Best Practice & Research Clinical Gastroenterology 28 (2014) 143–157

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Best Practice & Research Clinical Gastroenterology

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Transanal endoscopic microsurgery Christopher J. Smart, FRCS, Fellow in Colorectal Surgery a, *, Chris Cunningham, MD, FRCS, Consultant Colorectal Surgeon b,1, Simon P. Bach, MD, FRCS, Senior Lecturer and Honorary Consultant Colorectal Surgeon a, 2 a

School of Cancer Studies, Academic Department of Surgery, Room 28, 4th Floor, Queen Elizabeth Hospital Edgbaston, Birmingham B15 2TH, UK b Oxford University Hospitals NHS Trust, John Radcliffe Hospital, Headley Way, Headington, England OX3 9DU, UK

a b s t r a c t Keywords: Transanal endoscopic microsurgery TEM TEMS Early rectal cancer Rectal adenoma Short course radiotherapy Chemoradiotherapy

Transanal endoscopic microsurgery (TEMS) is a well established method of accurate resection of specimens from the rectum under binocular vision. This review examines its role in the treatment of benign conditions of the rectum and the evidence to support its use and compliment existing endoscopic treatments. The evolution of TEMS in early rectal cancer and the concepts and outcomes of how it has been utilised to treat patients so far are presented. The bespoke nature of early rectal cancer treatment is changing the standard algorithms of rectal cancer care. The future of TEMS in the organ preserving treatment of early rectal cancer is discussed and how as clinicians we are able to select the correct patients for neoadjuvant or radical treatments accurately. The role of radiotherapy and outcomes from combination treatment using TEMS are presented with suggestions for areas of future research. Ó 2014 Published by Elsevier Ltd.

Introduction In the early ‘80s a novel technique for resection of polyps from within the rectum was conceived by Professor Gerhard Buess from Tubingen, Germany [1]. Prior to this transanal resection of polypoid * Corresponding author. Tel.: þ44 0121 371 5888; fax: þ44 0121 371 5896. E-mail addresses: [email protected], [email protected] (C.J. Smart), [email protected] (C. Cunningham), [email protected] (S.P. Bach). 1 Tel.: þ44 1865 741166. 2 Tel.: þ44 0121 371 5888; fax: þ44 0121 371 5896. 1521-6918/$ – see front matter Ó 2014 Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.bpg.2013.11.005

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tissue, that was not amenable to flexible endoscopic resection, was restricted to the distal rectum in patients with favourable lesions [2]. This technique relied on traditional instruments and had limitations both in its indications and in success of removal of the pathological specimen in mid/upper rectum, resulting in piecemeal excision, positive margins and high recurrence rates [3]. Buess developed a specific surgical rectoscope and instruments to address this problem with Richard Wolf Medical Instruments. This facilitated a new way of operating in the rectum that was very precise and accurate due to its binocular vision and 3D visualisation. His technique of Transanal Endoscopic Microsurgery (TEMS) was finalised in 1984 [4]. Technique The equipment consists of a rigid rectoscope fixed to operating table with a multidirectional clamp (Martin’s Arm) and a unit to insufflate carbon dioxide and provide suction, irrigation and rectal pressure monitoring. See below Fig. 1 The rectoscope (Fig. 2) is 4 cm in diameter available in two main sizes, short (12 cm) or long scope (20 cm). Which one is used depends on the pre-operative location of the lesion in the rectum. The removable faceplate (Fig. 3) has specialist ports to facilitate the long instruments and suction required and accommodates the stereoscope (Fig. 4), through which the surgeon can see the lesion magnified six fold. In recent times this can be connected to a laparoscopic video stack, which some surgeons prefer or for teaching purposes. The pre-operative assessment of the lesion is critical, as this will reflect how the patient is positioned for the procedure and which rectoscope and instruments are required. For anterior lesions the patient is placed prone and for posterior lesions in the lithotomy position. It is important both the operating surgeon and supporting theatre team have a good understanding of the workings of the equipment, as some operations required multiple changes in position and different settings of the insufflation/suction unit. The operating surgeon now has a view of the distended rectum, with which a variety of instruments can be used to excise the lesion in the required fashion depending its histological type, size and location. Full thickness resection of the rectal wall is possible, as is closure of the defect using sutures.

Fig. 1. Insufflation unit.

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Fig. 2. Rectoscope.

TEMS was gradually adopted in many centres across Europe and America but some institutions found the high initial capital set up costs for the equipment prohibitive. Despite these initial costs, when compared to open procedures for the same indications, the technique is economically viable in high volume specialist centres [56]. Safety and morbidity profile TEMS has been widely studied for its safety and repeated use in patients for all indications [7]. Initially there were concerns over the 4 cm rectoscope being placed through the sphincter complex into rectum for potentially long operations. There is data to show reduced anorectal manometric pressures in patients who have undergone TEMS, particularly the internal anal sphincter resting pressure and that this is correlated to the length of their procedure. However this did not change continence scores or other anorectal parameters [8]. Several studies have demonstrated anorectal function is preserved with the TEMS technique, even after repeat surgery in the same patients [9,10]. Some patients will develop anorectal dysfunction but this is multifactorial and associated with excision of large specimens from the rectum and with resultant changes in capacity and compliance

Fig. 3. Faceplate.

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Fig. 4. Stereoscope.

[11]. Improvements in faecal continence scores have been demonstrated after TEMS, most likely secondary to excision of a benign mucous producing lesion, improving quality of life [12]. In similar large benign lesions removed by either TEMS or endoscopic mucosal resection (EMR), anal resting pressures are lower after TEMS excision, but continence in patients with a large rectal adenoma are improved after EMR or TEMS [13]. Morbidity from TEMS has been shown to range from 7.7% [14] to 21% [15] with the commonest reported problems being urinary retention, suture line dehiscence and bleeding. Entry into the peritoneal cavity occurs in 5.8% of cases and is associated with higher anterior tumours [16]. This may in fact be planned and is not regarded as a definitively morbid event [17]. The defect is simply sutured and antibiosis administered. This has been demonstrated to not affect short-term morbidity or oncological outcomes [16]. TEMS can be employed for excision of lesions up to 20 cm from the anal verge and for large lesion over 8 cm. Even in these challenging situations it has been demonstrated to be safe and efficacious [18]. The use of a harmonic scalpel can be employed through a standard TEMS port and may help reduce the incidence of bleeding during resection of lesions [19]. Recently there has been a vast increase in the techniques for transanal excision of specimens using existing laparoscopic instruments and disposable proctoscopes. The abbreviations TEO and TAMIS are most frequently seen in the literature. The relatively high set up cost and specific training for TEMS prompted surgeons to examine alternative methods for performing transanal surgery [20]. TEO (Transanal Endoscopic Operation) is a similar operating rectoscope manufactured by Karl Storz. This uses standard laparoscopic instruments and equipment and set up costs are lower, potentially opening the technique to any surgeon with an existing laparoscopic skill set. The main difference is a lack of binocular vision. Several studies have compared TEO with TEM for benign and malignant lesions and shown satisfactory outcomes [21–23]. TransAnal Minimally Invasive Surgery (TAMIS), conceived in 2010 [24], employs a standard single port laparoscopic device (SILSÔ, Covidien) to achieve the pneumorectum, facilitating excision with standard instruments, and heavily reducing expenditure. Initially confined to distal rectal lesions, more literature is emerging for its use in malignant disease and lesions higher in the rectum, with satisfactory results [25]. Its use of traditional ports has extended it applications for greater visualisation of the lesion using a flexible endoscope as a camera (eTAMIS) [26] and incorporating robotic technology in the cadaveric setting [27]. Certainly, at present, single port access TEMS (SPA TEMS) systems do not have the range of operating that TEMS does. For lesions high in the rectum SPA TEMS systems cannot visualise the lesions as well and struggle to develop pneumorectum with lesions at the dentate line or lower. It has not been embraced by all transanal specialists, with data demonstrating its inferiority to TEMS which remains the gold standard [28]. A simple device has been described to mimic the industry SPA TEMS appliances made of a simple operating glove and a circular anal dilator (CAD) to achieve pneumorectum and allow operating within the rectum. This has shown to be extremely cost-effective but should only be used where conventional TEMS expertise is available in case of equipment failure [29].

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There are concerns from specialist centres that non-specialists may undertake benign or malignant resections transanally given the ease of use, and industry drive, for SPA TEMS devices. These patients, however, may be offered inferior treatment pathways, especially for early rectal cancer, as discussed later. How SPA TEMS devices will compliment conventional TEMS remains unclear at present.

Indications for TEMS There three main indications for TEMS. 1) The excision of benign lesions, of the rectum or distal sigmoid colon, that cannot be removed with conventional techniques including large or carpet type lesions. 2) The role of excision of the specimen in the management of early rectal cancers. 3) It use as an operative intervention in an extended setting, e.g. repair of a rectovaginal fistula and in an experimental setting, as a platform for Natural Orifice Transluminal Endoscopic Surgery (NOTES) including rectal Total Mesorectal Excision (TME).

Benign lesion excision The transanal methods historically employed to remove benign lesions of the rectum each had significant drawbacks. The Parks produced high recurrence rates [2], while both transcoccygeal (Kraske) [30] and trans-sphincteric (Mason) [31] approaches were associated with significant morbidity. TEMS was designed to overcome these issues enabling removal of larger benign lesions of the rectum. Today, TEMS complements Endoscopic Mucosal Resection (EMR), and is particularly useful for large or recurrent lesions. Several series have compared TEMS to transanal techniques for removal of rectal adenomas. They demonstrate low morbidity with no difference in complication rates. Margin involvement by tumour and fragmentation of the specimen are less common with TEMS [32,33]. In large series of rectal adenoma resection with TEMS, low levels of recurrence, between 4.3 and 9.1% [34,35] were demonstrated, with similar rates of recurrence with extended follow up [36]. Repeat TEMS is highly successful in treating recurrence in most cases (87%–100%). Several factors have been implicated in the likely hood of recurrence after TEMS for adenoma. Previous resection, size, piecemeal excision and most importantly, involved margin (microscopic positive margin), are strong predictors of recurrence [37,38,39,40]. R1 resection can increase the rate of recurrence up to 29% (c/f 4% R0) with extended follow up [33,41]. Large adenomas (>3 cm) have a median time to recurrence of ten months, with over 75% recurring by 12 months [39]. Giant adenomas (>5 cm) can be successfully removed via TEMS but have an increased rate of occult carcinoma (13.5%), higher surgical complication rates and higher rates of recurrence, especially when in close proximity to the anal verge [42,17]. These lesions may also have delayed presentation of recurrence (over 40 months) when compared to smaller lesions and require extended follow up. The rate of incidental carcinoma in benign appearing lesions is significant even with multimodal pre-operative assessment. Of 167 benign lesions excised via TEMS with mucosectomy (i.e. non full thickness excision) 21 (13%) lesions were unexpected cancers: pT1 sm1 ¼ 9, pT1 sm2 ¼ 4, pT1 sm3 ¼ 4 and pT2 ¼ 4. This is not related to the type of lesion, although it should be noted that exophytic lesions may be harder to assess and classify by endorectal ultrasound (p.0.01) [43]. The true figure of occult carcinoma may be higher depending on the level of pre-operative imaging assessment, up to 40 % [56]. In the past we have perhaps been somewhat ‘relaxed’ regarding an unexpected diagnosis of cancer in the TEMS specimen. This was reflected by the term ‘big biopsy’, coined to describe TEMS excision of significant neoplasms of the rectum. The treatment pathway was relatively simple. Patients with unexpected malignancy could stick with their local excision if histology was favourable or convert to radical surgery if not. The advent of neoadjuvant treatment strategies for early stage rectal cancer to facilitate organ preservation has increased the importance of accurate pretreatment diagnosis.

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Circumferential lesions can be resected, particularly carpet adenomas, but lead to a higher rate of rectal stenosis. Dissection in the submucosal plane seems to exacerbate this issue; however, it is still preferred for benign lesions due to the reduction in peritoneal breach. Stenoses will normally respond to repeated surgical or balloon dilatations [44]. The use of endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) has increased over the last ten years. ESD is a versatile technique normally performed without anaesthesia and has been shown to have a role in the management of benign and, more controversially, malignant lesions of the rectum. A systematic review of its use in the colon and rectum has demonstrated it to be safe and effective but no randomised controlled trials exist comparing its use to TEMS in the rectum alone [45]. There are published case series outlining use of this technique for treating early rectal cancer, however, this is a controversial application requiring further formal evaluation [46]. The role of EMR in direct comparison to TEMS for benign neoplasms has not been subjected to randomised comparison but a systematic review has demonstrated the safety of EMR with a lower rate of morbidity (3.8% Vs 13.0%) but a higher recurrence rate of (11.2% Vs 5.4%). These were for mainly smaller lesions (approx 3 cm) and the review did not take in to account the increased morbidity of repeat EMR or indeed its benefits in recurrent adenoma [47]. This has been confirmed in a retrospective multicentre review, where EMR has been shown to be as effective as TEMS for adenoma excision, but smaller lesions were undertaken and repeated treatments were required to achieve similar efficacy [48]. The Transanal endoscopic microsurgery versus endoscopic mucosal resection for large rectal adenomas (TREND study) group has registered a randomised, multicentre Dutch trial to look at adenomata 3 cm. The primary outcome measure is the proportion of patients with recurrence after three months. Secondary outcome measures are: number of days not spent in hospital from initial treatment up to two years; major and minor morbidity; disease specific and general quality of life; anorectal function; health care utilization and costs [49]. We await results from this first randomized trial to determine exactly how EMR may compliment TEMS. TEMS in early rectal cancer Historical perspective Resection of malignant lesions in the rectum remains a challenge for surgeons and patients. There is, perhaps, a trade off between oncological efficacy, preservation of rectal function and quality of life, with the lowest morbidity and mortality possible. The treatment of rectal cancer has advanced rapidly over the last two decades with improvements in diagnosis, pre-operative imaging, neoadjuvant strategies and surgery. However Total Mesorectal Excision (TME) remains the gold standard for patients, especially with more advanced disease, as this most effectively treats the mesorectal lymph nodes and reduces recurrence [50]. Radical surgery for early rectal cancer has excellent results with low levels of local recurrence and good long-term survival [51]. However, the morbidity/ mortality rates of radical surgery remain high and anorectal and genito-urinary dysfunction common [52]. For early rectal cancer the role of ‘organ preserving’ techniques is growing, not only in patients un-fit for radical resection, but also in patients where predictive markers of local recurrence are low, meaning radical resection may not be of benefit to them. The impact of screening is undoubtedly increasing the diagnosis of early rectal cancer, and its management is becoming increasingly bespoke and specialised. Parks transanal resection of early rectal cancer is inferior to radical surgery with high rates of R1/R2 resections leading to higher rates of recurrence and worse disease survival (64% Vs 77% p ¼ 0.01) [53].

TEMS in isolation Several studies (only one RCT [54]) in the 1990s onwards, prompted a meta-analysis of the role of TEMS in excision of T1 rectal in comparison to radical surgery (RS). 397 patient outcomes (216 with TEMS) were examined. TEM was safer with 0% mortality (c/f RS 3.68% p ¼ 0.01) and lower morbidity (p ¼ 0.01) with a shorter hospital stay. The rate of recurrence was significantly higher in the TEMS

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group (12% Vs 0.5%, p ¼ 0.0004) but this did not translate to any differences in survival at five years in either group [55]. Substantial variation in outcomes exists within sub-groups of T1 tumours. This prompted attempts to stratify cases based upon histopathological differences in the TEMS specimen. The largest series examined outcomes from 487 patients in 21 centres [56]. 253 patients had T1 disease on resection specimens. A Cox regression model predicted local recurrence at three years using age, depth of tumour invasion, tumour diameter, presence of lymphovascular invasion, poor differentiation and conversion to radical surgery after histopathological examination of the TEMS specimen. Low morbidity and mortality were confirmed from the series (14.9% and 1.4% respectively). The level of submucosal invasion (sm level) was demonstrated to be a strong predictor of recurrence with sm1 lesions showing low levels of recurrence but sm2–3 lesions having similar recurrence rates to that of T2 lesions. Local recurrence rates were less than five per cent for locally excised pT1 Sm1 lesions without lymphovascular invasion and up to 3 cm in diameter and approximated to those for radical surgery. This model was able to define a ‘good prognosis’ sm2–3 and T2 group, however, recurrence rates of 10– 20% were not considered sufficiently low to change clinical practice in favour of organ preservation for fit patients with this tumour profile. Considering the population as a whole, TEMS does cure the majority of cases, but recurrence rates are considerably higher than following radical surgery. Tumour recurrence may be secondary to either occult micrometastases in locoregional lymph nodes, or through tumour implantation at the time of TEMS resection. The risk of nodal spread certainly increases with level of invasion [57,58]. One challenge is to more precisely identify those individuals with tumour progression at diagnosis without removing the mesorectum. The majority of T1 and T2 rectal cancers, perhaps 80% are N0. Routine mesorectal dissection in these patients introduces unnecessary risk in terms of morbidity, mortality and functional sequalae. Such information is currently rather crudely inferred using a combination of radiological imaging and the ‘big biopsy’ technique. Molecular biomarkers associated with tumour progression may hold promise in stratifying patients at high risk of recurrence following local treatment [59]. Measurement of biomarkers using pretreatment biopsy is potentially advantageous as treatment pathways may be optimized from the outset. Organ preserving strategies are now becoming more complex, aiming to deliver lower recurrence rates than is possible with TEMS alone by incorporating additional modalities such as radiotherapy, taking us away from the philosophy of ‘big biopsy’. This approach brings with it a requirement for accurate discrimination of benign and malignant rectal lesions. TEMS in isolation may therefore have similar cancer outcomes, but with far less morbidity to that of radical surgery in specific subgroups with favourable tumour biology. Identifying this group precisely remains a challenge. Histopathological risk stratification yields a group of good prognosis sm1 that are comfortably treated with TEMS alone. Recurrence rates are less than the peri-operative mortality from radical surgery. The problem remains that this constitutes a minority of patients presenting with early stage rectal cancer. Pre-operative staging of early rectal cancer Pre-operative staging of rectal cancers has improved in the last two decades with MRI being shown to be effective in assessment [60]. This era saw a marked reduction in local recurrence for symptomatically diagnosed, locally advanced tumours. Improvements were driven by standardized radiological assessment of the surgical margins, with selective application of pelvic radiotherapy in high risk cases prior to surgery. Considering organ preservation for T1 and T2 cancers, the key staging questions are quite different. Current radiological techniques cannot accurately determine whether a lesion is benign or malignant, or if a cancer has progressed to the mesorectal lymph nodes. Indeed these issues may be beyond the resolution of current imaging platforms. In early rectal cancer, MRI is normally complimented with endorectal ultrasound sound scan (ERUS). ERUS is operator dependant and cannot exclude all malignancy in apparently benign disease [42]. The technique is not well suited to discriminating benign from very early invasive disease due to interface echoes that occur at the of mucosal/submucosal junction. Historically its use has not been universally adopted with an uptake of only 33% in TEMS for rectal cancer in the UK, where it inaccurately staged rectal cancer in 44.8% of tumours and 32.7% were understaged [61]. Higher frequency scanning probes

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and coupling gels have advocates whom have shown increased sensitivity, specificity, positive predictive value and negative predictive value for ERUS (values 93.62%, 97.89%, 93.62% and 97.89%, respectively), especially for early stageT1 disease [62]. Real-time elastography visualizes tissue compliance using an ultrasound platform. It has been used to assess early rectal cancers and adenomas and has shown promising discrimination between them with high rates of sensitivity and specificity [63]. Conversion from TEMS to radical surgery Considering these difficulties it is prudent to counsel patients with significant rectal neoplasia as to the requirement for radical surgery if unexpected malignancy is found, especially combined with poor prognostic features, as per Association of Great Britain Coloproctology guidelines. Similarly, further intervention may be required if poor prognostic factors are present in the TEMS specimen (>sm 1, poor differentiation etc.) when performed on a known early rectal cancer, as potentially curative and organ preserving approach. These patients may require a TME resection as ‘completion’ in a potentially poor oncological outcome tumour to reduce the risk of local recurrence, if nothing further is done. Completion surgery has been demonstrated to be safe and return oncological outcome to that of primary TME surgery for matched tumour groups. In a series of 105 patients undergoing TEM for T1 rectal cancer the local recurrence rate was 6% for low risk T1 tumours with R0 resection whereas rate in the high risk group was 39%. In the high risk group this was reduced down to 6% in those that had immediate re-operation [64]. With 10 year follow up the cancer free survival was 93% in the reoperation group and 89% in the TEMS alone group. This effect is seen in series where local excision (other than TEMS) is used where immediate reoperation in high risk groups reduced recurrence from 50% (non-operated) to 7.7% (operated) [65]. A recent case matched study no difference was found in outcome between patients with rectal cancer undergoing completion TME after TEMS (n ¼ 25) compared to those undergoing primary TME (n ¼ 25), with similar pre and peri-operative parameters. Recurrence was 0% in the completion group and 8% (p ¼ 0.49) in the primary group. Follow up was short however, with a median of only 25 months (range of 3–126) but no difference in rates of distant metastases was observed (4% v 12%, p0.61) [66]. Practical considerations for radical surgery hinge upon the integrity of the circumferential mesorectal fascia following full thickness TEMS. One approach is to perform submucosal excision for presumed benign disease so that the fascia is never threatened in cases of unexpected malignancy. When performing TEMS for cancer a full thickness excision would be usual. A ‘conservative’ full thickness strategy aims to stay in a plane just deep to the muscularis propria. The mesorectal fascia is unlikely to be breached, unless the lesion is very low, and conversion to radical surgery should be relatively straightforward. We advocate reconstitution of the bowel wall with sutures following TEMS with the notion that this may help avoid fracture of the specimen during radical surgery. It is our experience that transmesorectal inflammation may occur deep to the TEMS site, even when this is several centimetres away from the mesorectal fascia. This can lead to relative fixity of the mesorectum at reoperation, which is overcome by sharp dissection. Some clinicians advocate a more aggressive TEMS that includes partial mesorectal excision. In this situation the mesorectal fascia is likely to have been breached. This also holds true of any low rectal cancer, as the mesorectum is generally sparse. If radiotherapy was not delivered prior to TEMS then it should be considered at this point. Adjuvant radiotherapy and TEMS 75 % of patients with T1/T2 disease have an intermediate risk of recurrence when treated with TEM alone, all risk factors accepted [56]. The benefit of radical surgery may not applicable to all people with this risk and the option of adjuvant radiotherapy to reduce recurrence in these higher risk patients is potentially beneficial and less morbid. Post-operative radiotherapy is less effective in resectional rectal cancer surgery than pre-operative treatment. In TEMS surgery the mesorectum and nodes remain and small cases series have shown benefit of post-operative radiotherapy in reducing recurrence after high risk cancer TEMS excision from 50% to 0% [67]. In patients that have a high risk TEMS specimen adjuvant radiotherapy remains an option for selected patients who decline radical surgery based on

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their risk from completion surgery vs risk of recurrence. Patients may opt for intense post-operative follow up to detect recurrence early and enable salvage surgery. Recurrence rates will vary between individuals but if detected early enables salvage surgery to be offered if applicable. In a series of 88 patients undergoing T1 TEMS excision a dedicated and intense endorectal post-operative surveillance regime detected 18 recurrences at a median of 10 months. 16 (89%) patients were suitable and had salvage surgery. 3 year cancer-related survival was 58% [68]. Organ preservation using combination treatment Rationale In patients with rectal cancer high rates of complete pathological response (ypCR) of 15–27% with chemo-radiotherapy (CRT) have been demonstrated with improved outcomes in local recurrence, distant failure and overall and disease free survival in this response group [69,70]. Neoadjuvant radiotherapy is proven to reduce local recurrence following radical surgery by approximately half and it may also be effective in improving oncological outcomes for local, organ preserving techniques. Several studies are testing this hypothesis (TREC, ACOSOG Z6041, CARTS, GRECCAR see below). In addition, tumour response to radiotherapy treatment may define a subset of patients with a particularly good prognosis, who are most likely to benefit from an organ preserving approach [70]. This is important, as patients with early stage rectal cancer may respond much better to this treatment than patients with more advanced tumours. Overall pre-operative radiotherapy with TEMS is appealing as: (1) (2) (3) (4)

radiotherapy may effectively treat microscopic mesorectal nodal metastases tumour downsizing should facilitate local excision with clear margins tumour downstaging is measured objectively rather than relying upon clinical examination, histopathological non-responders are converted to radical completion surgery.

It should also be stated that the long-term effects of irradiation on the rectum in an organ preserving setting are unknown as usually the mesorectum is excised along with the rectum via TME. How this affects long term rectal and pelvic floor function is difficult to predict. Overview To date these studies have opted to use radiotherapy protocols that were developed in conjunction with radical surgery. ACOSOG Z6041 and CARTS both used long course chemoradiation. Complete response rates in the order of 50% were observed at the expense of considerable treatment related morbidity and mortality. The Transanal Endoscopic Microsurgery (TEMS) and Radiotherapy in Early Rectal Cancer (TREC) study is based upon a 5  5 Gy regime, with fields optimised for small tumours. The use of SCPRT with delayed excision has only been reported in one trial in a non-randomized fashion [71]. The median time to local excision in this study was eight weeks (range 5.1–18.9 weeks) and in this group pCR rates 35.9%. Evidence suggests that the acute toxicity of SCPRT is lower than CRT [72]. The TREC study is on going. Rectal cancer exhibits a clear radiotherapy dose response relationship. Endoluminal techniques such as brachytherapy [73] and Papillion [74] are able to deliver very high treatment doses focally to the tumour bed. Cohort studies have documented impressive results in terms of clinical complete response. It is likely that optimisation of radiotherapy delivery; especially through the incorporation of endoluminal platforms into mainstream practice will be of benefit to this concept of organ preservation. TEMS excision following neoadjuvant treatment The role of TEMS in this multimodality setting is also likely to evolve. Currently studies such as TREC mandate TEMS, 8–10 weeks following completion of radiotherapy for T1 and T2 tumours. This provides

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objective evidence of tumour regression and is useful for the purposes of evaluating a new technique. Routine TEM resects the scar or residual abnormality so that no primary tumour cells remain. It also allows timely identification of patients with high-risk features so that conversion to radical completion surgery may be considered. Addition of TEMS following radiotherapy inevitably increases treatment related morbidity with wound dehiscence being the most troublesome side effect [75]. Improving our ability to discriminate patients with a complete response to radiotherapy may help avoid TEMS in some cases. TEMS excision may also disrupt planes for future radical surgery. It may commit a patient to an abdomino-perineal excision where a low anterior resection may have been possible pre-TEMS excision. Given this, there may be role for observation within this group of clinical complete response, depending on tumour position and patient preference. The accuracy of assessment of residual tissue after suspected clinical pathological response has been poor in the context of more advanced tumours. In analysis of 220 patients’ residual mucosal abnormalities after CRT, 19 of 31 patients with a complete pathological response had evidence of a residual mucosal abnormality consistent with an incomplete clinical response. This series did demonstrate the low risk of nodal disease (1 in 42 pts) that were down staged to ypT0/1 and confirmed its association with high risk features of poor tumour grade (P ¼ 0.027) and lymphovascular invasion (P ¼ 0.001) [76]. Outcomes of multimodal organ preserving treatment for rectal cancer A review of low-grade T2 tumours after R0 resection by local excision alone demonstrated a local recurrence rate of 19%. If high risk findings were also present, the recurrence rose to 52%. By immediate radical reoperation the recurrence rate decreased to 7% but after adjuvant therapy was 16%. In contrast, after neoadjuvant CRT resulted in recurrence rates of 9% [77]. CRT and then TEM excision for T2 cancer has been examined in case series [78]. 84 patients with T2 disease underwent neoadjuvant CRT and TEMS excision. Local recurrence occurred in four patients, all of whom failed to respond to CRT. Median follow up was 97 months and disease free survival in this group was 93%, comparable to radical surgery. A randomised control trial has examined outcomes in low risk T2 cancers receiving neoadjuvant CRT, comparing TEMS to radical laparoscopic surgery [79]. Fifty patients were recruited in each arm with homogenous parameters and tumour biology/location. 40 patients experienced toxicity from CRT but this did not affect the treatment course in any case, the pCR rate was 27%. In the TEMS group there were no conversions to open surgery and one delayed stoma formed for suture line dehiscence. In the TME group there were five conversions to open surgery and 23 patients had a stoma, with 12 being permanent due to abdomino-perineal resection. TEMS group had shorter length of stay (3 vs 6 days p ¼ 0.001), less blood loss (p ¼ 0.001), shorter operating time (p ¼ 0.001). No one in the TEMS group required a blood transfusion whilst ten in the TME did. There was no difference in disease free survival between the two groups (p ¼ 0.686) over 9.6 year median follow up. The role of neoadjuvant CRT in T3 disease is unclear with early non systematic reviews demonstrating local recurrence of up to 42% in tumours that did not respond to CRT [80]. A single case series has shown if a good response to CRT is seen (grade 2/3) in T3 tumours that are excised by TEMS after neoadjuvant CRT (patients were unfit or refused radical surgery) then over short term follow up (median 24 months) the rate of recurrence is nil [81]. In high risk groups across T1-T3 response to radiotherapy has been shown to predict well the need for a completion procedure. A single case series of 89 patients with large high risk T1 or T2/3 received modified short course radiotherapy 5  5 Gy plus 4 boost (SCPRT) or CRT. All underwent delayed local excision (41.6% TEM) and if histology demonstrated they were down staged to T0/ 1, they were deemed to have had definitive treatment (good responders). Radical surgery was offered to remaining patients. Good response to radiation was seen in 67.2% of patients in the SCPRT group and in 80.0% in the CRT group (p ¼ 0.30). Local recurrence at 2 years (median follow-up) in good responders was 11.8% in the short-course group and 6.2% in the CRT group (p ¼ 0.53) and lower in the elderly (>69 yrs).18 patients initially managed with local excision required radical surgery but either refused it or were unfit. In this group, local recurrence at 2 years was 37.1% [71]. Further outcomes from chemoradiation therapy and TEMS excision will be examined by the CARTS study: Chemoradiation therapy for rectal cancer in the distal rectum followed by organ-sparing transanal endoscopic microsurgery clinicaltrials.gov (NCT01273051) [82]. This will look at definitive

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pCR rates after TEMS excision if the patient responds well to CRT vs TME surgery for non-responders or unfavourable TEMS histology. Quality of life after combined modality treatment is important analysis in this trial. Some concerns have been raised as to level of morbidity after this modality with increased pain and readmissions. In a single centre series, patients having CRT and TEMS compared to TEMS alone, patients undergoing CRT were more likely to develop grade II/III immediate complications (56% vs 23%; p ¼ 0.05). Overall, the 30-day readmission rate was 30%. Wound dehiscence was significantly more frequent among patients undergoing CRT (70% vs 23%; p ¼ 0.03) and patients undergoing CRT were at much higher risk of readmission (43% vs 7%; p ¼ 0.02) [83]. In this same cohort of treated patients the rate of recurrence was high at 15% with only early follow up of median 15 months [84]. The wound complication rates were high in this cohort, in particular wound dehiscence (23% in non-irradiated group). It is apparent that neoadjuvant radiotherapy does increase wound complication rates in TEMS excision. In single case series, morbidity with neoadjuvant radiotherapy was 33% compared 5.3% with TEMS alone (p  0.05). Wound complication rates were 25.6% and 0% respectively (p ¼ 0.015) and most were minor wound dehiscences requiring outpatient antibiotics. Only one patient (2.3%) required a stoma for diversion [75]. Short term results of CRT with TEMS excision for early rectal cancers has demonstrated marked toxicity also. 90 patients were recruited into a phase II trial to assess the efficacy and safety of CRT and local excision for T2N0 rectal cancer (ACOSOG Z6041 trial). Capecitabine and radiation doses were both reduced due to toxicity, but pCR rate (44%) and downstaging rate (64%) was high. 39% of patients developed CRT-related grade 3 complications with rectal pain the most common [85]. Finally, patient choice is of paramount importance when considering each step of the patient’s intervention. This is especially true with low lying and very early stage disease. Contemporary decision analysis comparing local excision over abdomino-perineal excision (APE) for low lying T1 cancer found local excision to be preferable in most patients. APE confers a 3.5% longer life expectancy, but this advantage is lost when the quality-of-life reduction reported by stoma patients is taken in to account. It is the minority of patients who would not sacrifice a percentage of life expectancy to avoid a permanent stoma [86]. The role of TEMS in early rectal cancer is bespoke and further developments in the understanding of predictive biomarkers with increase this even more. TEMS will be suitable for a lot of patients with early rectal cancer and advocating TME for these patients will create unacceptable morbidity and over treat them. Predicting response to radiotherapy and nodal disease at presentation will help in reducing unnecessary TEMS excisions and completion procedures. The field is evolving rapidly as the understanding of this group of tumours biology is better understood.

Extended indications for TEM and NOTES The precise nature of TEM means it is suitable for a wide range of operative indications in the rectum. It is commonly used in the excision of small carcinoid tumours and GISTs and has been described in the repair of high rectovaginal fistulae, drainage of pelvic abscesses and treatment of colorectal anastomotic strictures.

Practice points  TEMS should be undertaken at specialist centres and with trained staff  Accurate multimodal pre-operative assessment is crucial to ensure correct position and technique  The use of TEMS in benign and malignant rectal resection is evolving  It provides an accurate method for removal of large specimens and should compliment other endoscopic techniques e.g. EMR  It role in early rectal cancer is developing still along with neoadjuvant therapies and the optimum surgical technique is yet to be defined

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Research agenda  In benign disease the role of TEMS in comparison to EMR is yet to be assessed by results of a randomised trial  Better research is required in to identifying benign from malignant disease pre-operatively  Identifying patients with biomarker susceptibility to radiotherapy  Identifying further predictive markers of advanced/nodal disease at presentation to select patients for organ preservation accurately  To discover which radiotherapy treatment course best compliments TEMS in early rectal cancer  Quality of life data to ensure patients are given the best options for optimal outcome in their disease treatment.

Natural Orifice Transluminal Endoscopic Surgery (NOTES) is becoming increasingly explored as a form of minimally invasive surgery. The first human NOTES procedure was a transgastric appendicectomy in India in 2004. The impact of NOTES on minimally invasive surgery could mirror that of laparoscopy on open surgery. There are obvious advantages to NOTES; no scars or sequalae of abdominal wall healing, better cosmesis and potentially quicker recovery times and less morbidity or mortality. This must be traded off with adequate data to support surgical and oncological safety outcomes however. The transrectal route using TEM provides an excellent platform with precise instrumentation for adequate rectal wall closure. It can also provide a ‘bottom up’ access to a challenging surgical avenue, the narrow male pelvis. A combined laparoscopic/transanal approach to oncological proctectomy with coloanal anastomosis is well described [87]. Transanal rectosigmoidectomy with total mesorectal excision (TME) using TEM is a feasible and oncologically safe option. Such use of currently available combined hybrid laparoendoscopic systems provides a safe platform to define future clinical applications and advantages of NOTES. Most recently the first entirely transanal resection of a rectosigmoid neoplasm was successfully undertaken, with full TME and sigmoid mobilization [88]. Summary TEM has been widely adopted by colorectal surgeons over the last 30 years. Although it requires specialist training and potentially expensive set up costs, it provides an invaluable resource for coloproctology. Its precise nature and resilient technique has ensured it has a major role in the resection of benign and malignant neoplasms of the rectum. Its role in the management of early rectal cancer is increasing as the indication for local excision combined with neoadjuvant therapies is growing. TEMS alone will treat a percentage of early rectal cancers and it will provide an oncologically sound, lower risk option for patients, with better functional outcome. On going research will dictate how we identify higher risk tumours pre-operatively and who will benefit from neoadjuvant radiotherapy or not. It may also provide an exciting and robust platform for transanal NOTES to be incorporated into mainstream colorectal operations in the future. Conflict of interest statement None. References [1] Buess G, Theiss R, Hutterer F, Pichlmaier H, Pelz C, Holfeld T, et al. Transanal endoscopic surgery of the rectum – testing a new method in animal experiments. Leber Magen Darm 1983;13(2):73–7. [2] Parks AG. A technique for excising extensive villous papillomatous change in the lower rectum. Proc R Soc Med 1968 May; 61(5):441–2. [3] Sakamoto GD, MacKeigan JM, Senagore AJ. Transanal excision of large, rectal villous adenomas. Dis Colon Rectum 1991 Oct;34(10):880–5.

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