as odds ratios (OR) with 95% c.i. A P value of <0.05 was considered significant. Statistical analysis was performed using R, version 3.6.2 (R Foundation for Statistical Computing, Vienna, Austria).
Results
A total of 1834 patients with rectal cancer were registered in the DCRA registry in the participating centres between January 2015 and December 2017. After excluding patients that did not meet the inclusion criteria and/or were located above the sigmoidal take-off, 1071 patients with rectal cancer remained. Among them 633 (59.1%) were classified as MRI-defined LOREC tumours (Fig. 1).
Fig. 1
Flow diagram of included patients
DCRA, Dutch Colorectal Audit; TME, total mesorectal excision; LOREC, LOw REctal Cancer; Lap, laparoscopic; Rob, robot assisted; Ta, transanal TME; HIPEC, hyperthermal intraperitoneal chemotherapy; IORT, intraoperative radiotherapy; TEM, transanal endoscopic microsurgery.
Baseline characteristics
Baseline patient and tumour demographics are displayed in Table 1. Patients from Ta-centres were younger, with a mean age of 65 years, compared with 67 years in L-centres and 68 years in R-centres, P = 0.04. Ta-centre patients had a shorter distance to the anorectal junction (ARJ), with a mean distance of 2 cm, compared with 3 cm in both L- and R-centres, P = <0.001. Additionally, Ta-centres had the highest proportion of patients with cN0 stage (52%), compared with 40% in L- and 36% in R-centres, P = 0.01. Patients in R-centres received the most neoadjuvant therapy (72%) compared with L-centres (65%) and Ta-centres (66%), P = 0.027.
Table1
Baseline characteristics MRI-defined LOREC patients, 2015–2017
| Patient characteristics | LOREC | |||||
|---|---|---|---|---|---|---|
| Total n = 633 (%) | L-centre n = 317 | R-centre n = 173 | Ta-centre n = 143 | P value | ||
| Age (years), mean(s.d.) | 67(10.5) | 67(9.9) | 68(10.6) | 65(11.7) | 0.038 | |
| BMI (kg/m2), mean(s.d.) | 26(4.3) | 26(4.4) | 26(4.0) | 26(3.9) | 0.475 | |
| Sex | ||||||
| Male | 63.5 | 197 (62.1) | 109 (63.6) | 95 (66.4) | 0.676 | |
| Female | 36.5 | 120 (37.9) | 63 (36.6) | 48 (33.6) | ||
| ASA | ||||||
| I | 19.7 | 55 (17.4) | 40 (23.1) | 30 (21.0) | 0.286 | |
| II | 60.3 | 200 (63.1) | 93 (53.8) | 89 (62.2) | ||
| III | 19.0 | 57 (18.0) | 40 (23.1) | 23 (16.1) | ||
| IV | 0.9 | 5 (1.6) | 0 (0.0) | 1 (0.7) | ||
| History of abdominal surgery | Yes | 30.0 | 98 (30.9) | 48 (27.7) | 44 (30.8) | 0.746 |
| Distance of tumour to ARJ (cm), median (i.q.r.) | 3 (0–5) | 3 (1–5) | 3 (1–5) | 2 (0–3) | <0.001 | |
| Preoperative MRF | ≤1 mm | 34.5 | 97 (30.9) | 67 (39.0) | 53 (37.1) | 0.129 |
| cT-stage | ||||||
| cT1 | 0.2 | 0 (0.0) | 0 (0.0) | 1 (0.7) | 0.183 | |
| cT2 | 27.7 | 87 (27.5) | 48 (27.9) | 40 (28.0) | ||
| cT3 | 61.3 | 202 (63.9) | 98 (57.0) | 87 (60.8) | ||
| cT4 | 10.8 | 27 (8.5) | 26 (15.1) | 15 (10.5) | ||
| cN-stage | ||||||
| cN0 | 41.7 | 128 (40.4) | 61 (35.5) | 74 (52.1) | 0.011 | |
| cN1 | 32.6 | 97 (30.6) | 65 (37.8) | 44 (31.0) | ||
| cN2 | 25.7 | 92 (29.0) | 46 (26.7) | 24 (16.9) | ||
| Neoadjuvant therapy | ||||||
| None | 32.6 | 107 (34.9) | 48 (27.7) | 48 (33.6) | 0.027 | |
| RT | 31.9 | 89 (29.0) | 72 (41.6) | 38 (26.6) | ||
| CRT | 35.5 | 111 (36.2) | 53 (30.6) | 57 (39.9) | ||
Open in a separate window
Values are n (%) unless otherwise stated. LOREC, LOw REctal Cancer; L-centre, laparoscopic TME centre; R-centre, robotic TME centre; Ta-centre, transanal total mesorectal excision centre; ARJ, anorectal junction; i.q.r., interquartile range; MRF, mesorectal fascia; cT, clinical tumour; cN, clinical nodal; cM, clinical metastasis; RT, radiotherapy; CRT, chemoradiotherapy.
Oncological outcomes
Table 2 displays the operative, postoperative and oncological outcomes. The R1 rate of the total cohort was 6.5%. L-centres showed a trend towards superior R1 rate (CRM+ and/or DRM+) with 4.4% versus 8.7% in R-centres and 8.4% in Ta-centres, P = 0.107. Overall CRM positivity rate was 5.5%, with again comparable numbers among all expert technique centres (L-centres 3.8%, R-centres 6.9%, Ta-centres 7.7%, P = 0.153). Restorative procedures showed a trend towards lower CRM+ margins with 2.3% compared with 7.1%, P = 0.305. The DRM+ rate and incompleteness of TME were also comparable among all three technique centres.
Table2
Operative and postoperative outcomes MRI-defined LOREC patients, 2015–2017
| Operative and postoperative outcomes | Total n = 633 (%) | LOREC | ||||
|---|---|---|---|---|---|---|
| L-centre n = 317 | R-centre n = 173 | Ta-centre n = 143 | P value | |||
| Technique used | ||||||
| Open | 3.8 | 16 (5.0) | 2 (1.2) | 6 (4.2) | <0.001 | |
| Lap | 53.0 | 283 (89.3) | 12 (7.0) | 40 (28.0) | ||
| TaTME | 17.4 | 12 (3.8) | 1 (0.6) | 97 (67.8) | ||
| Robot | 25.8 | 6 (1.9) | 157 (91.3) | 0 (0.0) | ||
| Procedure | ||||||
| Restorative | 33.7 | 78 (24.6) | 64 (37.2) | 71 (49.7) | <0.001 | |
| Non-restorative | 66.3 | 239 (75.4) | 107 (62.8) | 72 (50.3) | ||
| Diverting stoma* | ||||||
| No | 40.8 | 30 (38.5) | 17 (26.6) | 40 (56.3) | <0.001 | |
| Diverting ileostomy | 63.4 | 51 (16.1) | 50 (29.1) | 34 (23.8) | ||
| End colostomy | 63.5 | 231 (72.9) | 104 (60.1) | 67 (46.9) | <0.001 | |
| Converted procedures | ||||||
| Total | 4.1 | 16 (5.0) | 4 (2.3) | 6 (4.2) | 0.344 | |
| Restorative | 2.8 | 1 (1.3) | 2 (3.1) | 4 (5.6) | 0.334 | |
| Non-restorative | 4.5 | 15 (6.3) | 2 (1.9) | 2 (2.7) | ||
| Operating time (min), median (i.q.r.) | 178 (135–274) | 160 (135–195) | 195 (147–243) | 218 (171–274) | <0.001 | |
| Intraoperative complication | Yes | 5.7 | 16 (5.0) | 12 (6.9) | 8 (5.6) | 0.688 |
| Complications | CD ≥III | 21.5 | 70 (22.1) | 33 (19.2) | 33 (23.1) | 0.645 |
| Anastomotic leakage* | ||||||
| Total | 23.9 | 18 (23.1) | 15 (23.4) | 18 (25.0) | 0.942 | |
| Early (<30 days) | 86.3 | 15 (83.3) | 13 (86.7) | 16 (88.9) | 0.986 | |
| Late (>30 days) | 13.7 | 3 (16.7) | 2 (13.3) | 2 (11.1) | ||
| Leak grade (ISREC) | ||||||
| A | 15.7 | 2 (10.5) | 0 (0.0) | 6 (33.3) | 0.026 | |
| B | 49.0 | 13 (68.4) | 8 (53.3) | 5 (27.8) | ||
| C | 35.3 | 4 (21.1) | 7 (46.7) | 7 (38.9) | ||
| Reintervention | <30 days | 18.3 | 61 (19.2) | 28 (16.3) | 27 (18.9) | 0.692 |
| Secondary stoma | ||||||
| Ileostomy | 2.8 | 0 | 1 (1.6) | 5 (7.0) | 0.327 | |
| Colostomy | 4.2 | 3 (3.8) | 3 (4.7) | 3 (4.2) | ||
| Readmission | <30 days | 15.0 | 46 (14.5) | 25 (14.5) | 24 (16.8) | 0.796 |
| Pathological outcomes | ||||||
| R1 | Total | 6.5 | 14 (4.4) | 15 (8.7) | 12 (8.4) | 0.107 |
| CRM ≤1 mm | ||||||
| Total | 5.5 | 12 (3.8) | 12 (6.9) | 11 (7.7) | 0.153 | |
| Restorative | 2.3 | 0 | 2 (3.1) | 3 (4.2) | 0.305 | |
| Non-restorative | 7.1 | 12 (5.0) | 10 (9.3) | 8 (11.1) | ||
| DRM ≤1 mm | Total | 0.9 | 2 (0.6) | 3 (1.7) | 1 (0.7) | 0.456 |
| Incomplete TME | Total | 7.4 | 24 (7.6) | 16 (9.2) | 7 (4.9) | 0.337 |
| Composite endpoint† | Total | 13.1 | 38 (12.0) | 27 (15.6) | 18 (12.6) | 0.514 |
| Oncological outcomes | ||||||
| Follow-up | months | 35.3 | 36.0 | 34.6 | 34.7 | 0.374 |
| Local recurrence | 3-year | 5.9 | 19 (6.1) | 12 (6.7) | 6 (4.2) | 0.809 |
| Systemic recurrence | 3-year | 18.8 | 63 (19.8) | 35 (20.4) | 20.9 (14.6) | 0.373 |
| Disease-free survival | 3-year | 73.3 | 236 (74.6) | 120 (69.3) | 108 (75.6) | 0.347 |
| Overall survival | 3-year | 88.3 | 285 (90.0) | 148 (85.5) | 125 (87.5) | 0.436 |
Open in a separate window
Values are n (%) unless otherwise stated. *Diverting stoma and anastomotic leakage rates are calculated over the restorative procedures. †Composite endpoint consists of a positive resection margin with incompleteness of TME. LOREC, LOw REctal Cancer; L-centre, laparoscopic TME centre; R-centre, robotic TME centre; Ta-centre, transanal total mesorectal excision centre; lap, laparoscopic TME procedure; TaTME, transanal TME procedure; robot, robotic-assisted TME procedure; i.q.r., interquartile range; CD, Clavien–Dindo; ISREC, International Study Group of Rectal Cancer; R1, positive resection margin; CRM, circumferential resection margin; DRM, distal resection margin; TME, total mesorectal excision.
Median follow-up was 35.3 months with comparable 3-year local recurrence (4.2–6.7%, P = 0.809), systemic recurrence (14.6–20.4%, P = 0.373), disease-free survival (69.3–75.6%, P = 0.347) and overall survival (85.5–90.0%, P = 0.436).
Multivariable analysis for a positive circumferential resection margin (Table 3) showed that a threatened margin on preoperative MRI (MRF+) was the only independent risk factor (OR 4.77, P < 0.001).
Table3
Multivariable analysis for risk on positive circumferential resection margin
| CRM+ | LOREC | |||
|---|---|---|---|---|
| OR | 95% c.i. | P value | ||
| Technique | ||||
| Lap | Ref. | Ref. | Ref. | |
| Rob | NS | |||
| TaTME | NS | |||
| Age (years) | 70–80 years | NS | ||
| BMI (kg/m2) | NS | |||
| Sex | Male | NS | ||
| ASA | III/IV | NS | ||
| Abdominal history | Yes | NS | ||
| Distance to ARJ | 0–4 cm | NS | ||
| Tumour diameter | >50 mm | NS | ||
| MRF+ | ≤1 mm | 4.77 | 2.07,11.21 | <0.001 |
| cT-stage | cT4 | NS | ||
| cN-stage | cN+ | NS | ||
| cM-stage | cM1 | NS | ||
| Neoadjuvant therapy | Yes | NS | ||
Open in a separate window
LOREC, LOw REctal Cancer; OR, odds ratio; Lap, laparoscopic TME; Rob, robotic TME; TaTME, transanal total mesorectal excision; Ref., reference; NS, non-significant; ARJ, anorectal junction; MRF, mesorectal fasia; cT, clinical tumour; cN, clinical node; cM, clinical metastasis.
Intraoperative and postoperative outcomes
As documented in Table 2, the operations used in the different centres were consistent with their expertise. In laparoscopic expert centres 89.9% of procedures were laparoscopic, 3.8% were TaTME, 1.9% were robot assisted and 5.0% were open surgeries. In robot-assisted expert centres 91.3% were robot assisted, whereas 1.2%, 0.6% and 1.2% were laparoscopic, TaTME and open procedures respectively. Finally, in TaTME expert centres 67.8% were TaTME, 28.0% were laparoscopic, 0% were robot assisted and 4.2% were open procedures.
Ta-centres had the highest rate of restorative surgery (49.7%) followed by R-TME (37.2%), with the lowest rate of restorative procedures found in L-TME centres at 24.6%, P < 0.001. Among the restorative patients, Ta-centres opted not to construct a temporary stoma in 56.3% of cases, compared with 9.5% in L-centres and 26.5% in R-centres, P = <0.001.
The overall conversion rate in the entire LOREC group was 4.1%. The conversion rate was comparable among the expert technique centres with a trend towards less conversion in R-centres at 2.3%, compared with 5.0% in L-TME and 4.2% in TaTME, P = 0.344. Conversion was also comparable among restorative and non-restorative procedures, P = 0.334.
The overall anastomotic leakage rate increased from 13.7% after 30 days to 23.9% at the end of follow-up. The majority of the early leaks were grade B or C. Comparable numbers of major complications (Clavien–Dindo ≥ III, P = 0.645), reinterventions (P = 0.692) and readmissions (P = 0.796) were found.
Table 4 displays the agreed preoperative plan, the final procedure, final approach and the change in procedure or approach. In 10.4% of the patients treated in L-centres there was a change in procedural management, compared with 5.2% in R-centres and 2.1% in Ta-centres, P = 0.004. The majority of these changes were a change from a restorative procedure to a non-restorative procedure (5.1%), with the highest number occurring in the L-centres (9.6%) compared with R-centres (5.6%) and Ta-centres (4.2%), P = 0.033.
Table4
Change in preoperative management plan and outcome for MRI-defined LOREC patients, 2015–2017
| Change of management and outcome | LOREC | ||||
|---|---|---|---|---|---|
| Total n = 633 | L-centre n = 317 | R-centre n = 173 | Ta-centre n = 143 | P value | |
| Intended procedure | |||||
| LAR + anastomosis | 236 (37.3) | 95 (30.0) | 68 (39.5) | 73 (51.0) | <0.001 |
| LAR + colostomy | 68 (10.8) | 45 (14.2) | 8 (4.7) | 15 (10.5) | |
| APR | 310 (49.1) | 163 (51.4) | 94 (54.7) | 53 (37.1) | |
| Unknown | 18 (2.8) | 14 (4.4) | 2 (1.2) | 2 (1.4) | |
| Surgical procedure | |||||
| LAR + anastomosis | 213 (33.7) | 78 (24.6) | 64 (37.2) | 71 (49.7) | 0.001 |
| LAR + colostomy | 77 (12.2) | 54 (17.0) | 8 (4.7) | 15 (10.5) | |
| APR | 342 (54.1) | 185 (58.4) | 100 (58.1) | 57 (39.9) | |
| Change in procedural plan | |||||
| No | 587 (92.9) | 284 (89.6) | 163 (94.8) | 140 (97.9) | 0.004 |
| Yes | 45 (7.1) | 33 (10.4) | 9 (5.2) | 3 (2.1) | |
| Change in procedure | |||||
| TEM -> LAR | – | – | – | – | 1.000 |
| Non-rest -> Rest | 3 (0.5) | 1 (0.3) | 2 (1.2) | – | 0.287 |
| Non-rest -> Non-rest | 10 (1.6) | 9 (2.8) | 1 (0.6) | – | 0.134 |
| −Hartmann -> APE | 8 (1.3) | 7 (2.2) | 1 (0.6) | – | |
| −APE -> Hartmann | 2 (0.3) | 2(0.6) | – | – | |
| Rest -> Non-rest | 32 (5.1) | 23 (7.3)* | 6 (3.5) | 3 (2.1)* | 0.033 |
| −Hartmann | 12 (1.9) | 11 (3.5) | 1 (0.6) | 0 (0.0) | |
| −APE | 20 (3.2) | 12 (3.8) | 5 (2.9) | 3 (2.1) | |
| Cause of change in plan† | |||||
| Low tumour | 12 (28.6) | 5 (15.6) | 6 (85.7) | 1 (33) | |
| Stapling difficulty | 18 (42.9) | 18 (56.3) | – | – | |
| Functional outcome | 3 (7.1) | 3 (9.4) | – | – | |
| Vascularization | 1 (2.4) | – | – | 1 (33) | |
| Unclear | 6 (14.2) | 5 (15.6) | – | 1 (33) | |
| Other | 2 (4.8) | 1 (3.1) | 1 (14.3) | – | |
Open in a separate window
Values are n (%). *Difference is significant between L-centre and Ta-centre. †Cause of change of operative plan only given for change from restorative to non-restorative surgery and non-restorative to other non-restorative procedure. LOREC, LOw REctal Cancer; L-centre, laparoscopic TME centre; R-centre, robotic TME centre; Ta-centre, transanal total mesorectal excision centre; LAR, low anterior resection; APE, abdominal perineal excision; TEM, transanal endoscopic microsurgery; rest, restorative; non-rest, non-restorative.
The main reason for change in procedural management was stapling difficulty (n = 18, 42.9%), which was only found in L-centres. Other reasons for a change in management were: low lying tumour (n = 12), expected poor functional outcome (n = 3), vascularization problems of the bowel (n = 1), peritoneal depositions in Douglas (n = 1) and tearing of staple row (n = 1). Distance to the ARJ ≤1 cm (OR 0.25 (95% c.i. 0.083 to 0.59), P = 0.005) and L-TME were independent risk factors for change in the preoperative plan (L-TME: ref; R-TME: OR 0.34 (95% c.i. 0.12 to 0.77), P = 0.024; TaTME: OR 0.17 (95% c.i. 0.027 to 0.59), P = 0.021), see Table 5.
Table5
Multivariable analysis change of preoperative procedural plan
| Change of plan | LOREC OR (95% c.i.) | |
|---|---|---|
| Sex | Male | NS |
| ASA | III/IV | NS |
| History of abdominal surgery | Yes | NS |
| Distance to ARJ (MRI) | ≤1 cm | 0.25 (0.083,0.59) P = 0.005 |
| MRF involvement | ≤1 mm | NS |
| cT4 | Yes | NS |
| cM+ | Yes | NS |
| Neoadjuvant therapy | ||
| RTx | NS | |
| CRT | NS | |
| Technique | ||
| Lap | Ref. | |
| Rob | 0.34 (0.12,0.77) P = 0.024 | |
| TaTME | 0.17 (0.027,0.59) P = 0.021 | |
Open in a separate window
LOREC, LOw REctal Cancer; OR, odds ratio; NS, non-significant; ARJ, anorectal junction; MRI, magnetic resonance imaging; MRF, mesorectal fascia; cT, clinical tumour stage; cM, clinical metastasis stage; RTx, radiotherapy; CRT, chemoradiotherapy; Lap, laparoscopic TME, Rob, robotic-assisted TME; TaTME, transanal total mesorectal excision.
Discussion
This observational, retrospective, multicentre cohort study aimed to evaluate the use of laparoscopic, robot-assisted and transanal minimally invasive techniques in 11 expert centres for LOREC based on the MRI-defined LOREC definition. The main finding is that high-quality oncological outcomes can be achieved with all three techniques, even in LOREC. Additionally, although conversion rate was comparable between the groups, the rate of change of intended procedure was significantly higher in the L-centres.
The comparable and high-quality oncological outcomes align with the findings of a recent meta-analysis which showed comparable outcomes in oncologic efficacy for all three minimally invasive techniques25. The CRM+ rates observed in this study are favourable when compared with results from recent RCTs comparing minimally invasive techniques for rectal cancer, considering both LOREC and non-LOREC patients4,26–29. For instance, the COLOR (COlon cancer Laparoscopic or Open Resection) II-trial, which analysed tumours in the low rectum (<5 cm), separately found CRM+ rates of 9% in L-TME and 22% in open TME28. However, a more recent Dutch LOREC study with a similar cut-off of 5 cm from the anal verge found a CRM+ rate of 5.2%30. In the latter study, the mesorectal fascia was less often threatened (29.2% versus 34.5%), a known risk factor for a positive resection margin, as also shown in the current multivariable analysis, Table 430,31. The higher rate of CRM+ in the non-restorative cases is also consistent with contemporary literature30,32.
Interestingly, in R-centres and Ta-centres restorative surgery rates were higher (37.2% and 49.7%) when compared with L-centres (24.6%). Thus it seems that with the newer techniques the creation of an anastomosis is attempted more often. This is also seen in the recently published REAL trial comparing L-TME with R-TME. The fabrication of a low anastomosis is known to be more at risk for anastomotic leakage33. The anastomotic leakage rate among the three expert technique centres was spread evenly among the restorative procedures per expert technique centre, averaging 23.9%. Although this appears very high, anastomotic leak rates of around 20% are common when including late leakages (beyond 30 days)34–36.
While lower conversion rates might have been expected with R-TME or TaTME, these were actually comparable and most likely reflect the expertise of surgeons beyond their learning curve37. An interesting finding in the present study is the analysis of change of preoperative procedural plan during the procedure, which can be interpreted as a different type of conversion of the operation38. The majority of the procedural changes were observed in the L-TME group followed by R-TME and TaTME surgery, P = 0.004. The majority (70%) of these L-TME changes of plan were from a restorative procedure to a non-restorative procedure. The main reason for a change of management was difficulty with distal stapling, which was only reported for L-TME. The use of the Transanal rectal Transection with a Single Stapled (TTSS) anastomosis technique avoids distal stapling, even in L-TME and R-TME, by enabling a single stapled double pursestring anastomosis via a transanal approach without the need for a full transanal TME dissection39. However, low location of the tumour was found in all three techniques and could be a consequence of pushing the boundaries of the technique and/or misjudgment of the resection margins before surgery. This, despite improvements in diagnostic imaging, still remains one of the main reasons for changes in perioperative decision-making40.
Unfortunately, as is the case with a lot of retrospective reports, important information about quality of life after TME surgery is lacking41,42. However, a study in this field and a systematic review both showed that patients value not having a stoma in combination with being cured of cancer, whilst avoiding complications, as the most important factors in colorectal surgical care treatment43,44. It can be hypothesized that the impact of a change of preoperative management into an unexpected permanent stoma is even greater. For this reason, when encountering a LOREC patient, referral to an expert R-centre or Ta-centre can be considered.
The strength of this study lies in the ability to compare all three minimally invasive techniques side by side, utilizing a standardized MRI-based, reproducible classification method for LOREC. It is unique in describing the preoperative intent and how this differs from the final procedure. Several limitations should also be mentioned. Selection bias is of potential concern because of the retrospective collection of all operative cases (including non-dedicated procedures) from selected expert centres in The Netherlands. However, in multivariable analysis we corrected for the dedicated technique used. Although the entire cohort is of reasonable size, the group sizes per technique differ. This might have caused some factors not showing significance despite absolute differences between groups.
With all three minimally invasive TME techniques a high-quality oncological resection can be achieved in the treatment of MRI-defined LOREC. Higher rates of non-restorative procedures were observed in L-centres, and patients are prone to an intraoperative change in the surgical plan. For patients with LOREC with an explicit wish for a restorative procedure, referral to an experienced robotic or Ta-centre could be considered.
Acknowledgements
We would like to thank Susan van Dieren, statistician of the Amsterdam Medical Center, for her help with the analysis. Authors M.L.R. and T.A.B. contributed equally to this study.
Contributor Information
Marieke L Rutgers, Department of Surgery, Amsterdam University Medical Centre, Amsterdam, The Netherlands.
Thijs A Burghgraef, Department of Surgery, Meander Medical Centre, Amersfoort, The Netherlands. Department of Surgery, University Medical Centre, Groningen, The Netherlands.
Jeroen C Hol, Department of Surgery, Amsterdam University Medical Centre, Amsterdam, The Netherlands. Department of Surgery, Hospital Gelderse Vallei, Ede, The Netherlands.
Rogier M Crolla, Department of Surgery, Amphia Hospital, Breda, The Netherlands.
Nanette A van Geloven, Department of Surgery, Tergooi Hospital, Hilversum, The Netherlands.
Jeroen W Leijtens, Department of Surgery, Laurentius Hospital, Roermond, The Netherlands.
Fatih Polat, Department of Surgery, Canisius Wilhelmina Hospital, Nijmegen, The Netherlands.
Apollo Pronk, Department of Surgery, Diakonessenhuis, Utrecht, The Netherlands.
Anke B Smits, Department of Surgery, St. Antonius Hospital, Nieuwegein, The Netherlands.
Jurriaan B Tuyman, Department of Surgery, Amsterdam University Medical Centre, Amsterdam, The Netherlands.
Emiel G Verdaasdonk, Department of Surgery, Jeroen Bosch Hospital, Den Bosch, The Netherlands.
Colin Sietses, Department of Surgery, Hospital Gelderse Vallei, Ede, The Netherlands.
Esther C Consten, Department of Surgery, Meander Medical Centre, Amersfoort, The Netherlands. Department of Surgery, University Medical Centre, Groningen, The Netherlands.
Roel Hompes, Department of Surgery, Amsterdam University Medical Centre, Amsterdam, The Netherlands.
Funding
The authors have no funding to declare.
Disclosure
R.M.P.C. and E.C.J.C. received fees from Intuitive Surgical. C.S. received surgical lecturing fees from Medtronic. The authors declare no other conflict of interest.
Data availability
The data that support the findings of this study are available upon request from the corresponding author, R.H. The data are not publicly available due to information that could compromise the privacy of research participants, however most information is also accessible from the DCRA (Dutch ColoRectal Audit) upon request.
Author contributions
Marieke Rutgers (Data curation, Formal analysis, Writing—original draft, Writing—review & editing), Thijs Burghgraef (Data curation, Formal analysis, Writing—original draft, Writing—review & editing), Jeroen Hol (Data curation, Writing—review & editing), Rogier Crolla (Data curation, Methodology, Supervision, Writing—review & editing), Nanette van Geloven (Data curation, Supervision, Writing—review & editing), Jeroen Leijtens (Data curation, Supervision, Writing—review & editing), Fatih Polat (Data curation, Supervision, Writing—review & editing), Apollo Pronk (Data curation, Supervision, Writing—review & editing), Anke Smits (Data curation, Supervision, Writing—review & editing), Jurriaan Tuynman (Conceptualization, Data curation, Supervision, Writing—original draft, Writing—review & editing), Emiel Verdaasdonk (Data curation, Supervision, Writing—review & editing), Colin Sietses (Conceptualization, Data curation, Supervision, Writing—review & editing), Esther Consten (Conceptualization, Data curation, Supervision, Writing—original draft, Writing—review & editing) and Roel Hompes (Conceptualization, Data curation, Formal analysis, Supervision, Writing—original draft, Writing—review & editing)
References
1. Heald RJ, Husband EM, Ryall RD. The mesorectum in rectal cancer surgery–the clue to pelvic recurrence? Br J Surg 1982;69:613–616 [PubMed] [Google Scholar]
2. Kapiteijn E, Putter H, van de Velde CJ; Cooperative investigators of the Dutch ColoRectal Cancer Group . Impact of the introduction and training of total mesorectal excision on recurrence and survival in rectal cancer in The Netherlands. Br J Surg 2002;89:1142–1149 [PubMed] [Google Scholar]
3. Cecil TD, Taffinder N, Gudgeon AM. A personal view on laparoscopic rectal cancer surgery. Colorectal Dis 2006;8:30–32 [PubMed] [Google Scholar]
4. Jayne D, Pigazzi A, Marshall H, Croft J, Corrigan N, Copeland J et al. Effect of robotic-assisted vs conventional laparoscopic surgery on risk of conversion to open laparotomy among patients undergoing resection for rectal cancer: the ROLARR randomized clinical trial. JAMA 2017;318:1569–1580 [PMC free article] [PubMed] [Google Scholar]
5. Van Oostendorp SE, Koedam TWA, Sietses C, Bonjer HJ, Tuynman JB. Transanal total mesorectal excision compared to laparoscopic TME for mid and low rectal cancer—current evidence. ALES 2018;3:41 [Google Scholar]
6. Lee L, de Lacy B, Gomez Ruiz M, Liberman AS, Albert MR, Monson JRT et al. A multicenter matched comparison of transanal and robotic total mesorectal excision for mid and low-rectal adenocarcinoma. Ann Surg 2019;270:1110–1116 [PubMed] [Google Scholar]
7. Caycedo-Marulanda A, Lee L, Chadi SA, Verschoor CP, Crosina J, Ashamalla S et al. Association of transanal total mesorectal excision with local recurrence of rectal cancer. JAMA Netw Open 2021;4:e2036330. [PMC free article] [PubMed] [Google Scholar]
8. Kusters M, Slater A, Betts M, Hompes R, Guy RJ, Jones OM et al. The treatment of all MRI-defined low rectal cancers in a single expert centre over a 5-year period: is there room for improvement? Colorectal Dis 2016;18:O397–O404 [PubMed] [Google Scholar]
9. D'Souza N, de Neree Tot Babberich MPM, Lord A, Shaw A, Abulafi M, Tekkis P et al. The rectosigmoid problem. Surg Oncol 2018;27:521–525 [PubMed] [Google Scholar]
10. Memon S, Keating JP, Cooke HS, Dennet ER. A study into external rectal anatomy: improving patient selection for radiotherapy for rectal cancer. Dis Colon Rectum 2009;52:87–90 [PubMed] [Google Scholar]
11. Wasserman MA, McGee MF, Helenowski IB, Halverson AL, Boller AM, Stryker SJ. The anthropometric definition of the rectum is highly variable. Int J Colorectal Dis 2016;31:189–195 [PubMed] [Google Scholar]
12. Yun HR, Chun HK, Lee WS, Cho YB, Yun SH, Lee WY. Intra-operative measurement of surgical lengths of the rectum and the peritoneal reflection in Korean. J Korean Med Sci 2008;23:999–1004 [PMC free article] [PubMed] [Google Scholar]
13. Beets-Tan RGH, Lambregts DMJ, Maas M, Bipat S, Barbaro B, Curvo-Semedo L et al. Magnetic resonance imaging for clinical management of rectal cancer: updated recommendations from the 2016 European Society of Gastrointestinal and Abdominal Radiology (ESGAR) consensus meeting. Eur Radiol 2018;28:1465–1475 [PMC free article] [PubMed] [Google Scholar]
14. D'Souza N, Lord A, Shaw A, Patel A, Balyasnikova S, Tudyka V et al. The sigmoid take-off: an anatomical imaging definition of the rectum validated on specimen analysis. Eur J Surg Oncol 2020;46:1668–1672 [PubMed] [Google Scholar]
15. Roodbeen SX, Penna M, Mackenzie H, Kusters M, Slater A, Jones OM et al. Transanal total mesorectal excision (TaTME) versus laparoscopic TME for MRI-defined low rectal cancer: a propensity score-matched analysis of oncological outcomes. Surg Endosc 2019;33:2459–2467 [PMC free article] [PubMed] [Google Scholar]
16. Wasmuth HH, Faerden AE, Myklebust TÅ, Pfeffer F, Norderval S, Riss R et al. Transanal total mesorectal excision for rectal cancer has been suspended in Norway. Br J Surg 2020;107:121–130 [PubMed] [Google Scholar]
17. Koedam TWA, Veltcamp Helbach M, van de Ven PM, Kruyt PM, van Heek NT, Bonjer HJ et al. Transanal total mesorectal excision for rectal cancer: evaluation of the learning curve. Tech Coloproctol 2018;22:279–287 [PubMed] [Google Scholar]
18. Lee L, Kelly J, Nassif GJ, deBeche-Adams TC, Albert MR, Monson JRT. Defining the learning curve for transanal total mesorectal excision for rectal adenocarcinoma. Surg Endosc 2020;34:1534–1542 [PubMed] [Google Scholar]
19. Persiani R, Agnes A, Belia F, D’Ugo D, Biondi A. The learning curve of TaTME for mid-low rectal cancer: a comprehensive analysis from a five-year institutional experience. Surg Endosc 2021;35:6190–6200 [PMC free article] [PubMed] [Google Scholar]
20. Tang B, Li T, Gao G, Shi J, Li T. Learning curve of robotic-assisted total mesorectal excision for rectal cancer. Front Oncol 2022;12:931426. [PMC free article] [PubMed] [Google Scholar]
21. Burghgraef TA, Sikkenk DJ, Verheijen PM, Moumni ME, Hompes R, Consten ECJ. The learning curve of laparoscopic, robot-assisted and transanal total mesorectal excisions: a systematic review. Surg Endosc 2022;36:6337–6360 [PMC free article] [PubMed] [Google Scholar]
22. Castor electronic data capture system [Castor website] 1 August 2022. Available at: https://www.castoredc.com/electronic-data-capture-system/ (accessed 31 August 2022)
23. Clavien PA, Strasberg SM. Severity grading of surgical complications. Ann Surg 2009;250:197–198 [PubMed] [Google Scholar]
24. Rahbari NN, Weitz J, Hohenberger W, Heald RJ, Moran B, Ulrich A et al. Definition and grading of anastomotic leakage following anterior resection of the rectum: a proposal by the International Study Group of Rectal Cancer. Surgery 2010;147:339–351 [PubMed] [Google Scholar]
25. Ryan OK, Ryan ÉJ, Creavin B, Rausa E, Kelly ME, Petrelli F et al. Surgical approach for rectal cancer: a network meta-analysis comparing open, laparoscopic, robotic and transanal TME approaches. Eur J Surg Oncol 2021;47:285–295 [PubMed] [Google Scholar]
26. Fleshman J, Branda M, Sargent DJ, Boller AM, George V, Abbas M et al. Effect of laparoscopic-assisted resection vs open resection of stage II or III rectal cancer on pathologic outcomes: the ACOSOG Z6051 randomized clinical trial. JAMA 2015;314:1346–1355 [PMC free article] [PubMed] [Google Scholar]
27. Stevenson AR, Solomon MJ, Lumley JW, Hewett P, Clouston AD, Gebski WJ et al. Effect of laparoscopic-assisted resection vs open resection on pathological outcomes in rectal cancer: the ALaCaRT randomized clinical trial. JAMA 2015;314:1356–1363 [PubMed] [Google Scholar]
28. van der Pas MH, Haglind E, Cuesta MA, Furst A, Lacy AM, Hop WCJ et al. Laparoscopic versus open surgery for rectal cancer (COLOR II): short-term outcomes of a randomised, phase 3 trial. Lancet Oncol 2013;14:210–218 [PubMed] [Google Scholar]
29. Kang SB, Park JW, Jeong SY, Nam BH, Choi HS, Kim DW et al. Open versus laparoscopic surgery for mid or low rectal cancer after neoadjuvant chemoradiotherapy (COREAN trial): short-term outcomes of an open-label randomised controlled trial. Lancet Oncol 2010;11:637–645 [PubMed] [Google Scholar]
30. Rutgers ML, Detering R, Roodbeen SX, Crolla RM, Dekker JWT, Tuynman JB et al. Influence of minimally invasive resection technique on sphincter preservation and short-term outcome in low rectal cancer in The Netherlands. Dis Colon Rectum 2021;64:1488–1500 [PubMed] [Google Scholar]
31. Nagtegaal ID, Quirke P. What is the role for the circumferential margin in the modern treatment of rectal cancer? J Clin Oncol 2008;26:303–312 [PubMed] [Google Scholar]
32. European Society of Coloproctology (ESCP) collaborating group . An international multicentre prospective audit of elective rectal cancer surgery; operative approach versus outcome, including transanal total mesorectal excision (TaTME). Colorectal Dis 2018;20:33–46 [PubMed] [Google Scholar]
33. Bertelsen CA, Andreasen AH, Jørgensen T, Harling H; Danisch Colorectal Cancer Group . Anastomotic leakage after anterior resection for rectal cancer: risk factors. Colorectal Dis 2010;12:37–43 [PubMed] [Google Scholar]
34. Biondo S, Trenti L, Espin E, Bianco F, Barrios O, Falato A. Two-stage Turnbull-Cutait pull-through coloanal anastomosis for low rectal cancer: a randomized clinical trial. JAMA Surg 2020;155:e201625. [PMC free article] [PubMed] [Google Scholar]
35. Denost Q, Rouanet P, Faucheron JL, Panis Y, Meunier B, Cotte E et al. To drain or not to drain infraperitoneal anastomosis after rectal excision for cancer: the GRECCAR 5 randomized trial. Ann Surg 2017;265:474–480 [PubMed] [Google Scholar]
36. Borstlap WAA, Westerduin E, Aukema TS, Bemelman WA, Tanis PJ; Dutch Snapshot Research Group . Anastomotic leakage and chronic presacral sinus formation after low anterior resection: results from a large cross-sectional study. Ann Surg 2017;266:870–877 [PubMed] [Google Scholar]
37. Chan AC, Poon JT, Fan JK, Lo SH, Law WL. Impact of conversion on the long-term outcome in laparoscopic resection of colorectal cancer. Surg Endosc 2008;22:2625–2630 [PubMed] [Google Scholar]
38. Flin R, Youngson G, Yule S. How do surgeons make intraoperative decisions? Qual Saf Health Care 2007;16:235–239 [PMC free article] [PubMed] [Google Scholar]
39. Spinelli A, Carvello M, D'Hoore A, Foppa C. Integration of transanal techniques for precise rectal transection and single-stapled anastomosis: a proof of concept study. Colorectal Dis 2019;21:841–846 [PubMed] [Google Scholar]
40. Schwarz RE. Factors influencing change of preoperative treatment intent in a gastrointestinal cancer practice. World J Surg Oncol 2007;5:32. [PMC free article] [PubMed] [Google Scholar]
41. Emmertsen KJ, Laurberg S; Rectal Cancer Function Study Group . Impact of bowel dysfunction on quality of life after sphincter-preserving resection for rectal cancer. Br J Surg 2013;100:1377–1387 [PubMed] [Google Scholar]
42. Battersby NJ, Juul T, Christensen P, Janjua AZ, Branagan G, Emmertsen KJ et al. Predicting the risk of bowel-related quality-of-life impairment after restorative resection for rectal cancer: a multicenter cross-sectional study. Dis Colon Rectum 2016;59:270–280 [PubMed] [Google Scholar]
43. Wrenn SM, Cepeda-Benito A, Ramos-Valadez DI, Cataldo PA. Patient perceptions and quality of life after colon and rectal surgery: what do patients really want? Dis Colon Rectum 2018;61:971–978 [PubMed] [Google Scholar]
44. Currie A, Askari A, Nachiappan S, Sevdalis N, Faix O, Kennedy R. A systematic review of patient preference elicitation methods in the treatment of colorectal cancer. Colorectal Dis 2015;17:17–25 [PubMed] [Google Scholar]
Articles from BJS Open are provided here courtesy of Oxford University Press
