NATIONAL INSTITUTE FOR HEALTH AND CARE EXCELLENCE

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1 NATIONAL INSTITUTE FOR HEALTH AND CARE EXCELLENCE INTERVENTIONAL PROCEDURES PROGRAMME Transanal total mesorectal excision of the rectum This procedure is used for patients who need to have their whole rectum removed (for example, patients with rectal cancer or chronic inflammatory bowel disease that has not responded well enough to treatment). The rectum is removed using instruments introduced through the anus, combined with laparoscopic (keyhole) surgery through the abdomen, rather than through a long incision in the lower abdomen. Introduction The National Institute for Health and Care Excellence (NICE) has prepared this interventional procedure (IP) overview to help members of the Interventional Procedures Advisory Committee (IPAC) make recommendations about the safety and efficacy of an interventional procedure. It is based on a rapid review of the medical literature and specialist opinion. It should not be regarded as a definitive assessment of the procedure. Date prepared This IP overview was prepared in April Procedure name Transanal total mesorectal excision of the rectum Specialist societies Association of Coloproctology of Great Britain and Ireland British Association of Surgical Oncology (BASO). Page 1 of 50

2 Description Indications and current treatment Transanal total mesorectal excision (TaTME) can be used to treat malignant or benign disease of the rectum. Malignant disease: The incidence of rectal cancer rises sharply with age. Symptoms include rectal bleeding and change in bowel habit, although the early stages may be asymptomatic. Treatment of rectal cancer depends upon its stage which is conventionally assessed using Dukes classification system: stage A confined to the lining of the rectum stage B grown into the muscle wall stage C spread to at least one lymph node in the area stage D spread to another organ in the body. Surgery is the main treatment modality for patients with locally confined disease. It involves resection of the affected part of the rectum, with or without preservation of the anus (and formation of a colostomy when preservation of the anus is not technically possible). Adjunctive radiotherapy and chemotherapy may also be used to reduce the risk of local recurrence and prevent metastatic disease. Benign disease: Benign conditions that may lead to the need for resection of the rectum include ulcerative colitis and Crohn s disease. Both are chronic conditions, characterised by periods of clinical relapse and remission. Treatment depends on the severity and extent of the disease and is aimed at reducing the frequency and severity of recurrences. Drug therapy, which may include corticosteroids and immunosuppressive agents (such as azathioprine), usually controls the disease adequately. For more severe cases, treatment with a monoclonal antibody (such as infliximab) may be considered. Surgical removal of the affected areas may be necessary for severe cases that don t respond to medical treatment. What the procedure involves TaTME aims to improve the clinical outcome of rectal excision, and to reduce the length of stay in hospital and morbidity after surgery. It may facilitate proctectomy that would otherwise be difficult in people with a narrow pelvis or high body mass index or where the position of the tumour is low in the rectum. Page 2 of 50

3 Before surgery, the patient has bowel preparation and prophylactic antibiotics. With the patient under general anaesthesia and in the lithotomy position, an operating platform is inserted into the anus using endoscopic guidance. Laparoscopic instruments are usually inserted at this stage in order to assist with identification of the plane of excision for mesorectal dissection, mobilisation of the left colon and subsequent creation of an ileostomy. Dissection of the rectum is done through the anal platform. A purse-string suture is used to close the rectal lumen and then full-thickness proctectomy is done. The specimen can be removed through the transanal platform or, if the tumour is large, through the abdomen using a laparoscope. Anastomosis to connect the colon and the anus can be done using sutures (hand-sewn technique) or staples. When anastomosis is not possible, the patient is given a temporary or permanent colostomy. When an anastomosis is done, a temporary ileostomy is usually created. Outcome measures Quality of the mesorectal excision. Quirke's grading assesses the quality of the mesorectal envelope from 3 indicating a completely intact specimen to 1 indicating an incomplete mesorectal envelope. It is assigned by pathologists. Literature review Rapid review of literature The medical literature was searched to identify studies and reviews relevant to transanal total mesorectal excision of the rectum. Searches were conducted of the following databases, covering the period from their commencement to 16 April 2014: MEDLINE, PREMEDLINE, EMBASE, Cochrane Library and other databases. Trial registries and the Internet were also searched. No language restriction was applied to the searches (see appendix C for details of search strategy). Relevant published studies identified during consultation or resolution that are published after this date may also be considered for inclusion. The following selection criteria (table 1) were applied to the abstracts identified by the literature search. Where selection criteria could not be determined from the abstracts the full paper was retrieved. Page 3 of 50

4 Table 1 Inclusion criteria for identification of relevant studies Characteristic Publication type Patient Intervention/test Outcome Language Criteria Clinical studies were included. Emphasis was placed on identifying good quality studies. Abstracts were excluded where no clinical outcomes were reported, or where the paper was a review, editorial, or a laboratory or animal study. Conference abstracts were also excluded because of the difficulty of appraising study methodology, unless they reported specific adverse events that were not available in the published literature. Patients with benign or malignant rectal disease. Transanal total mesorectal excision of the rectum Articles were retrieved if the abstract contained information relevant to the safety and/or efficacy. Non-English-language articles were excluded unless they were thought to add substantively to the English-language evidence base. List of studies included in the IP overview This IP overview is based on approximately 170 patients from 1 non-randomised comparative study 1 and 9 case series Other studies that were considered to be relevant to the procedure but were not included in the main extraction table (table 2) have been listed in appendix A. Page 4 of 50

5 Table 2 Summary of key efficacy and safety findings on transanal total mesorectal excision of the rectum Study 1 Velthuis S (2014) Details Study type Country Recruitment period Study population and number Age and sex Patient selection criteria Technique Follow-up Conflict of interest/source of funding Non-randomised comparative study Netherlands (for transanal TME) and (for laparoscopic TME) n=50 patients with distal or mid rectum carcinomas (25 transanal TME versus 25 laparoscopic TME) Transanal TME mean 64 years [range 49 to 86 years]; 72% (18/25) male. Laparoscopic TME mean 65 years [range 38 to 81 years]; 72% (18/25) male. Mean BMI: 25 kg/ m 2 [range 20 to 36kg/ m 2 ] (transanal TME) versus mean BMI: 27 kg/ m 2 [range 21 to 34 kg/ m 2 ] (laparoscopic TME) Transanal TME group: consecutive patients with histologically proven distal or mid rectum carcinomas, without evidence of distant metastases. Exclusion criteria: T4 tumours or previous abdominal surgery. Cohort matched for gender and type of procedure with a cohort of patients who underwent traditional laparoscopic low anterior resection (LAR) or abdominoperineal resection (APR) by TME principles. Patients received mechanical bowel preparation before surgery, epidural analgesia for pain control after surgery, and prophylactic antibiotics. Patients were treated according to enhanced recovery after surgery (ERAS) guidelines. Transanal TME: a Scott retractor (Lone Star Medical Products) facilitated the full-thickness circumferential transection. Either a SILS port (Covidien) or a GelPOINT Path Transanal Access Platform (Applied Medical) were introduced into the anus and used for the TME. The laparoscopic part of the procedure was performed using a second SILS Port introduced at the future ileostomy site in the abdomen. A coloanal anastomosis was made either by hand or by using an EEA Haemorrhoid Stapler (Covidien). An ileostomy was created in all patients. Traditional laparoscopic TME: 4 trocars were used. An anastomosis was created by using an EEA Haemorrhoid Stapler (Covidien) after which an ileostomy was created. In case of distal tumours which needed an APR, an intersphincteric dissection was performed before closure of the rectal stump. Not reported. None. Analysis Follow-up issues: none. Study design issues: Matched case control study. The pathologist was not informed about the type of surgery performed. Retrospective study. Both procedures were performed by 2 experienced laparoscopic surgeons. Study population issues: Possible patients overlap with Velthuis 2013 (study 9). 2 groups were similar in the following characteristics: neoadjuvant therapy received, tumour distance to the anal verge, tumour stage, tumour size, lymph nodes status and number of lymph nodes. Mean distance of the tumour to the anal verge comparable in both groups. Neoadjuvant therapy: 76% (19/25) versus 80% (20/25) of patients received radiotherapy, completed 1 week before surgery and 24% (6/25) versus 20% (5/25) of patients received chemoradiotherapy completed 6 weeks before surgery. Other issues: In the first 5 patients, the surgeons started the dissection with the transanal phase. The sequence of phases was then reversed because of nuisance due to pneumatosis of the retroperitoneum while performing the abdominal phase after the transanal phase. Page 5 of 50

6 Key efficacy and safety findings Efficacy Number of patients analysed: 50 (25 transanal TME versus 25 laparoscopic TME) Safety Not reported Resection and staging characteristics Characteristic Number of lymph nodes Transanal TME (n=25) Laparoscopic TME (n=25) P value Mean (range) 14 (7-24) 13 (1-36) 0.42* Length of resected specimen (cm) Median (range) 18 (12-28) 20 (10-80) Circumferential resection margin involvement Positive (<2mm) 4% (1/25) 8% (2/25) Circumferential resection margin (mm) Mean (range) 13 (1.5-30) 12 (0-25) Distal resection margin (mm) Median (range) 23 (5-80) 25 (0-55) * Independent T test Macroscopic quality of mesorectum Mesorectum total Complete Nearly complete Incomplete Mesorectum LAR Complete Nearly complete Incomplete Mesorectum APR Complete Nearly complete Incomplete ** Pearson s chi-squared test Transanal TME (n=25) Laparoscopic TME (n=25) P value 96% (24/25) 72% (18/25) <0.05** 4% (1/25) 8% (2/25) 0 20% (5/25) 100% (19/19) 84% (16/19) 0 5% (1/19) 0 11% (2/19) 83% (5/6) 17% (1/6) 0 Abbreviations used: APR, abdominoperineal resection; ASA, American society of anesthesiology; BMI, body mass index; COPD, chronic obstructive pulmonary disease; CI, confidence interval; CRM, circumferential resection margin; CRT, chemoradiotherapy; ECOG, eastern cooperative oncology group; EEA, end-to-end anastomotic; FOLFOX, 5-FU + oxaliplatin; IMA, inferior mesenteric artery; ISR, intersphincteric resection; LAR, low anterior resection; LN, Lymph nodes; LOS, hospital length of stay; LRR, locoregional recurrence; MRI, magnetic resonance imaging; N, no; POSSUM, physiological and operative severity score for the enumeration of mortality and morbidity; SD, standard deviation; SE, standard error; SILS, single-incision laparoscopic surgery; TAEP, transanal endoscopic proctectomy; TAMIS, transanal minimally invasive surgery; TEMS, transanal endoscopic microsurgery; TEO, transanal endoscopic operation; TES, transanal endoscopic surgery; TME, total mesorectal excision; Y, yes. Page 6 of 50

7 Study 2 Rouanet P (2013) Details Study type Country Case series France Recruitment period Study population and number Age and sex Patient selection criteria Technique Follow-up Conflict of interest/source of funding Analysis n=30 patients with rectal cancer Median 65 years [range 43 to 82 years]; 100% (30/30) male Median BMI: 26 kg/ m 2 [range 21 to 32.4 kg/ m 2 ] All patients underwent laparoscopic resection by using a transanal endoscopic proctectomy (TAEP) procedure for rectal tumours. Indications for TAEP: combination of difficult anatomical conditions such as narrow pelvis (defined as a distance between the ischial tuberosities <10 cm and between the ischial spines< 12cm), fatty mesorectum, high BMI, large prostate, presence of fibrosis, with unfavourable tumour characteristics including a large anterior tumour and a weak predictive anterior radial margin ( 1mm) on MRI. The decision to perform the TAEP was made either preoperatively according to tumour and patient MRI characteristics, or during examination under general anaesthesia, or after unexpected intraoperative findings in relation to the pelvic anatomy or tumour bulk. Transanal endoscopic proctectomy procedure combined with standard laparoscopy. Patients received mechanical bowel preparation the day before surgery and prophylactic antibiotics during the procedure. A TEO proctoscope with a laparoscopic insufflator and a Harmonic scalpel (Ethicon endo-surgery) were used for the transanal dissection. In most cases, the surgeons began the TME dissection posteriorly. After the removal of the TEO device, the TME resection was finished with a classic abdominal laparoscopic approach. The surgeons removed the specimen either by a small suprapubic incision or through the anus and they performed a coloanal anastomosis. In all cases, the surgeons constructed a covering loop ileostomy. Median 21 months None reported. Follow-up issues: overall, 93% (27/29) patients completed the neoadjuvant treatment; 2 patients discontinued chemotherapy because of infectious complications or cardiotoxicity. Study design issues: selection bias related to the study cohort exclusively composed of high-risk patients with locally advanced tumours, sometimes with synchronous metastases. Study population issues: 27% (8/30) patients had a BMI 30 kg/m 2. 97% (29/30) patients received neoadjuvant treatment: 70% (21/30) long-courses chemoradiotherapy, 17% (5/30) induction chemotherapy followed by chemoradiotherapy and 10% (3/30) intensive chemotherapy alone (including 2 for locoregional recurrence and 1 because of previous pelvic radiotherapy). 10% (3/30) of patients had a diagnosis of synchronous liver or lung metastases. Main indications for TAEP: narrow pelvis (77% [23/30]), fatty mesorectum (47% [14/30]), large and anterior tumour (73% [22/30]), previous radiotherapy (7% [2/30]). Other issues: there might be an overlap between 1 death and 1 locoregional recurrence for the clinical outcomes at 21 months. Page 7 of 50

8 Key efficacy and safety findings Efficacy Number of patients analysed: 30 Surgical outcome Surgical outcome Patients TME grading Quirke 3 (=complete) 100% (30/30) Conversion to open surgery Cause: posterior fixity of the tumour 7% (2/30) Median lymph node yield (range) 13 (8-32) Clinical outcome at median 21-month follow-up Outcome Patients Other Disease-free survival Cancer-related deaths Locoregional or distant recurrence Survival estimation 43.3% (13/30) 13.3% (4/30) 40% (12/30) One death due to an isolated locoregional recurrence (LRR) and 1 death caused by cirrhosis. Four patients had a LRR alone (1 developed potentially resectable LRR 2 years after an R1 resection for a ypt3n1 residual tumour; 1 had LRR 6 months after curative resection for an initial pt4 prostate anterior tumour staged ypt2n0 with a CRM of 11mm on specimen; 1 was classified LRR for a persistent disease of a T4 prostatic tumour that remained ypt4r2 on specimen; 1 had perineal skin recurrence cured by abdominoperineal resection). Survival Time Value 95% CI Overall survival 12 months 96.6% 78.0 to 99.5 Overall survival 24 months 80.5% 53.0 to 92.9 Relapse-free survival 12 months 93.3% 75.9 to 98.3 Relapse-free survival 24 months 88.9% 69.0 to 96.3 Pathological findings Characteristic Median CRM, mm (range) 1 >1 Patients 7 (0-17) 13% (4/30) 87% (26/30) Median distal margins, mm (range) 9 (3-40) Curative resection R0 87% (26/30) Median operative time: 304 min (range 120 to 432 min) Median hospitalisation time: 14 days (range 9 to 25 days) Safety Reoperation (< 30 days): 7% (2/30) No 30-day postoperative mortality. Overall 30-day postoperative morbidity rate: 30% (9/30). Postoperative blood transfusion: 20% (6/30) Intraoperative complications Complication Patients Other Urethral injury 6.7% (2/30) 1 due to a difficult dissection of an anterior bulky tumour and 1 due to the presence of a concurrent prostatic carcinoma. These 2 localised wounds were diagnosed and sutured under TEO. The postoperative period was free of any complications for both patients. Air embolism 1 patient Patient showed an oxygen desaturation with suspicion of air embolism after the posterior prostate resection. Postoperative complications Early morbidity (< 30 days) Sepsis Peritonitis Septic shock Bowel obstruction Anastomotic leakage Transient postoperative urinary disorder Patients 6.7% (2/30) 1 patient Other 1 peritonitis was secondary to a minor ileal wound without a direct link with the TAEP procedure. One patient required critical care because of a sepsis (partly explained by his general condition and comorbidities including a lymphoma associated with chronic renal failure and diabetes). 6.7% (2/30) Both patients recovered after medical treatment. 1 patient 6.7% (2/30) Incontinence 12 months after stoma closure: - 15% of patients reported incontinence to liquids, 35% to gas, and 25% had stool fragmentation (only percentages reported). - Median Wexner score (from 0 to 20 with 0 indicating perfect faecal continence and 20 complete faecal incontinence): 11. Page 8 of 50

9 Abbreviations used: APR, abdominoperineal resection; ASA, American Society of Anesthesiology; BMI, body mass index; COPD, chronic obstructive pulmonary disease; CI, confidence interval; CRM, circumferential resection margin; CRT, chemoradiotherapy; ECOG, eastern cooperative oncology group; EEA, end-to-end anastomotic; FOLFOX, 5-FU + oxaliplatin; IMA, inferior mesenteric artery; ISR, intersphincteric resection; LAR, low anterior resection; LN, Lymph nodes; LOS, hospital length of stay; LRR, locoregional recurrence; MRI, magnetic resonance imaging; N, no; POSSUM, physiological and operative severity score for the enumeration of mortality and morbidity; SD, standard deviation; SE, standard error; SILS, single-incision laparoscopic surgery; TAEP, transanal endoscopic proctectomy; TAMIS, transanal minimally invasive surgery; TEMS, transanal endoscopic microsurgery; TEO, transanal endoscopic operation; TES, transanal endoscopic surgery; TME, total mesorectal excision; Y, yes. Page 9 of 50

10 Study 3 Atallah S (2013) Details Study type Country Case series Not reported Recruitment period Study population and number Age and sex Patient selection criteria Technique Follow-up Conflict of interest/source of funding Analysis n=20 patients with rectal cancer Median 57 years [range 36 to 73 years]; 70% (14/20) male Locally advanced rectal cancer of the middle and distal rectum. Distal rectal cancer in combination with obesity and anatomic constraints such as a narrow male pelvis. Transanal total mesorectal excision (TME) using the transanal minimally invasive surgery (TAMIS) platform. TAMIS-TME uses a combined abdominal approach for proximal colonic mobilization and for initiation of the medial to lateral approach, as well as construction of a diverting or permanent stoma. The approach used was laparoscopic + TAMIS-TME in 55% (11/20) of the patients, robotic-assisted + TAMIS-TME in 30% (6/20) of the patients and open + TAMIS-TME in 15% (3/20) of the patients. The abdominal portion of the operation was completed first. For transanal TME using TAMIS, the patient was placed in the dorsal lithotomy position. For TAMIS access, a GelPOINT Path Transanal Access Platform (Applied Medical) was used in 90% (18/20) of the patients and a SILS TM Port (Covidien) was used in 10% (2/20) of the patients. For low-lying tumours, an intersphincteric dissection was started prior to admission of a TAMIS port, under direct vision using an anorectal retractor and electrocautery. For higher lesions, the TAMIS port was introduced first and the purse-string suture was performed at a safe distance from the tumour distally. Median 6 months [range 1 to 24 months] None Follow-up issues: anoscopy, rigid proctosigmoidoscopy, and digital rectal examination were performed every 3 months during the follow-up period. Study design issues: Operations were undertaken by 4 experienced surgeons. Initially, 23 patients were selected to undergo TAMIS-TME but 3 were excluded from further study because their procedures were completed for benign disease (ulcerative colitis). 3 different methods were used for the abdominal portion of the operation as well as variations in the approach to transanal TME. When robotic-assisted + TAMIS-TME approach was used, in one case robotic-assisted transanal surgery was performed. When laparoscopic + TAMIS-TME approach was used, in one case TAMIS-assisted APR was performed. Study population issues: 30% (6/20) patients had a BMI 30 kg/m 2. 85% (17/20) patients received neoadjuvant chemoradiotherapy. Other issues: The TME resection quality was not formally graded for 1 patient. Ileostomy closure was performed within the first 3 months after TAMIS-TME in 64% (9/14) of patients who underwent diversion of the faecal stream. The remaining 36% (5/14) were closed within 1 year. Page 10 of 50

11 Key efficacy and safety findings Efficacy Number of patients analysed: 20 Surgical outcomes Characteristic TME grading Quirke 3 Quirke 2 Quirke (complete or nearly complete mesorectal envelope) Quirke 1 Unknown Value 55% (11/20) 30% (6/20) 85% (17/20) 10% (2/20) 5% (1/20) Lymph node harvest* 22.5 (9-51) Negative surgical margins (distal and circumferential) Recurrence rate *Median (range) Mean operative time: 243 min (range 140 to 495 min) 90% (18/20) 1 patient developed distant metastasis 9 months after surgery (case 4). However he was not eligible to receive adjuvant chemotherapy due to grade III toxicity encountered during neoadjuvant therapy. Mean postoperative hospital length of stay: 4.5 days (range 3 to 24 days) Safety IP 1184 [IPGXXX] No intraoperative complications. No 30-day postoperative mortality. Death at 8 weeks: 1 patient died suddenly, without prodrome, 8 weeks after TAMIS-TME. The cause of death was acute pulmonary embolism. Mean estimated blood loss: 153ml (range 30 to 500 ml) Surgical complications after surgery Early morbidity Patients Pelvic abscess 20% (4/20) Prolonged ileus 20% (4/20) Wound infection 10% (2/20) Pneumonia Acute renal failure Anastomotic leak Late morbidity Anastomotic strictures* Peri-anastomotic fluid collections 1 patient 1 patient 1 patient Patients 20% (4/20) 10% (2/20) *Subclinical structuring noted on physical exam, patients asymptomatic. All surgical complications were managed conservatively and resolved without sequelae except the anastomotic leak which necessitated permanent end colostomy. The anastomotic disruption was secondary to ischemia. Faecal incontinence after ileostomy closure Most patients stated they had mild faecal incontinence (< 1 accident/ day). 5% (1/20) of patients reported lifestylelimiting incontinence which had not improved 12 months post-resection. Abbreviations used: APR, abdominoperineal resection; ASA, American Society of Anesthesiology; BMI, body mass index; COPD, chronic obstructive pulmonary disease; CI, confidence interval; CRM, circumferential resection margin; CRT, chemoradiotherapy; ECOG, eastern cooperative oncology group; EEA, end-to-end anastomotic; FOLFOX, 5-FU + oxaliplatin; IMA, inferior mesenteric artery; ISR, intersphincteric resection; LAR, low anterior resection; LN, Lymph nodes; LOS, hospital length of stay; LRR, locoregional recurrence; MRI, magnetic resonance imaging; N, no; POSSUM, physiological and operative severity score for the enumeration of mortality and morbidity; SD, standard deviation; SE, standard error; SILS, single-incision laparoscopic surgery; TAEP, transanal endoscopic proctectomy; TAMIS, transanal minimally invasive surgery; TEMS, transanal endoscopic microsurgery; TEO, transanal endoscopic operation; TES, transanal endoscopic surgery; TME, total mesorectal excision; Y, yes. Page 11 of 50

12 Study 4 De Lacy AM (2013) Details Study type Country Case series Spain Recruitment period Study population and number Age and sex Patient selection criteria Technique Follow-up Conflict of interest/source of funding Analysis n=20 patients with rectal adenocarcinoma or high-grade dysplasia arising from rectal polyps Mean 65 years [range 44 to 77 years]; 55% (11/20) male Mean BMI: 25.3 kg/ m 2 [range 19 to 33 kg/ m 2 ] Biopsy-proven rectal adenocarcinoma or high-grade dysplasia arising from rectal polyps. Exclusion criteria: BMI>35 kg/m 2, presence of ct4 disease, tumour recurrence, contraindications to pneumoperitoneum. The day before surgery, patients underwent anterograde lavage with Bohn solution. Prophylactic antibiotics were administered intravenously. Patients placed in lithotomy position. Combined transrectal and laparoscopy dissection (using 3 ports) for all cases using a multiport rectal device (GelPOINT Path Transanal; Applied Medical, USA). A 3D flexible-tip endoscope (3D EndoEye 5 mm flexible-tip videolaparoscope; Olympus KeyMed, Europe) was introduced through the single port device. Full-thickness rectal transection was initiated circumferentially and the posterior dissection was done in accordance with TME principles. The mesorectal plane was dissected entirely transanally up to the level of peritoneal reflection in the superior pelvis. In all cases, the specimen was removed transanally. Proximal colonic resection was performed extracorporeally. Pain control via epidural catheter perioperatively. 30 days Dr A Lacy is a consultant for Covidien and Olympus Medical. Dr P Sylla has received an honorarium from Genzyme for consulting and an honorarium from Applied Medical for teaching. Dr Rattner is a consultant for Olympus. Follow-up issues: none Study design issues: none Study population issues: 70% (14/20) patients received neoadjuvant chemoradiotherapy completed 6-8 weeks before surgery. Authors stated study has bias in the selection of patients. 25% patients (5/20) had a previous abdominal surgery. 75% patients had mild systemic disease and 25% patients had severe, non incapacitating systemic disease (American Society of Anesthesiologists classification). 15% (3/20) patients had high-grade dysplasia polyps. Other issues: none Page 12 of 50

13 Key efficacy and safety findings Efficacy Number of patients analysed: 20 Pathological case characteristics Characteristic Value Distal margin* 2.6 ± 1.6 cm (0.7-5) Circumferential margin* 1.8 ± 0.7 cm (0.5-3) Number of retrieved lymph nodes* Number of patients with lymph nodes retrieved > 12 Pathological stage High-grade dysplasia polyps, yptnm stage I II III IV *mean ± SE (range) 15.9 ± % (16/20) 10% (2/20) 20% (4/20) 35% (7/20) 30% (6/20) 5% (1/20) Distal and circumferential margins free of tumour (confirmed by pathologic analysis). Quality of the mesorectal plane reported as satisfactory in all the specimens. No laparoscopic/ open conversion. Safety Complications after surgery Postoperative morbidity, Clavien- Dindo grade Value I 10% (2/20) II 10% (2/20) III 0% IV 0% V (death) 0% Complication 2 patients had urinary retention 1 patient had postoperative ileus and 1 patient had severe dehydration due to increased ileostomy output No additional complications or readmissions at 15 and 30 days. Mean estimated blood loss: 45 ± 15 ml (range 10 to 110 ml) Recovery outcomes after surgery Characteristic Value Days until oral intake* 1.8 ± 0.9 Days until regular diet* 3.8 ± 2.1 Days until discharge* 5.8 ± 2.6 Pain control with oral analgesia* 5.4 ± 2.2 *mean ± SE Mean operative time: ± 56 min (range 150 to 325 min) Mean postoperative hospital length of stay: 6.5 ± 3.1 days Abbreviations used: APR, abdominoperineal resection; ASA, American society of anesthesiology; BMI, body mass index; COPD, chronic obstructive pulmonary disease; CI, confidence interval; CRM, circumferential resection margin; CRT, chemoradiotherapy; ECOG, eastern cooperative oncology group; EEA, end-to-end anastomotic; FOLFOX, 5-FU + oxaliplatin; IMA, inferior mesenteric artery; ISR, intersphincteric resection; LAR, low anterior resection; LN, Lymph nodes; LOS, hospital length of stay; LRR, locoregional recurrence; MRI, magnetic resonance imaging; N, no; POSSUM, physiological and operative severity score for the enumeration of mortality and morbidity; SD, standard deviation; SE, standard error; SILS, single-incision laparoscopic surgery; TAEP, transanal endoscopic proctectomy; TAMIS, transanal minimally invasive surgery; TEMS, transanal endoscopic microsurgery; TEO, transanal endoscopic operation; TES, transanal endoscopic surgery; TME, total mesorectal excision; Y, yes. Page 13 of 50

14 Study 5 Wolthuis AM (2014) Details Study type Country Case series Belgium Recruitment period 2012 to 2013 Study population and number Age and sex Patient selection criteria Technique Follow-up Conflict of interest/source of funding Analysis n=14 patients with benign disease (64.3% [9/14]) and American society of Anaesthesiology (ASA) grade 3 patients with a rectal carcinoma (35.7% [5/14]) who required either intersphincteric proctectomy or coloanal anastomosis. Median 65 years [range 28 to 87 years]; 36% (5/14) male Median BMI: 25 kg/ m 2 [range 17 to 32 kg/ m 2 ] Consecutive patients who were candidates for either proctectomy or manual coloanal anastomosis for benign disease. Exclusion criteria: locally advanced rectal cancer or neoadjuvant chemoradiotherapy. Patients had standard preoperative bowel preparation the day before surgery. All procedures were performed with the patient under general anaesthesia and prophylactic antibiotics were given. First, a Lone Star Retractor (CooperSurgical) was inserted. After a sleeve mucosectomy or intersphincteric dissection, a Gelpoint path (Applied Medical) was placed into the anal muscular cuff. Standard laparoscopic insufflator and Chip-on-the-tip laparoscope A50002A (EndoEye, Olympus Medical Europe Holding GmbH) were used. In case of a reconstruction, a handsewn straight coloanal anastomosis was made. Median 6 months [range 2 to 14 months] Not reported. Follow-up issues: none Study design issues: none Study population issues: Benign indications were intractable supralevatoric fistula (7.1% [1/14]), refractory faecal incontinence (7.1% [1/14]),rectovaginal fistula and incontinence after a failed stapled transanal resection of the rectum procedure (7.1% [1/14]), iatrogenic rectal stenosis after stapled hemorrhoidopexy (14.3% [2/14]), Crohn s proctitis (7.1% [1/14]), ulcerative colitis (7.1% [1/14]), and circular tubulovillous adenoma (14.3% [2/14]). Other issues: none Page 14 of 50

15 Key efficacy and safety findings Efficacy Number of patients analysed: 14 Conversion rate to open proctectomy Type of procedure Laparoscopically assisted procedure (hybrid TAMIS-rectal excision) Pure TAMISrectal excision Patie nts 79% (11/1 4) 21% (3/14) Operative characteristics Type of procedure Conversion rate to open proctectomy Reason 18% (2/11) Extensive intraabdominal adhesions after previous laparotomy and BMI= 32 kg/m 2 None Hand-sewn coloanal anastomosis with temporary defunctioning ileostomy* TAMIS-rectal excision with end colostomy for 1 of the patients N/A Patients 50% (7/14) 43% (3/7) 43% (6/14) Proctocolectomy with end ileostomy 7% (1/14) *All ileostomies had been closed when the paper went to press. Median operative time TAMIS: 55 min (range 35 to 95min) [calculated by IP analyst] Mean total operating time: 148 min (range 85 to 250min) [calculated by IP analyst] Mean postoperative hospital length of stay: 8.7 days (range 3 to 14 days) [calculated by IP analyst] Safety Intraoperative difficulties hindering dissection: Type of intraoperative difficulty Patients Maintaining insufflation 14.3% (2/14) Bleeding Fibrosis after radiotherapy for prostate cancer Rectal perforation in a patient who had rectal cancer with metastasis to the liver and the lungs Postoperative complications Postoperative morbidity, Clavien-Dindo grade Patients I 43% (6/14) II 0% III 0% IV 0% V (death) 0% 1 patient 1 patient 1 patient Complication 2 transient fever 3 urinary tract infections 1 small pelvic hematoma requiring no surgical treatment No readmissions within 30 days. Mean estimated blood loss: 48.6 ml (range 0 to 150ml) [calculated by IP analyst] Abbreviations used: APR, abdominoperineal resection; ASA, American society of anesthesiology; BMI, body mass index; COPD, chronic obstructive pulmonary disease; CI, confidence interval; CRM, circumferential resection margin; CRT, chemoradiotherapy; ECOG, eastern cooperative oncology group; EEA, end-to-end anastomotic; FOLFOX, 5-FU + oxaliplatin; IMA, inferior mesenteric artery; ISR, intersphincteric resection; LAR, low anterior resection; LN, Lymph nodes; LOS, hospital length of stay; LRR, locoregional recurrence; MRI, magnetic resonance imaging; N, no; POSSUM, physiological and operative severity score for the enumeration of mortality and morbidity; SD, standard deviation; SE, standard error; SILS, single-incision laparoscopic surgery; TAEP, transanal endoscopic proctectomy; TAMIS, transanal minimally invasive surgery; TEMS, transanal endoscopic microsurgery; TEO, transanal endoscopic operation; TES, transanal endoscopic surgery; TME, total mesorectal excision; Y, yes. Page 15 of 50

16 Study 6 Liyanage C (2013) Details Study type Country Case series Not reported Recruitment period 2007 to 2011 Study population and number Age and sex Patient selection criteria Technique Follow-up Conflict of interest/source of funding Analysis n=12 patients with ulcerative colitis (50% [6/12]), Crohn s disease ( 25% [3/12]), rectal adenomas (17% [2/12]), or radiation proctitis (8% [1/12]). Mean 66 years [range 41 to 88 years]; 58% (7/12) male Consecutive patients needing proctectomy. Exclusion criteria: unfitness for general anaesthesia Transanal endoscopic microsurgery proctectomy. A single surgeon performed all the procedures under general anaesthesia with patients in the lithotomy position and standard thrombo-prophylaxis and antibiotics. Excision began with an intersphincteric dissection following which the transanal endoscopic microsurgery (TEMS) (WOLF) proctoscope was inserted and close rectal dissection was performed using the Ultracision Harmonic scalpel (Ethicon Endosurgery), entering the peritoneal cavity. Following perineal extraction of the specimen, the external sphincter and skin were closed with an absorbable suture. 30 days Not reported Follow-up issues: none Study design issues: The perineal approach was supplemented by an abdominal approach in 17% (2/12) of patients. Planned laparoscopy was performed in1 patient to free potentially adherent small bowel. Mobilisation of small-bowel adhesions was performed successfully through the TEMS scope in 92% (11/12) of patients. 1 patient required a small laparotomy. Study population issues: 92% (11/12) of patients had an American Society of Anesthesiology (ASA) grade of II, 8% (1/12) of patients had an ASA grade of III on a scale from I to VI with I indicating a normal healthy patient and VI a declared brain-dead patient. Mean Physiological and operative severity score for the enumeration of mortality and morbidity (POSSUM) score: 18.2 (range 13.7 to 30.3). Page 16 of 50

17 Key efficacy and safety findings Efficacy Number of patients analysed: 12 Mean operative time: 215.4min (range 123 to 345min) [calculated by IP analyst] Median postoperative hospital length of stay: 5.5 days (range 1 to 28 days). Mean (SD) rectal stump length: 17.8 (±6.1) cm Safety Complications after surgery Complicatio n Delayed healing of the perineal wound Incarcerated parastomal hernia Colocutaneou s fistula Value 33.3% (4/12) 1 patien t 1 patien t Other 16.7% (2/12) patients required drainage of a perineal wound infection Authors say this was presumably precipitated by the pneumoperitoneum. After routine use of an abdominal binder, this complication did not occur again. The proximal end of the TEMS proctectomy was stapled across leaving the loop stoma in situ with a distal blind efferent limb. A leak from the staple line led to the formation of a fistula to the perineal wound which was successfully treated by resecting the blind efferent limb and converting the stoma to an end colostomy. No perioperative (30-day) mortality. Estimated blood loss< 100ml in all patients. Abbreviations used: APR, abdominoperineal resection; ASA, American society of anesthesiology; BMI, body mass index; COPD, chronic obstructive pulmonary disease; CI, confidence interval; CRM, circumferential resection margin; CRT, chemoradiotherapy; ECOG, eastern cooperative oncology group; EEA, end-to-end anastomotic; FOLFOX, 5-FU + oxaliplatin; IMA, inferior mesenteric artery; ISR, intersphincteric resection; LAR, low anterior resection; LN, Lymph nodes; LOS, hospital length of stay; LRR, locoregional recurrence; MRI, magnetic resonance imaging; N, no; POSSUM, physiological and operative severity score for the enumeration of mortality and morbidity; SD, standard deviation; SE, standard error; SILS, single-incision laparoscopic surgery; TAEP, transanal endoscopic proctectomy; TAMIS, transanal minimally invasive surgery; TEMS, transanal endoscopic microsurgery; TEO, transanal endoscopic operation; TES, transanal endoscopic surgery; TME, total mesorectal excision; Y, yes. Page 17 of 50

18 Study 7 McLemore EC (2013) Details Study type Country Retrospective case series USA Recruitment period 2011 to 2013 Study population and number Age and sex Patient selection criteria Technique Follow-up Conflict of interest/source of funding Analysis n=6 patients with proctitis: diversion (17%[1/6]), radiation (17%[1/6]), ulcerative colitis (33%[2/6]), Crohn s disease (33%[2/6]). Mean 49 years [range 22 to 74 years]; 33% (2/6) male Mean BMI: 30.5 kg/m 2 [range 22 to 51 kg/m 2 ] Proctitis in a retained rectum. Patients were in the lithotomy position in 83% (5/6) of cases and in the prone position in 1 case because of severe osteoarthritis and contractures limiting hip flexion. The Gelpoint Path (Applied Medical) transanal access platform was used. Range 3 to 19 months. Not reported Follow-up issues: none Study design issues: 4 applications of transanal endoscopic surgical (TES) proctectomy were performed. Study population issues: patient 4 had CRT completed 11 months before surgery. Other issues: none. Page 18 of 50

19 Key efficacy and safety findings Efficacy Number of patients analysed: 6 Operative data TES operation Patients TES completion proctectomy 50% (3/6) TES assisted single incision abdominal perineal resection TES assisted laparoscopic proctosigmoidectomy with coloanal anastomosis and diverting loop ileostomy TES assisted laparoscopic restorative proctocolectomy with ileal pouch anal anastomososis and diverting loop ileostomy Mean operative time: min (range 140 to 557 min) [calculated by IP analyst] Mean postoperative hospital length of stay: 14.2 days (range 2 to 66 days) [calculated by IP analyst] Safety Complications after surgery Complicatio n (1 each) Urinary tract infection (UTI) Chronic draining sinus from the perineal wound Perineal wound infection and dehiscence Other Patient is doing well at 19-month follow-up Re-operative excision of the sinus tract. Patient is doing well at 12-month follow-up. Complications managed with soft tissue reconstructive surgery. Patient remained in hospital for 2 months for management of his perineal wound dehiscence with prolonged inpatient hospitalisation secondary to lack of eligibility for skilled nursing facility or home based wound care. Patient is doing well at 15-month follow-up. Abbreviations used: APR, abdominoperineal resection; ASA, American society of anesthesiology; BMI, body mass index; COPD, chronic obstructive pulmonary disease; CI, confidence interval; CRM, circumferential resection margin; CRT, chemoradiotherapy; ECOG, eastern cooperative oncology group; EEA, end-to-end anastomotic; FOLFOX, 5-FU + oxaliplatin; IMA, inferior mesenteric artery; ISR, intersphincteric resection; LAR, low anterior resection; LN, Lymph nodes; LOS, hospital length of stay; LRR, locoregional recurrence; MRI, magnetic resonance imaging; N, no; POSSUM, physiological and operative severity score for the enumeration of mortality and morbidity; SD, standard deviation; SE, standard error; SILS, single-incision laparoscopic surgery; TAEP, transanal endoscopic proctectomy; TAMIS, transanal minimally invasive surgery; TEMS, transanal endoscopic microsurgery; TEO, transanal endoscopic operation; TES, transanal endoscopic surgery; TME, total mesorectal excision; Y, yes. Page 19 of 50

20 Study 8 Sylla P (2013) Details Study type Country Case series USA Recruitment period 2011 to 2012 Study population and number Age and sex Patient selection criteria Technique Follow-up Conflict of interest/source of funding Analysis n=5 patients with rectal cancer Mean 48.6 years [range 36 to 63years]; 60% (3/5) male Mean BMI: 25.7 kg/m 2 [range 21.7 to 27.6 kg/m 2 ] Adult patients with clinically staged T1 (with 1 or more high-risk histologic features identified on pathology), T2 or T3 node-negative rectal adenocarcinoma, a predictive mesorectal margin 5mm on pelvic MRI and no evidence of metastasis, who were deemed good candidates for laparoscopic low anterior resection with TME and creation of a temporary diverting loop ileostomy. Tumours located 4 to 12 cm from the anal verge and over 1 cm from the anorectal ring. Exclusion criteria: severely symptomatic rectal tumours, inflammatory bowel disease, prior colorectal malignancy, extensive prior abdominal or pelvic surgery or pelvic radiation, large uterine fibroids, or fecal incontinence. Pregnant patients or patients with an ASA class 3 or 4, an Eastern Cooperative Oncology Group (ECOG) score> 2, and a BMI> 40kg/m 2. Transanal endoscopic TME with laparoscopic assistance. Standard preoperative intravenous antibiotherapy. Number and location of laparoscopic trocars and use of a pelvic drain used at the discretion of the primary surgeon. Tumours located 1 to 1.5 cm from the anorectal ring: partial intersphincteric resection was performed. Tumours> 1.5 cm from the anorectal ring: the PPH anoscope (Covidien) was inserted for exposure. Following rectal occlusion, the TEO proctoscope (Karl Storz) was inserted transanally. Full-thickness rectal dissection was done using a flexible-tip L-hook with monopolar cautery (Cambridge Endo) and the Harmonic scalpel (Ethicon). Patients were discharged when a soft solid diet was tolerated with a functioning stoma. Epidural catheter provided postoperative pain control, Adjuvant therapy for patients with stage IIA or IIIA rectal cancer was initiated 6 to 8 weeks after surgery. Mean 5.4 ± 2.3 months (SD) 5 of the authors have received honoraria from manufacturers. The study was funded by a Grant from the Center for Integration of Medicine and Innovative Technology (CIMIT). Follow-up issues: none Study design issues: none Study population issues: Tumours stage: T1N0M0 (2/5), T2N0M0 (1/5) and T3N0M0 (2/5). Patients with T3 tumours underwent standard preoperative CRT for 6 weeks followed by surgical resection and completion of 4 months of postoperative chemotherapy with FOLFOX prior to ileostomy closure. Tumours were located in the lower rectum ( 5 cm from the anal verge) in 80% (4/5) of patients and in the upper rectum (10 cm from the anal verge) in 1 patient. Among patients with clinical T1N0M0 rectal tumours, 1 was found to have 3 polypoid masses in the rectum with the 1 polyp containing at least intramucosal carcinoma. The other one had undergone transanal excision of a 1.8 cm invasive adenocarcinoma arising in a tubulovillous adenoma 2 months earlier. On pathology review, invasive cancer was noted to extend to within 1 mm of the tumour margin. Page 20 of 50

21 Key efficacy and safety findings Efficacy Number of patients analysed: 5 Mean number of lymph nodes harvested: 33 ± 15 (range 16 to 53) No conversions to open TME. All patients are disease-free at mean 5.4-month follow-up. Intraoperative outcomes Patient Gende r ISR Pelvi c drain Approach for TME Approach for IMA division 1 F N N Complete transanal Transanal 2 M Y Y Partial transanal* Laparoscopic 3 M Y Y Complete transanal Transanal 4 M Y Y Partial transanal* Transanal 5 F N N Complete transanal Transanal *Anterior mesorectal dissection was performed in part transanally and in part laparoscopically. Pathologic characteristics Pt Final TNM stage LN harves t TME quality Distal margin (cm) CRM (cm) 1 ypt2n0m0 41 Complete ypt2n0m0 16 Complete pt1n0m0 53 Complete pt2n1m0 34 Complete pt0n0m0 21 Complete N/A* N/A* *No residual tumour Mean operative time: ± 85.4 min (range min) Mean postoperative hospital length of stay: 5.2 ± 2.6 days (range 4-10 days) Safety No intraoperative complications Complications after surgery Complicatio n (1 each) Urinary dysfunction and acute renal failure Urinary dysfunction Ileus Other Occurred 15 days after removal of Foley catheter in male patient who underwent pisr and was complicated by readmission for acute renal failure. Urodynamic testing 1 month after surgery demonstrated minimal detrusor activity consistent with a neurogenic bladder. Patient required selfcatheterization for 5 months but completely recovered normal urinary function thereafter. Occurred following Foley removal at day 2 in a male patient who underwent pisr, requiring Foley reinsertion. Catheter was removed at 1 month with full recovery of normal urinary function. Managed conservatively without nasogastric tube decompression. Timing not reported. Mean estimated blood loss: 166 Page 21 of 50

22 ± 101 ml (range 80 to 300 ml) Abbreviations used: APR, abdominoperineal resection; ASA, American society of anesthesiology; BMI, body mass index; COPD, chronic obstructive pulmonary disease; CI, confidence interval; CRM, circumferential resection margin; CRT, chemoradiotherapy; ECOG, eastern cooperative oncology group; EEA, end-to-end anastomotic; FOLFOX, 5-FU + oxaliplatin; IMA, inferior mesenteric artery; ISR, intersphincteric resection; LAR, low anterior resection; LN, Lymph nodes; LOS, hospital length of stay; LRR, locoregional recurrence; MRI, magnetic resonance imaging; N, no; POSSUM, physiological and operative severity score for the enumeration of mortality and morbidity; SD, standard deviation; SE, standard error; SILS, single-incision laparoscopic surgery; TAEP, transanal endoscopic proctectomy; TAMIS, transanal minimally invasive surgery; TEMS, transanal endoscopic microsurgery; TEO, transanal endoscopic operation; TES, transanal endoscopic surgery; TME, total mesorectal excision; Y, yes. Page 22 of 50

23 Study 9 Velthuis S (2013) Details Study type Country Case series Netherlands Recruitment period June to August 2012 Study population and number Age and sex Patient selection criteria Technique Follow-up Conflict of interest/source of funding Analysis n=5 consecutive unselected patients with rectal adenocarcinomas Mean 69.4 years [range 63 to 79 years] (calculated by IP analyst) ; 60% (3/5) male Histologically proven mid-rectal T2 or T3 adenocarcinomas. Exclusion criteria: previous history of abdominal surgery. Combination of transanal TME technique and SILS. Prophylactic antibiotics were given. Transanal phase of the procedure used a Scott retractor (Lone Star Medical Products) to facilitate the full-thickness circumferential resection. One single-incision laparoscopic surgery (SILS) port (Covidien) was introduced into the anus. Another SILS port was introduced at the previously marked future ileostomy site. A hand-sutured coloanal anastomosis was created for the first 2 patients and a stapled anastomosis was formed in the last 3 patients. A loop ileostomy was created after removing the SILS port. Postoperative pain was controlled with an epidural. Not reported None Follow-up issues: none Study design issues: none Study population issues: Patients with T2-3N0-1 tumours underwent preoperative radiotherapy. Surgery was performed in the week following cessation of radiotherapy. Patients with T2-3N2 tumours underwent CRT and surgery was performed 6 weeks after the end of the neoadjuvant treatment. Possible patients overlap with Velthuis 2014 (study 1). Other issues: none Page 23 of 50

24 Key efficacy and safety findings Efficacy Number of patients analysed: 5 Transanal endoscopic dissection of the complete rectum possible in all patients. Complete mobilisation of the sigmoid possible using the SILS port at the ileostomy site in 80% (4/5) of patients. In 1 patient, 2 extra trocars were used for complete mobilisation because the mesentery of the sigmoid was too bulky. Clear surgical margins (circumferential and distal): 100% (5/5) Median number of lymph nodes harvested: 12 (range 11 to 17) Intact mesorectal fascia: 100% (5/5) Tumour pathology and perioperative outcomes Patient Gender Distance to anal verge (cm) Tumou r stage (MRI) Histology after neoadjuvan t therapy 1 F 5 T3N0 ypt3n M 5 T3N2 ypt0n M 8 T3N0 ypt2n F 5 T3N0 ypt3n M 7 T2N0 ypt2n0 15 Number of lymph nodes harveste d Median operative time: 175min (range 160 to 194 min) Safety Perioperative complications 1 patient developed extreme perioperative pneumatosis of the retroperitoneum and mesentery of the small bowel, making laparoscopic mobilisation of the sigmoid difficult. Postoperative complications (1 each) Complicatio n Day 5: small bowel ileus Pneumonia Presacral abscess Other Patient with pneumatosis. Ileus resolved with conservative measures. Patient had severe COPD and developed pneumonia necessitating antibiotic treatment. Treated by repeat laparoscopic drainage. CT did not reveal anastomotic leakage. Abbreviations used: APR, abdominoperineal resection; ASA, American society of anesthesiology; BMI, body mass index; COPD, chronic obstructive pulmonary disease; CI, confidence interval; CRM, circumferential resection margin; CRT, chemoradiotherapy; ECOG, eastern cooperative oncology group; EEA, end-to-end anastomotic; FOLFOX, 5-FU + oxaliplatin; IMA, inferior mesenteric artery; ISR, intersphincteric resection; LAR, low anterior resection; LN, Lymph nodes; LOS, hospital length of stay; LRR, locoregional recurrence; MRI, magnetic resonance imaging; N, no; POSSUM, physiological and operative severity score for the enumeration of mortality and morbidity; SD, standard deviation; SE, standard error; SILS, single-incision laparoscopic surgery; TAEP, transanal endoscopic proctectomy; TAMIS, transanal minimally invasive surgery; TEMS, transanal endoscopic microsurgery; TEO, transanal endoscopic operation; TES, transanal endoscopic surgery; TME, total mesorectal excision; Y, yes. Page 24 of 50