Addendum to clinical guideline 131, Colorectal cancer

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1 : National Institute for Health Care Excellence Final Addendum to clinical guideline 131, Colorectal cancer Clinical guideline addendum Methods, evidence recommendations December 2014 Final version National Institute for Health Care Excellence

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3 Contents Disclaimer Healthcare professionals are expected to take NICE clinical guidelines fully into account when exercising their clinical judgement. However, the guidance does not override the responsibility of healthcare professionals to make decisions appropriate to the circumstances of each patient, in consultation with the patient /or their guardian or carer. Copyright National Institute for Health Care Excellence, All rights reserved. This material may be freely reproduced for educational not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the express written permission of NICE.

4 Contents Contents Clinical guidelines update Summary section Update information Recommendations Patient-centred care Methods Evidence review recommendations Review question 1: stenting as a bridge to surgery for bowel obstruction caused by suspected colorectal cancer Review question Evidence review Health economic evidence Evidence statements Evidence to recommendations Recommendations Review question 2: treatments for early rectal cancer Review question Evidence review Health economic evidence Evidence statements Evidence to recommendations Recommendations Research recommendation References Glossary abbreviations Appendices Appendix A: Committee members NICE teams A.1 Sting Committee members A.2 Topic-specific Committee members A.3 Clinical guidelines update team A.4 NICE project team Appendix B: Declaration of s Appendix C: Review protocol, review question Appendix D: Search strategy, review question Appendix E: Review flowchart, review question Appendix F: Excluded studies, review question Appendix G: Evidence tables, review question Appendix H: GRADE profiles, review question

5 Contents Appendix I: Forest plots, review question Appendix J: Economic search strategy, review question Appendix K: Economic review flowchart, review question Appendix L: Economic excluded studies, review question Appendix M: Economic summary table of included studies, review question Appendix N: Economic evidence tables, review question Appendix O: Review protocol, review question Appendix P: Search strategy, review question Appendix Q: Review flowchart, review question Appendix R: Excluded studies, review question Appendix S: Evidence tables, review question S.1 Romised controlled trials S.2 Observational studies Appendix T: GRADE profiles, review question T.1 Transanal endoscopic microsurgery vs radical bowel resection T.2 Chemoradiation with transanal endoscopic microsurgery (TEMS) vs chemoradiation with radical bowel resection T.3 Transanal endoscopic microsurgery vs transanal excision T.4 Endoscopic resection vs transanal endoscopic microsurgery vs transanal excision vs radical bowel resection Appendix U: Economic search strategy, review question Appendix V: Economic review flowchart, review question Appendix W: Economic excluded studies, review question

6 Clinical guidelines update Clinical guidelines update The NICE Clinical Guidelines Update Team update discrete parts of published clinical guidelines as requested by NICE s Guidance Executive. Suitable topics for update are identified through the surveillance programme (see surveillance programme interim guide). These guidelines are updated using a sting Committee of healthcare professionals, research methodologists lay members from a range of disciplines localities. For the duration of the update the core members of the Committee are joined by up to 5 additional members who are have specific expertise in the topic being updated, hereafter referred to as topic-specific members. In this document where the Committee is referred to, this means the entire Committee, both the core sting members topic-specific members. Where sting committee members is referred to, this means the core sting members of the Committee only. Where topic-specific members is referred to this means the recruited group of members with topic-specific expertise. All of the sting members the topic-specific members are fully voting members of the Committee. Details of the Committee membership the NICE team can be found in appendix A. The Committee members declarations of can be found in appendix B. 6

7 Summary section 1 Summary section 1.1 Update information The colorectal cancer improving outcomes guidance (NICE cancer service guideline CSGCC) was reviewed in 2012 as part of NICE s routine surveillance programme to decide whether it required updating. The surveillance report identified new evidence relating to two areas of the guidance: The delivery of services for the management of people presenting with acute bowel obstruction caused by colorectal cancer; The delivery of services for the management of early rectal cancer. The Colorectal cancer improving outcomes guidance is closely related to the Colorectal cancer guideline (NICE clinical guideline 131). The surveillance report recommended that the NICE clinical guideline 131 is considered for update in conjunction with NICE cancer service guideline CSGCC. The full report can be found here: New recommendations relating to the use of stenting as a treatment for bowel obstruction caused by colorectal cancer, the management of early rectal cancer have been made in this addendum. The recommendations made in this update replace recommendations in section recommendation in section of the original guideline. Some recommendations can be made with more certainty than others. The wording used in the recommendations in this addendum denotes the certainty with which the recommendation is made (the strength of the recommendation). For all recommendations, NICE expects that there is discussion with the patient about the risks benefits of the interventions, their values preferences. This discussion aims to help them to reach a fully informed decision (see also Patient-centred care ). Recommendations that must (or must not) be followed We usually use must or must not only if there is a legal duty to apply the recommendation. Occasionally we use must (or must not ) if the consequences of not following the recommendation could be extremely serious or potentially life threatening. Recommendations that should (or should not) be followed a strong recommendation We use offer ( similar words such as refer or advise ) when we are confident that, for the vast majority of people, following a recommendation will do more good than harm, be cost effective. We use similar forms of words (for example, Do not offer ) when we are confident that actions will not be of benefit for most people. Recommendations that could be followed We use consider when we are confident that following a recommendation will do more good than harm for most people, be cost effective, but other options may be similarly cost effective. The course of action is more likely to depend on the person s values preferences than for a strong recommendation, so the healthcare professional should spend more time considering discussing the options with the person. 7

8 Summary section 1.2 Recommendations For patients with acute left-sided large bowel obstruction caused by colorectal cancer that is potentially curable, for whom surgery is suitable: 1. Resuscitate patients explain to them their family members or carers (as appropriate) that acute bowel obstruction can initially be managed either with emergency surgery or a colonic stent, that there is no clear evidence that one treatment is better than the other. [new 2014] 2. Offer patients the chance to take part in a romised controlled trial a (if available) that compares emergency surgery with colonic stent insertion to initially manage acute bowel obstruction. [new 2014] For patients with acute left-sided large bowel obstruction caused by colorectal cancer that is not potentially curable, or for whom surgery is unsuitable: [new 2014] 3. Resuscitate patients with acute large bowel obstruction, then consider placing a self-exping metallic stent to initially manage a left-sided complete or nearcomplete colonic obstruction. [2011] 4. A consultant colorectal surgeon should consider inserting a colonic stent in patients presenting with acute large bowel obstruction. They should do this together with an endoscopist or a radiologist (or both) who is experienced in using colonic stents. [2011] For patients with stage I rectal cancer: 5. After discussion in the MDT responsible for the management of stage I rectal cancer, discuss uncertainties about the potential risks benefits of all treatment options with patients their family members carers (as appropriate), taking into account each patient s circumstances. [new 2014] 6. Explain to patients their family members or carers (as appropriate) that there is very little good-quality evidence comparing treatment options for stage I rectal cancer. [new 2014] 7. Offer patients the chance to take part in a romised controlled trial (if available) that compares treatment options for stage I rectal cancer. [new 2014] 1.3 Patient-centred care Patients healthcare professionals have rights responsibilities as set out in the NHS Constitution for Engl all NICE guidance is written to reflect these. Treatment care should take into account individual needs preferences. People should have the opportunity to make informed decisions about their care treatment, in partnership with their healthcare professionals. If someone does not have the capacity to make decisions, healthcare professionals should follow the Department of Health s advice on consent, the code of practice that accompanies the Mental Capacity Act the supplementary code of practice on deprivation of liberty safeguards. In Wales, healthcare professionals should follow advice on consent from the Welsh Government. a At the time of publication (December 2014), the CReST trial was recruiting patients with acute bowel obstruction caused by suspected colorectal cancer for romisation to either colonic stent insertion or emergency surgery. 8

9 Summary section NICE has produced guidance on the components of good patient experience in adult NHS services. All healthcare professionals should follow the recommendations in Patient experience in adult NHS services. 1.4 Methods This update was developed based on the process methods described in the guidelines manual Where there are deviations from the process methods, these are stated in the interim process methods guide for updates pilot programme

10 Evidence review recommendations 2 Evidence review recommendations Introduction Evidence reviews were conducted for two areas of the colorectal cancer clinical guideline. Review question 1 covers the use of colonic stents as a bridge to surgery for the treatment of acute bowel obstruction. Review question 2 covers treatment options for early rectal cancer. 2.1 Review question 1: stenting as a bridge to surgery for bowel obstruction caused by suspected colorectal cancer Acute bowel obstruction is a common first presentation of colorectal cancer, requires urgent treatment. One approach is to offer emergency surgery to remove the obstruction. An alternative approach is to place a self-exping metal stent to relieve the obstruction, then carry out elective surgery at a later time. The aim of this review was to determine the effectiveness of stenting followed by elective bowel resection compared with emergency bowel resection Review question What is the effectiveness of stenting followed by planned elective bowel resection compared with emergency bowel resection for suspected colorectal cancer causing acute bowel obstruction? Evidence review A systematic search was conducted (see appendix D) which identified 5700 articles. The titles abstracts were screened 55 articles were identified as potentially relevant. Full-text versions of these articles were obtained reviewed against the criteria specified in the review protocol (appendix C). Of these, 48 were excluded as they did not meet the criteria 7 met the criteria were included. Two articles reported the same study, so there were 6 included studies. A list of excluded studies together with the reason for their exclusion is provided in appendix F. Important outcomes were chosen ranked by the topic-specific members of the Committee. The relative value of different outcomes was discussed, the final rankings were completed by each topic-specific member independently, collated, then agreed by the other Committee members before the review was carried out. The following outcomes (listed in order of importance) were considered important for decision making: quality of life, bowel function, permanent stoma formation mortality (equal ranking), success of procedure total hospital stay (equal ranking) metastatic recurrence. The review protocol (appendix C) specified that the population for the review was patients with acute bowel obstruction causes by suspected colorectal cancer. The term suspected was used because acute bowel obstruction presents as an emergency definitive diagnosis is often not possible. Two of the 6 studies reported the proportion of patients included in the study who were subsequently found not to have colorectal cancer (5 8.2%). For most of the outcomes, it was not possible to combine data statistically in a meta-analysis, either because only 1 study reported the outcome (quality of life bowel function), or because there were differences in the time point at which the outcome was reported across 10

11 Evidence review recommendations studies (mortality metastatic recurrence), or because data were not reported in a format that allowed studies to be meta-analysed (total hospital stay, which was reported as median with a range or interquartile range). Data for the remaining two outcomes (permanent stoma formation success of procedure) were combined using meta-analyses. Four studies were combined for the outcome permanent stoma formation 6 studies were combined for the outcome success of procedure. A rom-effects model was used using the Mantel- Haenszel method because the treatment effects were unlikely to be identical across studies due to the different surgeons surgical procedures used. The I 2 tau 2 statistics were calculated to assess heterogeneity. Forest plots showing the outcome of these metaanalyses are shown in appendix I. Two studies were excluded from these meta-analyses presented separately because the surgical procedure specified for the emergency surgery group was different to the surgical procedure for the stenting group (for the other studies included in the meta-analysis, the surgical procedure was at the choice of the surgeon for both the emergency surgery stenting arms). Details of the included studies are given in evidence tables in appendix G. The quality of evidence for each important outcome was appraised using the approach recommended by the Grading of Recommendations, Assessment, Development Evaluation (GRADE) working group (see appendix H). Typical reasons for downgrading the evidence for risk of bias included lack of blinding (evidence was only downgraded for lack of blinding for outcomes judged particularly susceptible to bias due to open treatment), lack of clarity in how outcomes were reported, differences between groups other than the comparison of to the review question. Inconsistency was only assessed when data was combined in a meta-analysis. The degree of heterogeneity was assessed, 95% confidence intervals were examined to determine whether serious inconsistency was present, using the methods described by the GRADE working group. Indirectness was assessed by noting whether the evidence directly applied to the review question; no cases of serious indirectness were noted. Imprecision was assessed by determining whether 95% confidence intervals incorporated clinically significant harm, no effect clinically significant benefit. If all three were incorporated in the confidence interval, imprecision was judged very serious. If two of the three were incorporated, imprecision was considered serious. Minimally important differences were used to assess clinical significance; for dichotomous variables, the stard values of , recommended by the GRADE working group were used. For continuous measures, reference was made to published clinically importance differences. Other factors were also considered, but none gave rise to serious uncertainty, so this column was omitted from the GRADE tables for clarity Health economic evidence An additional search was done using the same search terms with an economic evaluations filter to identify studies assessing the cost-effectiveness or cost-utility of stenting elective surgery versus emergency surgery (see appendix J). The same criteria were used as for the clinical review. The search retrieved 1428 articles. The titles abstracts were screened for possible inclusion, 19 articles were selected for further examination of the full-text version. Two economic evaluations were included. A summary table full evidence tables are provided in appendices M N. A review flowchart is provided in appendix K, the excluded studies (with reasons for exclusion) are shown in appendix L. Govindarajan et al. (2007) conducted a cost-utility analysis using a Markov chain decision analytic model comparing emergency colonic stenting as a bridge to definitive surgery, to emergency surgery. The base-case patient was a 70 year old male with a complete emergent malignant left colonic obstruction secondary to a left-sided colon cancer with no evidence of metastatic disease. Parameters for the effectiveness of stent placement the 11

12 Evidence review recommendations risk of adverse events were obtained from a systematic review. Probabilities of tumour recurrence were derived from published survival curves. The perspective on costs was from the healthcare payer although this was not explicitly stated. The time horizon was the life of the hypothetical cohort a discount rate of 3% was applied. Health effects were modelled using a utility measure unique to the present study termed Quality Adjusted Life Months (QALM). The utilities used to inform this measure were obtained from a separate study using the stard gamble method. The authors found that emergency colonic stenting was a dominant strategy resulting in an increase in health effects decreased costs compared to emergency surgery. A scenario analysis in which the patient s physiologic status was minimally impaired (i.e. less acute) was conducted also resulted in stenting being a dominant intervention. A series of one-way sensitivity analyses were conducted found that the results were robust with conclusions only changing at extreme threshold values (see appendix N). Probabilistic sensitivity analysis was conducted found that there was a 94% probability that stenting was both more effective less costly based on a willingness to pay threshold of CAD$20,000 per quality adjusted life year (QALY). However, this conclusion is likely to be invalid as it is unknown how it was derived when QALYs were not used as the measure of health effects in the model no supporting methodology is provided. The study is partially applicable but subject to several methodological limitations restricting its generalisability to the present guideline update. The utility values used to model health effects were obtained through direct elicitation using the stard gamble method rather than the EQ-5D instrument preferred as the NICE reference case. Costs are based on the Canadian healthcare system may not apply to the United Kingdom. It is not clear how the results of the probabilistic sensitivity analysis were obtained as distribution parameters are not specified no details of the Monte Carlo simulation are provided. Overall, there were serious methodological limitations preventing the application of the study s findings to the development of recommendations. Singh et al. (2006) conducted a cost-effectiveness analysis that compared colonic stenting, emergent resective surgery, emergent diverting colostomy followed by elective resective surgery. The base-case patient was a 70 year old individual (sex unspecified) with significant yet nonterminal medical comorbidities who presented with acute colonic obstruction. Health effects were measured in terms of the proportion of mortality, proportion of patients with permanent stoma, proportion of patients who received a temporary stoma the mean number of operations per patient. The costs were estimated from the perspective of a Canadian provincial health plan results reported in 2004 Canadian dollars. Parameters were obtained from secondary sources in the scientific literature. The time horizon was 6 months no discounting was applied due to this short timeframe. The results of the decision analytic model found that the strategy of diverting colostomy was the least costly (CAD$11,851) followed by colonic stenting (CAD$13,164) resective surgery (CAD$13,820). Colonic stenting resulted in the least mortality (5%) followed by resective surgery (11%) diverting colostomy (13%). Diverting colostomy was associated with the highest mean number of operations per patient (1.90) compared to resective surgery (1.32) colonic stenting (1.03). The strategy of colonic stenting resulted in the lowest proportion of permanent stomas (2%) compared to resective surgery (14%) diverting colostomy (14%). The authors combined these results to report incremental costeffectiveness ratios (ICERs) of colonic stenting compared to diverting colostomy: CAD$1,415 to prevent a temporary stoma, CAD$1,516 to prevent an operation, CAD$10,791 to prevent a permanent stoma CAD$15,734 to prevent one additional death. ICERs for colonic stenting compared to resective surgery were not reported as resective surgery is dominated by colonic stenting (colonic stenting resulted in decreased costs improved health effects across all measures). b b Costs ICERs have not been converted to 2014 UK due to the limited relevance of the study. 12

13 Evidence review recommendations The study is partially applicable but contains a number of serious limitations preventing its generalisability to the UK setting. Costs are based on the Canadian healthcare setting may not apply to the United Kingdom healthcare system. Although stomas have a substantive impact on quality of life, quality of life was not modelled as a health effect preventing the calculation of quality adjusted life years. The relevance of the ICERs reported is unknown as NICE does not have a stard willingness to pay for these health outcomes. The time horizon of 6 months is short does not allow for modelling for longer-term health outcomes such as tumour recurrence. Probabilistic sensitivity analysis has not been conducted Evidence statements Six romised controlled trials compared stenting followed by elective surgery to emergency surgery for bowel obstruction caused by suspected colorectal cancer. All studies included patients with left-sided obstruction only. One study found no clear difference in quality of life bowel function between groups at 6 months following treatment [low moderate quality, respectively]. Four studies assessed permanent stoma formation. Three were combined in a meta-analysis which showed no clear difference between groups, although a clinically important reduction in stoma formation associated with stenting could not be excluded [moderate quality]. One study was not included in the meta-analysis because, unlike the other studies, the surgical procedure was specified as different for the stenting emergency surgery groups in the trial protocol. This study found no clear difference between groups, although a clinically important reduction, or increase, in stoma formation associated with stenting could not be excluded [low quality]. Four studies found no clear difference in mortality between groups, although a clinically important reduction, or increase, in mortality associated with stenting could not be excluded. Mortality was assessed at different time-points across studies [low to very low quality]. Six studies assessed success of procedure (defined as successful treatment of the obstruction by the initially allocated method). Four studies were combined in a meta-analysis showed no clear difference between groups, although a clinically significant lower procedure success in the stenting group could not be excluded [very low quality]. Two other studies were not included in the meta-analysis because, unlike the other studies, the surgical procedure was specified as different for the stenting emergency surgery groups in the trial protocol. These studies also showed no clear difference between groups, but again, clinically important lower procedure success in the stenting group could not be excluded [very low quality]. Five studies assessed total hospital stay, although the time periods over which this was measured were not reported no effect sizes were given. There were no statistical comparisons between groups [very low quality]. Two studies found no clear difference in metastatic recurrence between groups, although a clinically important increase, or decrease, in metastatic recurrence associated with stenting could not be excluded [low quality] Evidence to recommendations Relative value of different outcomes See section for a list of outcomes (in order of importance) that were considered important for decision making. The Committee noted that mortality was an important outcome in both the short long term short term mortality could occur due to surgical 13

14 Evidence review recommendations complications which the topic-specific members noted are common for emergency bowel resection. Long term mortality could occur due to the underlying cancer. Metastatic recurrence long-term mortality were thought to be important outcomes for this question because there is some concern that stenting may cause tumour cells to migrate, potentially aiding cancer spread. Permanent stoma formation was highlighted as an outcome that was very important to patients, as it was thought to have a large impact on quality of life body image, may require substantial psychological adjustment. Sexual dysfunction was also highlighted as a potentially important outcome by some Committee members, although this outcome was not included in the review. Other members indicated that sexual dysfunction was unlikely to be a major complication of bowel resection for acute bowel obstruction, that this outcome was unlikely to differ between the two interventions. Success of procedure was defined in one of two ways: either as successful treatment of the initial obstruction by the originally allocated procedure, or as R0 resection (tumour removal with no tumour cells in tumour margins) at the end of treatment. Evidence was only found for the former definition. The Committee noted that this definition of success does not encompass all aspects of successful treatment, but nevertheless considered that it was an important outcome because if the initial treatment is not successful, then patients must undergo an additional procedure which has clinical economic costs (for example, due to treatment delay). Trade-off between benefits harms Trade-off between net health benefits resource use Quality of evidence It was also noted that there may be some more intangible benefits of stenting that are not easily captured as outcomes. For example, stenting may allow time for informed decisions about treatment to be made outside of an emergency setting, which might be important to patients. The evidence showed no clear difference between stenting emergency surgery for any of the included outcomes, therefore the Committee concluded that there was no reason to favour either treatment, based on current limited evidence the treatments appear to be balanced in terms of harms benefits. Two Canadian economic evaluations were included in the review of health economic studies for this question. The Committee discussed the poor applicability of the studies to the UK healthcare system the serious methodological limitations present in both studies. The Committee determined that the two economic evaluations were of little relevance to the review question on stenting. The Committee did not undertake any further discussion on resource implications due to the evidence showing no clear difference between stenting emergency surgery for any of the included outcomes. The review protocol specified that a step-wise approach would be taken to searching for evidence, with evidence lower down the specified hierarchy (see appendix C) only being considered if there were no studies higher up the hierarchy (or only studies of such low quality they would be insufficient to support recommendations). Evidence from romised controlled trials was available for all outcomes, so observational studies were not considered. The Committee noted that observational studies were very prone to bias in this area, as groups of patients receiving not receiving stents were likely to differ in their baseline characteristics (for example, patients in the stenting group might be more likely to have comorbidities that made them unfit for emergency surgery). The quality of evidence for most outcomes was low or very low. All of the included studies were small (fewer than 51 participants per group), which meant that they were underpowered to detect differences in dichotomous 14

15 Evidence review recommendations outcomes (permanent stoma formation, mortality, success of procedure metastatic recurrence), especially when they could not be combined in a meta-analysis (mortality metastatic recurrence). Three of the 6 trials were closed early due to concerns of their data monitoring committees (one due to excess morbidity in the emergency surgery group, one due to high rates of stent failure, one due to high rates of complications in the stenting group), so did not recruit as many participants as planned, meaning that they were underpowered. None of the trials reported predetermined criteria for stopping the trial early. Other considerations The Committee discussed the fact that blinding of patients clinicians is not usually possible in this treatment area, all of the included studies were un-blinded. This creates potentially serious risk of bias, but the Committee agreed that the impact of lack of blinding was likely to be more serious for patient-reported outcomes (quality of life, bowel function) than outcomes that could be objectively measured (local metastatic recurrence, mortality, permanent stoma formation). Total hospital stay was also considered at serious risk of bias due to the lack of blinding, as this outcome can be directly influenced by patients clinicians. The topic-specific members noted that the stent failure rate in some of the trials was higher than would be expected for routine practice in the UK, this may limit the applicability of the evidence. It was also noted that current management of acute bowel obstruction varies widely across the UK, with some centres routinely offering stenting, some centres routinely offering emergency surgery because of differences in opinion about the best management strategy /or due to a lack of equipment or expertise. A multi-centre romised controlled trial is ongoing in the UK which aims to resolve the uncertainties identified in this review (the CReST trial, coordinated by the Birmingham clinical trials unit). The Committee felt that a successful high-quality romised controlled trial in a UK setting would be extremely valuable, thought that, given the current clinical equipoise in this area, patients (in discussion with families or carers if appropriate) should be offered the opportunity to if such a trial is available Recommendations For patients with acute left-sided large bowel obstruction caused by colorectal cancer that is potentially curable, for whom surgery is suitable: 1. Resuscitate patients explain to them their family members or carers (as appropriate) that acute bowel obstruction can initially be managed either with emergency surgery or a colonic stent, that there is no clear evidence that one treatment is better than the other. [new 2014] 2. Offer patients the chance to take part in a romised controlled trial c (if available) that compares emergency surgery with colonic stent insertion to initially manage acute bowel obstruction. [new 2014] c At the time of publication (December 2014), the CReST trial was recruiting patients with acute bowel obstruction caused by suspected colorectal cancer for romisation to either colonic stent insertion or emergency surgery. 15

16 Evidence review recommendations For patients with acute left-sided large bowel obstruction caused by colorectal cancer that is not potentially curable, or for whom surgery is unsuitable: [new 2014] 3. Resuscitate patients with acute large bowel obstruction, then consider placing a self-exping metallic stent to initially manage a left-sided complete or nearcomplete colonic obstruction. [2011] 4. A consultant colorectal surgeon should consider inserting a colonic stent in patients presenting with acute large bowel obstruction. They should do this together with an endoscopist or a radiologist (or both) who is experienced in using colonic stents. [2011] 2.2 Review question 2: treatments for early rectal cancer Screening for bowel cancer has led to the diagnosis of more cases of early stage rectal cancer. The stard treatment for rectal cancer is radical bowel resection. However, for early rectal cancer, less invasive treatments are available, with the possible benefit of reduced post-operative complications. The aim of this review was to compare the effectiveness of treatments for early rectal cancer Review question What is the most effective treatment for early rectal cancer? Evidence review A systematic search was conducted (see appendix P) which identified 4019 articles. The titles abstracts were screened 75 articles were identified as potentially relevant. Full-text versions of these articles were obtained reviewed against the criteria specified in the review protocol (appendix O). Of these, 65 were excluded as they did not meet the criteria 10 met the criteria were included. Three articles reported the same study at different time points, so there were 8 included studies in total. A list of excluded studies together with the reason for their exclusion is provided in appendix G. Important outcomes were chosen ranked by the topic-specific members of the Committee. The relative value of different outcomes was discussed, the final rankings were completed by each topic-specific member independently, then collated then agreed by the other Committee members before the review was carried out. The following outcomes (listed in order of importance) were considered important for decision making: local cancer recurrence, mortality permanent stoma formation (equal ranking), metastatic cancer recurrence, quality of life, bowel function, sexual dysfunction. A step-wise approach was taken when considering evidence from different study types (see appendix O for details). Romised controlled trials, prospective observational studies retrospective observational studies were included for all outcomes comparisons because the evidence was sparse. Evidence was found for 4 comparisons: 4 studies compared transanal endoscopic microsurgery (TEMS) with bowel resection, 1 study (reported in 3 articles) compared chemoradiation followed by TEMS with chemoradiation followed by bowel resection, 2 studies compared TEMS with transanal excision, 1 study compared TEMS, transanal excision, endoscopic resection bowel resection. It was not possible to combine data statistically in a meta-analysis for any outcome or comparison, either because only 1 study reported the outcome for each comparison (quality of life, bowel function permanent stoma formation), or due to differences in the time points at which the outcome was reported across studies (mortality, local metastatic 16

17 Evidence review recommendations recurrence). The outcome sexual dysfunction was not reported in any study for any comparison. Details of the included studies are given in evidence tables in appendix S. The quality of evidence for each critical important outcome was appraised using the approach recommended by the Grading of Recommendations, Assessment, Development Evaluation (GRADE) working group (see appendix T). Typical reasons for downgrading the evidence for risk of bias included lack of blinding (evidence was only downgraded for lack of blinding for outcomes judged particularly susceptible to bias due to open treatment), lack of clarity in how outcomes were reported, differences between groups other than the comparison of to the review question. Inconsistency was not assessed for any outcome, as no data was combined in a meta-analysis. The degree of heterogeneity was assessed, 95% confidence intervals were examined to determine whether serious inconsistency was present, using the methods described by the GRADE working group. Indirectness was assessed by noting whether the evidence directly applied to the review question; no cases of serious indirectness were noted. Imprecision was assessed by determining whether 95% confidence intervals incorporated clinically significant harm, no effect clinically significant benefit. If all three were incorporated in the confidence interval, imprecision was judged very serious. If two of the three were incorporated, imprecision was considered serious. Minimally importance differences were used to assess clinical significance; for dichotomous variables, the stard values of , recommended by the GRADE working group were used. For continuous measures, reference was made to published clinically importance differences. Other factors were also considered, but none gave rise to serious uncertainty, so this column was omitted from the GRADE tables for clarity Health economic evidence An additional search was done using the same search terms with an economic evaluations filter to identify studies assessing the cost-effectiveness or cost-utility of treatments for early rectal cancer (see appendix U). The same criteria were used as for the clinical review. The search retrieved 1009 articles. The titles abstracts were screened for possible inclusion, 15 articles were selected for further examination of the full-text version. All of these articles were excluded following examination of the full-text articles, leaving no included studies. A review flowchart is provided in appendix V the excluded studies (with reasons for exclusion) are shown in appendix W Evidence statements Transanal endoscopic microsurgery (TEMS) vs radical resection Two romised controlled trials 2 observational studies compared transanal endoscopic microsurgery (TEMS) with radical bowel resection for early rectal cancer. All studies assessed local recurrence. Follow up periods ranged from 18 months to 7.5 years. Two studies assessed recurrence in patients with T1 tumours 2 in patients with a mix of T1 T2 tumours. There was no clear difference in recurrence rates between groups across studies, except for a subgroup with T2 tumours in 1 observational study which showed higher local recurrence in the TEMS group. Local recurrence rates were low in both groups [low to very-low quality]. Two observational studies assessed mortality (1 at 5 years, 1 at a median follow up period of 7.5 years). One study assessed mortality in patients with T1 tumours the other in patients with a mix of T1 T2 tumours. There was no clear difference in mortality between groups, although a clinically important reduction, or increase, in mortality associated with TEMS could not be excluded. Mortality was low in both groups [very-low quality]. 17

18 Evidence review recommendations Two romised controlled trials 1 observational study assessed metastatic recurrence, 2 in patients with T1 tumours 1 in patients with a mixture of T1 T2 tumours. Follow up periods ranged from 18 months to 7.5 years. There was no clear difference in metastatic recurrence between groups for any study, although a clinically important increase, or decrease, in metastatic recurrence associated with TEMS could not be excluded. Metastatic recurrence was low in both groups [low to very-low quality]. One observational study assessed quality of life bowel function in patients with T1 tumours before up to 6 months following treatment. Groups were not statistically compared [very-low quality] Chemoradiation TEMS vs chemoradiation radical resection One romised controlled trial compared chemoradiation TEMS with chemoradiation radical bowel resection for patients with T2 tumours. Local recurrence, mortality, metastatic recurrence were assessed at 3 points during follow up, ranging from 4.7 to 9.6 years (mortality was also assessed at 30 days following treatment). There were no clear differences between groups on any of these outcomes, although a clinically important increase, or decrease, in recurrence or mortality could not be excluded. Local recurrence, metastatic recurrence mortality rates were low in both groups [very-low quality]. There was a clinically important reduction in permanent stoma formation in the chemoradiation TEMS group [moderate quality] TEMS vs transanal excision One observational study compared TEMS with transanal excision for patients with a mix of T1 T2 tumours. Local recurrence mortality at 5 years were reported for all patients separately for patients with tumours equal to or more than 5cm from the anal verge. In both cases there was no clear difference in either local recurrence or mortality between groups, although a clinically important increase, or decrease, in recurrence mortality associated with TEMS could not be excluded [very-low quality] TEMS vs transanal exicision vs endoscopic resection vs radical resection One observational study compared relative 5 year survival in patients with a mixture of T1 T2 tumours undergoing TEMS, endoscopic resection, transanal excision a number of types of radical bowel resection. However, no effect sizes comparing treatments were reported, there was no statistical comparison between groups [very-low quality] Evidence to recommendations Relative value of different outcomes See section for a list of outcomes (in order of importance) that were considered important for decision making. The topic-specific committee members noted that local metastatic recurrence mortality were generally low for early rectal cancer treated with radical resection (the stard treatment in the UK). The Committee therefore felt that it was important that there was good evidence that recurrence mortality were not substantially higher for any of the other treatments considered. Bowel function, permanent stoma formation sexual dysfunction were all considered important as they were commonly affected by bowel resection for rectal cancer with profound impacts on quality of life. 18

19 Evidence review recommendations Trade-off between benefits harms Trade-off between net health benefits resource use Quality of evidence The Committee noted that the relative value of different outcomes was likely to differ among individuals, that this should be taken into account by clinicians when advising patients. There was moderate quality evidence of reduced stoma formation for chemoradiation followed by transanal endoscopic microsurgery (TEMS) compared with chemoradiation followed by resection. Conversely there was some very limited low-quality evidence of higher local recurrence for TEMS compared with resection for patients with T2 tumours. For all other outcomes comparisons, there was no clear difference between treatments, or no evidence. Due to the sparse nature of the evidence, the Committee felt unable to assess the trade-off between benefits harms for different treatments for early rectal cancer. No studies were included in the review of health economic studies for this question (see section 2.2.3). The Committee did not discuss the implications for resource use further due to the lack of evidence favouring any treatment option. The review protocol specified that a step-wise approach would be taken to searching for evidence, with evidence lower down the specified hierarchy (see appendix O) only being considered if there were no studies higher up the hierarchy (or only studies of such low quality they would be insufficient to support recommendations). Evidence from romised controlled trials was only available for a limited number of outcomes comparisons, therefore comparative observational studies were also included. The Committee noted that observational studies in this area were particularly prone to bias because groups of patients who were given different interventions were likely to have different baseline characteristics (for example, patients might be more likely to be treated with TEMS if they had comorbidities that meant radical surgical carried large risks). The Committee suggested that the results of observational studies in this review should be treated with extreme caution. The Committee noted that the evidence across the range of treatments for early rectal cancer was sparse; 15 potential treatments were compared, yet evidence was only found on 4 comparisons, no comparison had evidence for each of the important outcomes. There was no evidence on sexual dysfunction for any of the comparisons. Included studies were mostly small, meaning that estimates of effect were often very imprecise, particularly for dichotomous outcomes where there were few events in either study arm (mortality, local metastatic recurrence). Three articles reported a romised controlled trial comparing chemoradiation TEMS with chemoradiation resection. These studies initially appeared to report separate studies, but communication with the authors indicated that in fact the 3 studies reported the same trial. There was inconsistency in the way that the trial was reported across the three articles, so this study is at serious risk of bias. Other The Committee discussed the fact that blinding of patients clinicians is not usually possible in this treatment area, all of the included studies were un-blinded. This creates potentially serious risk of bias, but the Committee agreed that the impact of lack of blinding was likely to be more serious for patient-reported outcomes (quality of life, bowel function sexual dysfunction) than outcomes that could be objectively measured (local metastatic recurrence, mortality, permanent stoma formation). The Committee discussed the potential equality impact of the new 19

20 Evidence review recommendations considerations recommendations. It was noted that different groups may value outcomes differently, it was important for clinicians to be aware of this when discussing possible treatments with patients. The Committee felt that it was particularly important that clinicians took into account individual preferences when discussing treatments. The 2011 Colorectal cancer guideline states Discuss the risks benefits of all treatment options with the patient after discussion in the MDT. The committee felt that, in light of the current evidence review, this recommendation should be updated to highlight the uncertainties in the evidence, the particular importance of considering individual preferences when discussing treatments. The Committee were concerned about the lack of evidence about treatments for early rectal cancer, wished to send a strong message to clinicians working in this area that romised controlled trials should be conducted patients should be offered the opportunity to Recommendations For patients with stage I rectal cancer: 5. After discussion in the MDT responsible for the management of stage I rectal cancer, discuss uncertainties about the potential risks benefits of all treatment options with patients their family members carers (as appropriate), taking into account each patient s circumstances. [new 2014] 6. Explain to patients their family members or carers (as appropriate) that there is very little good quality evidence comparing treatment options for stage I rectal cancer. [new 2014] 7. Offer patients the chance to take part in a romised controlled trial (if available) that compares treatment options for stage I rectal cancer. [new 2014] Research recommendation 1. Well-designed romised controlled trials should be conducted comparing treatment options for stage I rectal cancer. Outcomes should include recurrence, mortality quality of life, measured over a follow up period of at least 3 years. Why is this important? Rectal cancer is usually treated with radical bowel resection. This procedure has a high cure rate for stage I rectal cancer, but may result in permanent stoma formation, changes in bowel function sexual dysfunction, which have large impacts on quality of life. New treatments for stage I rectal cancers have been developed with the aim of reducing the impact of treatment on quality of life. The effectiveness of treatments for early rectal cancer was investigated in the evidence review, but the few romised controlled trials that were identified were of low quality were too small to provide useful information, particularly on the important outcomes of recurrence mortality. The Committee were unable to recommend treatments for stage I rectal cancer based on the evidence that is currently available. Therefore, well-designed romised controlled trials are needed to resolve this. 20

21 References 3 References Alcantara M, Serra-Aracil X, Falco J et al. (2011) Prospective, controlled, romized study of intraoperative colonic lavage versus stent placement in obstructive left-sided colonic cancer. World Journal of Surgery 35: Chen Yy, Liu Zh, Zhu K et al. (2013) Transanal endoscopic microsurgery versus laparoscopic lower anterior resection for the treatment of T1-2 rectal cancers. Hepatogastroenterology 60: Cheung HYS, Chung CC, Tsang WWC et al. (2009) Endolaparoscopic approach vs conventional open surgery in the treatment of obstructing left-sided colon cancer: a romized controlled trial. Archives of Surgery (Chicago, Ill.: 1960) 144: Christoforidis D, Cho HM, Dixon MR et al. (2009) Transanal endoscopic microsurgery versus conventional transanal excision for patients with early rectal cancer. Annals of Surgery 249: Ghazal AH, El-Shazly WG, Bessa SS et al. (2013) Colonic endolumenal stenting devices elective surgery versus emergency subtotal/total colectomy in the management of malignant obstructed left colon carcinoma. Journal of Gastrointestinal Surgery: Official Journal of the Society for Surgery of the Alimentary Tract 17: Ho KS, Quah HM, Lim JF et al. (2012) Endoscopic stenting elective surgery versus emergency surgery for left-sided malignant colonic obstruction: a prospective romized trial. International Journal of Colorectal Disease 27: Lee W, Lee D, Choi S et al. (2003) Transanal endoscopic microsurgery radical surgery for T1 T2 rectal cancer: Retrospective study. Surgical Endoscopy Other Interventional Techniques 17: Lezoche E, Guerrieri M, Paganini AM et al. (2005) Transanal endoscopic versus total mesorectal laparoscopic resections of T2-N0 low rectal cancers after neoadjuvant treatment: a prospective romized trial with a 3-years minimum follow-up period. Surgical Endoscopy 19: 751v-756 Lezoche E, Baldarelli M, Lezoche G et al. (2012) Romized clinical trial of endoluminal locoregional resection versus laparoscopic total mesorectal excision for T2 rectal cancer after neoadjuvant therapy. The British Journal of Surgery 99: Lezoche E, Paganini AM, Fabiani B et al. (2014) Quality-of-life impairment after endoluminal locoregional resection laparoscopic total mesorectal excision. Surgical Endoscopy Other Interventional Techniques 28: Lezoche G, Baldarelli M, Guerrieri M et al. (2008) A prospective romized study with a 5- year minimum follow-up evaluation of transanal endoscopic microsurgery versus laparoscopic total mesorectal excision after neoadjuvant therapy. Surgical Endoscopy 22: Palma P, Horisberger K, Joos A et al. (2009) Local excision of early rectal cancer: is transanal endoscopic microsurgery an alternative to radical surgery? Revista Espanola de Enfermedades Digestivas: Organo Oficial de la Sociedad Espanola de Patologia Digestiva 101: Pirlet IA, Slim K, Kwiatkowski F et al. (2011) Emergency preoperative stenting versus surgery for acute left-sided malignant colonic obstruction: a multicenter romized controlled trial. Surgical Endoscopy 25:

22 References Saraste D, Gunnarsson U, Janson M (2013) Local excision in early rectal cancer-outcome worse than expected: a population based study. European Journal of Surgical Oncology: the Journal of the European Society of Surgical Oncology the British Association of Surgical Oncology 39: Tung KLM, Cheung HYS, Ng LWC et al. (2013) Endo-laparoscopic approach versus conventional open surgery in the treatment of obstructing left-sided colon cancer: long-term follow-up of a romized trial. Asian Journal of Endoscopic Surgery 6: van Hooft JE, Bemelman WA, Oldenburg B et al. (2011) Colonic stenting versus emergency surgery for acute left-sided malignant colonic obstruction: a multicentre romised trial. The Lancet Oncology 12: Winde G, Nottberg H, Keller R et al. (1996) Surgical cure for early rectal carcinomas (T1). Transanal endoscopic microsurgery vs. anterior resection. Diseases of the Colon Rectum 39:

23 Glossary abbreviations 4 Glossary abbreviations Please refer to the NICE glossary. Additional terms used in this document are listed below: Colonic stent A self-exping metal tube that is placed using a guide wire introduced through the anus. The stent is placed at the site of a bowel obstruction with the aid of an endoscope, in order to relieve the obstruction. Endoscopic mucosal resection A procedure used to remove a section of bowel mucosa in order to remove early rectal tumours using an endoscope to access the rectum through the anus. Transanal endoscopic microsurgery (TEMS) A procedure used to remove early rectal tumours using an endoscope to access the rectum through the anus. The full thickness of bowel wall surrounding the tumour is removed. Radical bowel resection A procedure used to remove a whole section of bowel through the abdominal wall using open or laparoscopic surgery. The remaining ends of bowel are either re-joined, or brought through the abdominal wall to form a stoma. 23

24 Committee members NICE teams Appendices Appendix A: Committee members NICE teams A.1 Sting Committee members Name Role Susan Bewley (Chair) Gita Bhutani Jennifer Bostock Simon Corbett John Graham Peter Hoskin Roberta James Asma Khalil Manoj Mistry Amaka Offiah Mark Rodgers Nicholas Steel Sietse Wieringa Professor of Complex Obstetrics, Kings College London Clinical Psychologist, Lancashire Care NHS Foundation Trust Lay Member Cardiologist, University Hospital Southampton NHS Foundation Trust Consultant Oncologist & Trust Cancer Lead Clinician, Taunton & Somerset Hospital Consultant in Clinical Oncology, Mount Vernon Hospital Programme Lead, Scottish Intercollegiate Guidelines Network (SIGN) Obstetrician, St George s Hospital University London Lay member Radiologist Clinical Senior Lecturer, Sheffield University Research Fellow, University of York Clinical Senior Lecturer in Primary Care, Norwich Medical School A.2 Topic-specific Committee members Name Role Sunil Dolwani James Hill Clive Kay Jonathan Tobutt General Practitioner, Barts & the London School of Medicine & Dentistry Consultant Gastroenterologist, Cardiff Vale University Health Board Colorectal Surgeon, Central Manchester NHS Foundation Trust Consultant Gastrointestinal Radiologist, Bradford Teaching Hospitals NHS Trust Lay member A.3 Clinical guidelines update team Name Role Phil Alderson Jenny Craven Nicole Elliott Kathryn Hopkins Susannah Moon Charlotte Purves Paul Sutton Toni Tan A.4 NICE project team Name Role Martin Allaby Clinical Advisor Information specialist Associate Director Technical Analyst Project Manager Administrator NICE Scholar Technical Advisor Clinical Advisor 24

25 Committee members NICE teams Name Ben Doak James Hall Barbara Meredith Sharon Summers-Ma Judith Thornton Jennifer Wells Role Guideline Commissioning Manager Senior Medical Editor Public Involvement Advisor Guideline Lead Technical Lead Guideline Co-ordinator 25

26 Declaration of s Appendix B: Declaration of s Member name Interest declared Sting Committee members Susan Bewley Susan Bewley Susan Bewley Susan Bewley Susan Bewley Self-employed academic obstetric expert. 100 hour per annum teaching contract with Kings College London. In the last 12 months received income or fees for: Research projects as a principal or co-investigator or giving expert advice (presently these include projects on major postpartum haemorrhage, the organisation of maternity care, gestation time for abortion) Academic supervision (PhD on implementation of external cephalic version, chair of 35/39 TSC on the timing of induction) Teaching (BSc law ethics tutor at KCL, occasional fees for lectures on obstetrics) Medico-legal reports (approx. 2/year) Medical Defence Union cases committee council External reviews for NHS organisations related to my obstetric expertise (serious incident maternal mortality investigations, RCOG review) Chairing NICE GDG Expert advice to NHS Quest (development of a maternity safety thermometer ) Royalties from edited books Advice to Marie Stopes International about obstetric stards Expenses paid to attend conferences to lecture on obstetric topics. In the last year this included speaking to a Human Rights conference at the Hague, the Royal Society of Edinburgh, the International Society of Psychosomatic Obstetrics Gynaecology, attending the British Maternal Fetal Medicine Society conference. Received a community grant to attend the British HIV Association conference. Joint intellectual property rights in a new neonatal resuscitation trolley, but Date declared Type of 30/05/2013 Personal pecuniary 30/05/2013 Personal pecuniary 30/05/2013 Personal pecuniary 30/05/2013 Personal pecuniary 30/05/2013 Non-personal pecuniary Decision 26

27 Declaration of s Member name Susan Bewley Susan Bewley Susan Bewley Susan Bewley Susan Bewley Gita Bhutani Gita Bhutani Jennifer Bostock (Dec 13 Sept 14) Interest declared these were negotiated to be hed over to Liverpool University Inditherm. In return, the inventors have negotiated that a fee generated on the sale of each trolley will be given to charity. Expressed views in publications about obstetric matters, largely based on evidence. A trustee committee member of Healthwatch (a charity devoted to evidence for treatments that work ) a trustee of Sophia (a charity devoted to women with HIV the UK arm of the Global Coalition for Women AIDS). Member of the following editorial boards: Medical Law Review, International Journal of Childbirth, JASS (Journal Article Summary Service); Member of the London Clinical Senate; Member of the Mayor's Office for Policing Crime Violence Against Women Girls Panel; Member All-Parliamentary Party Group on Maternity; Trustee of Maternity Action (a charity which aims to end inequality improve the health well-being of pregnant women, partners young children), one of seven members of the Women s Health Equality Consortium which is a Strategic Partner of the Department of Health. Expert advice to Salamer Trust (funded by WHO to perform a global community consultation of women living with HIV to inform Sexual Reproductive Health Human Rights guideline update). Expenses paid to attend present at Changing Motherhood Assisted reproduction that harms conferences. Chair of Psychological Professions Network North West Member of British Psychological Society; Division of Clinical Psychology; Faculty of Leadership Management Committee Member 2013 current, Lay Member/PPI Advisor CEDAR Institute of Public Health, University of Cambridge 2013 current, PPI Board Member NIHR School of Public Health, NIHR Date declared Type of 30/05/2013 Personal nonpecuniary 30/05/2013 Personal nonpecuniary 11/04/2014 Personal nonpecuniary 11/04/2014 Personal pecuniary 11/04/2014 Personal pecuniary 27/03/2014 Personal nonpecuniary 27/03/2014 Personal nonpecuniary 01/12/2013 Personal nonpecuniary Decision 27

28 Declaration of s Member name Interest declared - University of Sheffield (host) & 7 others 2011 current, Lay Member Advisory Group Healthcare Quality Improvement Partnership 2011 current, PPI Advisor, King s College London (MOVE IT & Pembury studies) 2010 current, Lay Member PPI research group, Healthcare Acquired Infection Research Network 2010 current, PPI Collaborator & Co-Applicant & Trial Steering Committee, Infection RCTrials: Oviva; ARREST & ASSIST + Coapp FAST-GAIN - & FACT - MRC; St Thomas Hospital & University of Oxford & University of Sussex 2009-current, Public Advisor, Dept of Population health University of Oxford 2010 current, Public Involvement Implementation Group Core Member Quality & Outcomes of person-centred care policy research unit: LSE/Oxford & Kent Universities 2010 current, Lay Reviewer, NIHR & Department of Health (Policy Research Programme) 2010 current, Public Member H Acquired Infection Research Network University of West London 2006 current, Committee Member - Lead Reviewer & Sub Com member & Proportionate Review analyst, NHS Research Ethics Committee (Institute of Psychiatry REC MCA flagged.) 2010 current, Lay Committee Member, NIHR: RfPB; PgfAR HS&DR & TCC 2012 current, Ethics Consultant Scabies Study, Public Health Engl, University of Sussex & British Skin Foundation 2010 current, Visiting Guest Lecturer, Dept of Psychological Medicine: Kings College London 2014 current, Lay Reviewer & Ethics Advisor King s Centre for Military Health 2013 current, Committee Member (Trauma) Royal College of Physicians, National Clinical Guidelines Centre current, Lay Research Advisor Date declared Type of Decision 28

29 Declaration of s Member name Simon Corbett Simon Corbett Gail Fortes Mayer (Dec 13 Sept 14) John Graham John Graham John Graham Interest declared Very Brief Interventions Project, University of Cambridge current, Research Design Service PPI Consultant, Research Design Service London & South Central 2011-current, Lay Member Advisor, Guys & St Thomas Biomedical Research Centre Advisory Group 2011 current, FAST-R Consultant (lay), Mental Health Research Network 2014 current, Lay Reviewer, Dept of Health: Policy Research Programme 2011 current, Lay Advisory Group Member, Health Quality Improvement Partnership 2010 current, Independent Mental Health Act Manager, Oxleas NHS FT 2014 current, Lay Research Advisor, Imperial Faculty of Medicine Network Service Adviser for the British Cardiovascular Society. This role incorporates the regional specialty adviser role for the Royal College of Physicians. Acting Director for Clinical Effectiveness for employer (University Hospital Southampton NHS Foundation Trust). Part of this role involves the dissemination implementation of NICE guidance in the Trust. Date declared Type of 21/05/2014 Personal nonpecuniary 21/05/2014 Personal nonpecuniary Decision None 31/01/2014 No action Director of National Collaborating Centre for Cancer this post is funded through a contract with NICE to produce NICE s clinical guidelines. Principal investigator for an ongoing clinical trial in prostate cancer with Custirsen funded by OncoGenex Technologies Inc Teva Pharmaceutical Industries Ltd. Principal investigator for 8 ongoing clinical trials in breast prostate cancer run via the National Cancer Research Network (not pharmaceutical industry funded) 06/12/2013 Non-personal pecuniary 06/12/2013 Non-personal pecuniary 06/12/2013 Non-personal pecuniary 29

30 Declaration of s Member name Interest declared Date declared Type of Decision John Graham Member of the trial management groups for 2 prostate cancer trials: RT01 CHHIP. Both are closed to recruitment but continuing to report trial results. 06/12/2013 Personal nonpecuniary John Graham Principal investigator for a study of radium-223 in prostate cancer that is funded by Bayer Pharmaceuticals. It is non-personal pecuniary started on 12th June. 18/06/2014 Non-personal pecuniary John Graham In May 2014 I did some work for NICE International on a project with the Philippines Department of Health received a consultancy fee, travel subsistence payments. 18/06/2014 Personal nonpecuniary Peter Hoskin Research grant paid to department from Varian Medical (until Dec 2013) 04/06/2013 Non-personal pecuniary Peter Hoskin Investigator in research studies sponsored by various companies with payment for expenses to NHS Trust department which fund research staff. Recent studies have been on behalf of Millenium, Astellas, Ipsen Amgen. 04/06/2013 Non-personal pecuniary Peter Hoskin Fellow of the Royal College of Radiologists member of Faculty Board, Specialist Training Board Chair of Exam Board. 04/06/2013 Personal nonpecuniary Peter Hoskin Consultant to the IAEA; Undertake by invitation lectures working group meetings for which expenses may be paid. 04/06/2013 Personal pecuniary Peter Hoskin Received reimbursement of travelling expenses conference registration fee for attending the European Society of Radiation Oncology (ESTRO) in December /06/2013 Personal pecuniary Peter Hoskin Chief investigator for a trial investigating brachytherapy +/- external bean radiotherapy, which received funding from Dept of Health CRUK. Continues to follow those patients up publish data from the study. 04/06/2013 Non-personal pecuniary Peter Hoskin Holds a research grant from Varian which pays the salary for a data manager working of HDR boost, for Brachytherapy in prostate cancer. 04/06/2013 Non-personal pecuniary Peter Hoskin Department reimbursed for studies on abiraterone by Cougar. 04/06/2013 Non-personal pecuniary Peter Hoskin Department reimbursed for studies on alpharadin by Astellas. 04/06/2013 Non-personal pecuniary 30

31 Declaration of s Member name Peter Hoskin Peter Hoskin Peter Hoskin Peter Hoskin Peter Hoskin Peter Hoskin Peter Hoskin Peter Hoskin Peter Hoskin Peter Hoskin Peter Hoskin Peter Hoskin Peter Hoskin Peter Hoskin Peter Hoskin Peter Hoskin Peter Hoskin Interest declared Department reimbursed for studies on MDV 3100 by Medivation. Department reimbursed for studies on Denosumab for prostate cancer. Funded by Amgen. Department receives grants from Astellas for trials in prostate cancer. Department receives grants from Bayer for trails in prostate cancer. Department received grants from Millennium for trials in prostate cancer. Department received grants from Varian for trials in prostate cancer Trustee for funding research within the unit/department. Funded by Donations/Legacies. No Non- Hodgkin s lymphoma research has been funded in the last 12 months. Chair Steering Group for National Cancer Intelligence Network (NCIN) Member of the committee of Medical Aspects for Radiation Exposure (COMARE) Chair of the executive committee of GEC ESTRO Brachytherapy Group. Member of the faculty board of the Royal College of Radiologists. Member of the specialist training committee for the Royal college of Radiologists. Member of the specialist training advisory committee (STAC) for the Royal College of Radiologist. Editorial board member for the Journal of Clinical Oncology. Editorial board member for the Journal of Contemporary Brachytherapy. Date declared Type of 04/06/2013 Non-personal pecuniary 04/06/2013 Non-personal pecuniary 04/06/2013 Non-personal pecuniary 04/06/2013 Non-personal pecuniary 04/06/2013 Non-personal pecuniary 04/06/2013 Non-personal pecuniary 04/06/2013 Personal non pecuniary 04/06/2013 Personal non pecuniary 04/06/2013 Personal non pecuniary 04/06/2013 Personal non pecuniary 04/06/2013 Personal non pecuniary 04/06/2013 Personal non pecuniary 04/06/2013 Personal non pecuniary 04/06/2013 Personal non pecuniary 04/06/2013 Personal non pecuniary Member of the East of Engl senate. 04/06/2013 Personal non pecuniary Member of the NICE sting committee for rapid updates / non- Hodgkin s lymphoma GDG. 04/06/2013 Personal non pecuniary Decision 31

32 Declaration of s Member name Roberta James Roberta James Roberta James Roberta James Asma Khalil Manoj Mistry Manoj Mistry Manoj Mistry Manoj Mistry Manoj Mistry Manoj Mistry Manoj Mistry Amaka Offiah Amaka Offiah Amaka Offiah Amaka Offiah Interest declared Programme Lead at Scottish Intercollegiate Guidelines Network (SIGN) Validation of systematic review of guideline methodology, Belgian healthcare organisation KCE one off payment. Member of Guideline Implementability Research Application network (GIRAnet). Expert group member of Project on a Framework for Rating Evidence in Public Health (PRECEPT). Date declared Type of 26/05/14 Personal pecuniary 26/05/14 Personal pecuniary 26/05/14 Personal nonpecuniary 26/05/2014 Personal nonpecuniary Decision None 05/07/2013 No action Public member of Penine Care NHS FT as a carer for my sister. Attend monthly meetings PPI representative for the Health Research Authority (HRA). Attended 2 meetings to date PPI representative for the Health Quality Health Improvement Partnership (HQIP) (London). Attended 1 meeting to date PPI representative for the Primary Care Research in Manchester Engagement Resource (PRIMER) group at the University of Manchester. Attended 2 meetings to date Carer representative on NICE Guideline Development Group: Transition between inpatient hospital settings community or care home settings for adults with social care needs. Attended 3 meetings to date. Appointed Lay representative for the Msc Clinical Science (Clinical Bio in formatics) at the University of Manchester. Appointed 'Lay Educational Visitor' at the Health Care Professions Council. (HCPC London) Provision of expert advice to Her Majesty s Courts in cases of suspected child abuse. Recipient of honoraria expenses for lectures guidelines development from BioMarin. Chairperson Skeletal Dysplasia Group for Teaching Research Chairperson Child Abuse Taskforce of the European Society of Pediatric 11/07/2014 Personal nonpecuniary 11/07/2014 Personal nonpecuniary 11/07/2014 Personal nonpecuniary 11/07/2014 Personal nonpecuniary 11/07/2014 Personal nonpecuniary 11/07/2014 Personal nonpecuniary 11/07/2014 Personal nonpecuniary 07/09/2013 Personal pecuniary 22/06/2014 Personal pecuniary 22/06/2014 Personal nonpecuniary 22/06/2014 Personal nonpecuniary 32

33 Declaration of s Member name Amaka Offiah Amaka Offiah Amaka Offiah Amaka Offiah Amaka Offiah Amaka Offiah Amaka Offiah Amaka Offiah Mark Rodgers Mark Rodgers Nicholas Steel Nicholas Steel Nicholas Steel Nicholas Steel Date Type of Interest declared declared Decision Radiology. Member Joint RCR/RCPCH NAI Working Party for Guideline Update - Imaging in Suspected Non-Accidental Injury. Member of the Royal College of Radiology Academic Committee. Committee member of the International Consortium for Vertebral Anomalies Scoliosis. Member of South Yorkshire (Sheffield) Research Ethics Committee. Medical Academic Staff Committee Representative of the Yorkshire Regional Council of the BMA. Partner Governor of the Sheffield Children s NHS Foundation Trust (representing the University of Sheffield). Editorial Committee Member of the journal Paediatric Radiology. Recipient of research funding from NIHR, ARUK, The Sheffield Children s Charity, Skeletal Dysplasia Group for Teaching Research Associate editor of the journal Systematic Reviews that publishes research on health social care. Research fellow in health services research; has provided independent academic reviews of clinical effectiveness diagnostic accuracy evidence for funders including NIHR NICE. Currently finishing work as the principal investigator on a National Institute of Health Research (NIHR) funded project on: Are NICE clinical guidelines for primary care based on evidence from primary care? National Institute for Health Research (NIHR) Health Services & Delivery Research Programme Healthcare Delivery Research Panel member NIHR Regional Advisory Committee for the Research for Patient Benefit Programme East of Engl region Norfolk & Suffolk Primary & Community Care Research Steering Group 22/06/2014 Personal nonpecuniary 22/06/2014 Personal nonpecuniary 22/06/2014 Personal nonpecuniary 22/06/2014 Personal nonpecuniary 22/06/2014 Personal nonpecuniary 22/06/2014 Personal nonpecuniary 22/06/2014 Personal nonpecuniary 22/06/2014 Non-personal pecuniary 21/05/2014 Personal nonpecuniary 21/05/2014 Personal nonpecuniary 31/12/2013 Non-personal pecuniary 06/06/2014 Personal nonpecuniary 06/06/2014 Personal nonpecuniary 06/06/2014 Personal nonpecuniary Nicholas Advisory Committee on Clinical 06/06/2014 Personal non- 33

34 Declaration of s Member name Steel Nicholas Steel Nicholas Steel Nicholas Steel Nicholas Steel Nicholas Steel Nicholas Steel Nicholas Steel Sietse Wieringa Sietse Wieringa Sietse Wieringa Sietse Interest declared Excellence Awards (ACCEA) East of Engl Implementation Science Editorial Board member Quality in Primary Care Editorial Board member Faculty of Public Health Part A MFPH Examiner Faculty of Public Health Part A MFPH Development Committee Honorary Public Health Academic Consultant, Public Health Engl Research grant: Are NICE clinical guidelines for primary care based on evidence from primary care? (Chief Investigator) - National Institute for Health Research, RfPB Publication in press: Steel N, Abdelhamid A, Stokes T, Edwards H, Fleetcroft R, Howe A, Qureshi N. Publications cited in national clinical guidelines for primary care were of uncertain relevance: literature review. In Press Journal of Clinical Epidemiology At the Centre for Primary care & Public Health at Barts & The London School of Medicine & Dentistry/Queen Mary University I am working on a literature review of 'mindlines' (related to communities of practice) a qualitative study of a large group of GPs on a virtual social network sharing medical knowledge. I am funded for this via an NIHR In practice fellowship. I co-own a small social enterprise called ZorgIdee that develops ideas to help GPs to collaborate. There are no current funders. Board member of the Platform of Medical Leadership in the Netherls, via which I am involved in a mixed methods study for the development of a medical leadership competency framework. The study group receives funds from KNMG (Royal Dutch College of Medicine) SBOH which receives its funds from the Dutch Ministry of Health. Member of Generation Next, a think tank network of young GPs. It's Date declared Type of pecuniary 06/06/2014 Personal nonpecuniary 06/06/2014 Personal nonpecuniary 06/06/2014 Personal nonpecuniary 06/06/2014 Personal nonpecuniary 06/06/2014 Personal nonpecuniary 06/06/2014 Personal nonpecuniary 06/06/2014 Personal nonpecuniary 14/05/2014 Personal pecuniary 14/05/2014 Personal pecuniary 14/05/2014 Non-personal pecuniary 14/05/2014 Personal nonpecuniary Decision 34

35 Declaration of s Member name Wieringa Sietse Wieringa Interest declared indirectly funded by the Ministry of Health. Member of NHG (Dutch GP Society), which produces guidelines I worked for this organisation in the past. Topic-specific Committee members Clive Kay Clive Kay James Hill Jonathan Tobutt Sunil Dolwani I am on the Steering Committee of UKRC CTAAC-funded romised multi-centre study of colorectal stenting versus surgery in colonic obstruction (the CReST trail). I have been fully involved in Trial Design, patient selection, protocol development grant application. I am the Lead National Radiologist for the Trail. I review all the serious adverse incidents. I am the chief investigator for the CReST trial of stenting vs surgery for the management of patients with obstructing carcinoma of the left colon. This is a CRUK funded multicentre trial which is expected to stop romisation at the end of Date declared Type of 14/05/2014 Personal nonpecuniary 25/02/2014 Non-personal pecuniary 25/02/2014 Non-personal pecuniary 20/02/2014 Personal nonpecuniary Decision None 08/06/2014 No action None 11/03/2014 No action 35

36 Review protocol, review question 1 Appendix C: Review protocol, review question 1 Details Review Question Objectives Type of Review Language Study Design Status Population What is the effectiveness of stenting followed by planned elective bowel resection compared with emergency bowel resection for suspected colorectal cancer causing acute bowel obstruction? Acute bowel obstruction is a common first presentation of colorectal cancer, requires urgent treatment. One approach is to offer emergency surgery to remove the obstruction. However, mortality morbidity are higher for bowel resection carried out as an emergency procedure than as an elective procedure. An alternative approach is to place a self-exping metal stent to relieve the obstruction, then carry out elective surgery at a later time. However, there are risks associated with the stenting procedure. The aim of this review is to determine the effectiveness of stenting followed by elective bowel resection compared with emergency bowel resection. Intervention English only Systematic reviews, Romised controlled trials, non-romised controlled studies, prospective comparative observational studies (a step-wise approach will be used: see other criteria for inclusion/exclusion below). Published papers (full text only) Adults (aged 18+) with acute large bowel obstruction caused by suspected colorectal cancer which is potentially curable. Intervention Comparator Outcomes Subgroups: Sites of obstruction (left colon, transverse colon, right colon, rectum) Stenting followed by planned elective bowel resection Emergency bowel resection Listed in order of importance: Quality of life Bowel function, Permanent stoma formation (equal ranking) Mortality (measured at any time point between 30 days 3 years**), success of procedure* (equal ranking) Total hospital stay Metastatic cancer recurrence *Success of procedure will be defined as: 1) EITHER Successful treatment of the original obstruction following initial intervention 2) OR R0 resection (defined as tumour removal with no tumour cells in tumour margins) at the end of treatment Data will be extracted separately for each definition. Other criteria for inclusion / exclusion of studies **Modified post-hoc to include mortality at all later time points, due to lack of mortality data between 30 days 3 years. For each outcome, we will search for evidence using a step-wise approach based on the following hierarchy of evidence. If no evidence or evidence that is insufficient to support a recommendation is found following each step, we will proceed to the next level of evidence: 36

37 Review protocol, review question 1 Details Systematic reviews* Romised controlled trials Non-romised controlled studies Prospective comparative observational studies *Systematic reviews must have the same inclusion exclusion criteria as defined in this protocol, meet the quality stards defined in the NICE clinical guidelines methods hbook. Exclude: Narrative reviews, retrospective comparative observational studies, noncomparative studies, case series, case reports Search strategies Review strategies Studies assessing the effectiveness of stenting for palliation only (as judged by the clinician at the time of treatment). Search filters will be applied to limit the search to romised controlled trials comparative observational studies. Data on all included studies will be extracted into evidence tables (where data on whether participants were identified via screening is available, this will be extracted) Where statistically possible, a meta-analytical approach will be used to give an overall summary effect All important outcomes from the evidence will be presented in GRADE profiles or modified profiles further summarized in evidence statements 37

38 Search strategy, question 1 Appendix D: Search strategy, review question 1 Databases that were searched, together with the number of articles retrieved from each database are shown in Table 1. The MEDLINE search strategy is shown in Table 2. The same strategy was translated for the other databases listed. Table 1: Clinical search summary Database Date searched Number retrieved CDSR (Wiley) 11/03/ Database of Abstracts of Reviews of Effects DARE (Wiley) 11/03/ HTA database (Wiley) 11/03/ CENTRAL (Wiley) 11/03/ MEDLINE (Ovid) 07/03/ MEDLINE In-Process (Ovid) 07/03/ EMBASE (Ovid) 07/03/ PsycINFO (Ovid) 11/03/ PubMed 11/03/ Table 2: Clinical search terms (MEDLINE) Line number Search term Number retrieved 1 exp Colorectal Neoplasms/ ((colorect* or colon* or rectal* or rectum* or bowel*) adj4 (cancer* or neoplas* or oncolog* or malignan* or tumor* or tumour* or carcinoma* or adenocarcinoma*)).tw or Intestinal Obstruction/ ((colon* or bowel* or intestin*) adj4 (obstruct* or block*)).tw or/ or exp Stents/ (stent* or sems).tw or Colectomy/ ((colon* or bowel* or intestin*) adj4 (resection or remov*)).tw (colectomy or colectomies).tw or/ or animals/ not human/ not limit 18 to english language Observational Study as Topic/ 83 38

39 Search strategy, question 1 Line number Search term Number retrieved 21 Observational Study/ Epidemiologic Studies/ exp Case-Control Studies/ exp Cohort Studies/ Cross-Sectional Studies/ Comparative Study.pt case control$.tw case series.tw (cohort adj (study or studies)).tw cohort analy$.tw (follow up adj (study or studies)).tw (observational adj (study or studies)).tw longitudinal.tw prospective.tw retrospective.tw cross sectional.tw or/ Romized Controlled Trial.pt Controlled Clinical Trial.pt Clinical Trial.pt exp Clinical Trials as Topic/ Placebos/ Rom Allocation/ Double-Blind Method/ Single-Blind Method/ Cross-Over Studies/ ((rom$ or control$ or clinical$) adj3 (trial$ or stud$)).tw (rom$ adj3 allocat$).tw placebo$.tw ((singl$ or doubl$ or trebl$ or tripl$) adj (blind$ or mask$)).tw (crossover$ or (cross adj over$)).tw or/ or

40 Review flowchart, review question 1 Appendix E: Review flowchart, review question 1 Figure 1: Clinical review flowchart, review question 1 40

41 Excluded studies, review question 1 Appendix F: Excluded studies, review question 1 Reference Reason for exclusion Amin AI, Ramalingam T, Sexton R et al. (2003) Comparison of transanal stent with defunctioning stoma in low anterior resection for rectal cancer. The British Journal of Surgery 90: Angenete E, Asplund D, Bergstrom M et al. (2012) Stenting for colorectal cancer obstruction compared to surgery--a study of consecutive patients in a single institution. International Journal of Colorectal Disease 27: Audisio RA, Zbar AP, Johnson FE (2007) Clinical trials for colonic stents. Lancet 369: Baik SH, Kim NK, Cho HW et al. (2006) Clinical outcomes of metallic stent insertion for obstructive colorectal cancer. Hepato-gastroenterology 53: Bashir RM, Fleischer DE, Stahl TJ et al. (1996) Selfexpable nitinol coil stent for management of colonic obstruction due to a malignant anastomotic stricture. Gastrointestinal Endoscopy 44: Breitenstein S, Rickenbacher A, Berdajs D et al. (2007) Systematic evaluation of surgical strategies for acute malignant left-sided colonic obstruction. The British Journal of Surgery 94: Bridoux V, Schwarz L, Kianifard B et al. (2012) Systematic review meta-analysis of romized clinical trials of selfexping metallic stents as a bridge to surgery versus emergency surgery for malignant left-sided large bowel obstruction. The British Journal of Surgery 99: Ceglie A, Filiberti R, Baron TH et al. (2013) A meta-analysis of endoscopic stenting as bridge to surgery versus emergency surgery for left-sided colorectal cancer obstruction (Provisional abstract). Database of Abstracts of Reviews of Effects: Cennamo V, Luigiano C, Manes G et al. (2012) Colorectal stenting as a bridge to surgery reduces morbidity mortality in left-sided malignant obstruction: a predictive risk score-based comparative study. Digestive liver disease: official journal of the Italian Society of Gastroenterology the Italian Association for the Study of the Liver 44: Cennamo V, Luigiano C, Coccolini F et al. (2013) Metaanalysis of romized trials comparing endoscopic stenting surgical decompression for colorectal cancer obstruction. International Journal of Colorectal Disease 28: Cheung DY, Kim JY, Hong SP et al. (2012) Outcome safety of self-expable metallic stents for malignant colon obstruction: a Korean multicenter romized prospective study. Surgical Endoscopy 26: Chiarugi M, Galatioto C, Panicucci S et al. (2007) Oncologic colon cancer resection in emergency: are we doing enough? Surgical Oncology 16 Suppl 1: S73-S77. Cirocchi R, Farinella E, Trastulli S et al. (2013) Safety Incorrect population (patients without colonic obstruction) Incorrect intervention (compared stenting with emergency surgery, but did not require stenting followed by elective surgery as intervention) Not primary research (letter/comment) Retrospective observational study Incorrect population (people with colon obstruction following bowel resection) Systematic review that does not meet review protocol - use for cross check Not primary research (letter/comment) Systematic review that does not meet review protocol (included noncomparative studies) Use for cross checking Prospective observational study - higher quality (romised control trial) evidence available for all reported outcomes specified in review protocol Systematic review that does not meet review protocol (included palliative studies) Used for cross checking Incorrect comparator (compares two types of stent) Incorrect comparison (comparison of elective vs emergency surgery) Systematic review that does not 41

42 Excluded studies, review question 1 Reference efficacy of endoscopic colonic stenting as a bridge to surgery in the management of intestinal obstruction due to left colon rectal cancer: a systematic review meta-analysis. Surgical Oncology 22: Currie A, Christmas C, Aldean H et al. (2013) Systematic review of self-exping stents in the management of benign colorectal obstruction (Provisional abstract). Database of Abstracts of Reviews of Effects: epub. Dastur JK, Forshaw MJ, Modarai B et al. (2008) Comparison of short- long-term outcomes following either insertion of self-exping metallic stents or emergency surgery in malignant large bowel obstruction. Techniques in Coloproctology 12: De CA, Filiberti R, Baron TH et al. (2013) A meta-analysis of endoscopic stenting as bridge to surgery versus emergency surgery for left-sided colorectal cancer obstruction. Critical Reviews in Oncology/Hematology 88: Fiori E, Lamazza A, Demasi E et al. (2013) Endoscopic stenting for gastric outlet obstruction in patients with unresectable antro pyloric cancer. Systematic review of the literature final results of a prospective study. the point of view of a surgical group. American Journal of Surgery 206: Gianotti L, Tamini N, Nespoli L et al. (2013) A prospective evaluation of short-term long-term results from colonic stenting for palliation or as a bridge to elective operation versus immediate surgery for large-bowel obstruction. Surgical Endoscopy 27: Gorissen KJ, Tuynman JB, Fryer E et al. (2013) Local recurrence after stenting for obstructing left-sided colonic cancer. The British Journal of Surgery 100: Guo MG, Feng Y, Zheng Q et al. (2011) Comparison of selfexping metal stents urgent surgery for left-sided malignant colonic obstruction in elderly patients. Digestive Diseases Sciences 56: Hill J, Gray R, Morton D et al. (2012) Systematic review meta-analysis of romized clinical trials of self-exping metallic stents as a bridge to surgery versus emergency surgery for malignant left-sided large bowel obstruction. The British Journal of Surgery 99: Huang X, Lv B, Zhang S et al. (2014) Preoperative Colonic Stents Versus Emergency Surgery for Acute Left-Sided Malignant Colonic Obstruction: A Meta-analysis. Journal of Gastrointestinal Surgery: official journal of the Society for Surgery of the Alimentary Tract 18: Kavanagh DO, Nolan B, Judge C et al. (2013) A comparative study of short- medium-term outcomes comparing emergent surgery stenting as a bridge to surgery in patients with acute malignant colonic obstruction. Diseases of the Colon Rectum 56: Khot UP, Lang AW, Murali K et al. (2002) Systematic review of the efficacy safety of colorectal stents. The British Journal of Surgery 89: Liu Z, Kang L, Li C et al. (2014) Meta-Analysis of Reason for exclusion meet review protocol (only included left-side obstruction) Used for cross checking Incorrect population (people with benign colorectal obstruction) Retrospective study Systematic review that does not match review protocol included retrospective studies) Used for cross checking Incorrect population (people with gastric outlet obstruction) Prospective observational study - Higher quality (romised control trial) evidence available for all reported outcomes specified in review protocol Prospective observational study - higher quality (romised control trial) evidence available for all reported outcomes specified in review protocol Retrospective observational study Not primary research (letter/comment) Systematic review that does not meet review protocol (only included left-sided obstruction). Used for cross checking. Retrospective observational study Systematic review that does not meet review protocol, use for cross checking Systematic review that does not 42

43 Excluded studies, review question 1 Reference Complications of Colonic Stenting Versus Emergency Surgery for Acute Left-sided Malignant Colonic Obstruction. Surgical Laparoscopy, Endoscopy & Percutaneous Techniques 24: Martinez-Santos C, Lobato RF, Fradejas JM et al. (2002) Self-expable stent before elective surgery vs. emergency surgery for the treatment of malignant colorectal obstructions: comparison of primary anastomosis morbidity rates. Diseases of the Colon Rectum 45: McGregor M (2003) Should the MUHC approve the use of colorectal stents? (Structured abstract). Health Technology Assessment Database Ng KC, Law WL, Lee YM et al. (2006) Self-exping metallic stent as a bridge to surgery versus emergency resection for obstructing left-sided colorectal cancer: a casematched study. Journal of Gastrointestinal Surgery: Official Journal of the Society for Surgery of the Alimentary Tract 10: Park IJ, Choi GS, Kang BM et al. (2009) Comparison of onestage managements of obstructing left-sided colon rectal cancer: stent-laparoscopic approach vs. intraoperative colonic lavage. Journal of Gastrointestinal Surgery: Official Journal of the Society for Surgery of the Alimentary Tract 13: Sabbagh C, Chatelain D, Trouillet N et al. (2013) Does use of a metallic colon stent as a bridge to surgery modify the pathology data in patients with colonic obstruction? A casematched study. Surgical Endoscopy Other Interventional Techniques 27: Sabbagh C, Bartoli E, Regimbeau JM (2011) Which data should be used to define the role of the colonic stent in the management of acute, left-side, malignant colonic obstruction? Clinics Research in Hepatology Gastroenterology 35: Sagar J (2011) Colorectal stents for the management of malignant colonic obstructions. The Cochrane Database of Systematic Reviews: CD Sankararajah D, Forshaw MJ, Parker MC (2005) Multicentre prospective romised controlled trial of pre-operative endoluminal stenting vs. surgery in large bowel obstruction? interim analysis of short term outcomes. Colorectal Disease 7: 73. Slim K (2011) When a seductive concept does not st the test of romized trials: example of preoperative endolumenal colonic stenting. Journal of Visceral Surgery 148: e229-e231. Slim K, Pirlet I, Millat B (2010) Stenting or not stenting before operating malignant colonic obstruction? That is the question. Archives of Surgery (Chicago, Ill.: 1960) 145: Tan CJ, Dasari BVM, Gardiner K (2012) Systematic review meta-analysis of romized clinical trials of selfexping metallic stents as a bridge to surgery versus emergency surgery for malignant left-sided large bowel obstruction. The British Journal of Surgery 99: Tilney HS, Lovegrove RE, Purkayastha S et al. (2007) Comparison of colonic stenting open surgery for Reason for exclusion meet quality stards (criteria for inclusion/exclusion not explicit, only included left-sided obstruction). Used for cross checking. Non-Romised controlled trial - higher quality (romised control trial) evidence available for all reported outcomes specified in review protocol Systematic review that does not match the review protocol (includes non-comparative studies) Observational study - higher quality (romised control trial) evidence available for all reported outcomes specified in review protocol Observational study - higher quality (romised control trial) evidence available for all reported outcomes specified in review protocol Retrospective observational study Not primary research (letter/comment) Systematic review that does not meet review protocol (updated in 2011), use for cross checking Conference abstract (no full text available) Not primary research (narrative review/editorial) Not primary research (letter/comment) Systematic review that does not meet review protocol (updated 2011) Used for cross checking Systematic review that does not meet review protocol (updated in 43

44 Excluded studies, review question 1 Reference malignant large bowel obstruction. Surgical Endoscopy 21: van Hooft JE, Fockens P, Marinelli AW et al. (2008) Early closure of a multicenter romized clinical trial of endoscopic stenting versus surgery for stage IV left-sided colorectal cancer. Endoscopy 40: van Hooft JE, Fockens P, Marinelli AW et al. (2006) Premature closure of the Dutch Stent-in I study. Lancet 368: van Hooft JE, Bemelman WA, Breumelhof R et al. (2007) Colonic stenting as bridge to surgery versus emergency surgery for management of acute left-sided malignant colonic obstruction: a multicenter romized trial (Stent-in 2 study). BMC Surgery 7: 12. Varadarajulu S, Roy A, Lopes T et al. (2011) Endoscopic stenting versus surgical colostomy for the management of malignant colonic obstruction: comparison of hospital costs clinical outcomes. Surgical Endoscopy 25: Warden C, Stupart D, Goldberg P (2013) Stenting as first-line management for all patients with nonperforating left-sided obstructing colorectal cancer. Colorectal disease: the Official Journal of the Association of Coloproctology of Great Britain Irel 15: e389-e395. Warden C, Goldberg PA (2010) The role of colonic stents in South African Journal of Surgery.Suid-Afrikaanse ydskrif vir chirurgie 48: Watt A (2006) Self-exping metallic stents (SEMS) for relieving malignant colorectal obstruction: a systematic review (Structured abstract). Health Technology Assessment Database: 250. Wu J, Rong D-Q, Liu Q-F et al. (2013) Endoscopic stenting combined with neoadjuvant chemotherapy for treatment of malignant colorectal obstruction. World Chinese Journal of Digestology 21: Ye GY, Cui Z, Chen L et al. (2012) Colonic stenting vs emergent surgery for acute left-sided malignant colonic obstruction: a systematic review meta-analysis. World Journal of Gastroenterology: WJG 18: Zhang Y, Shi J, Shi B et al. (2012) Self-exping metallic stent as a bridge to surgery versus emergency surgery for obstructive colorectal cancer: a meta-analysis. Surgical Endoscopy 26: Zhou J-M, Yao L-Q, Xu J-M et al. (2013) Self-expable metallic stent placement plus laparoscopy for acute malignant colorectal obstruction. World Journal of Gastroenterology 19: Reason for exclusion 2005), use for cross checking Treatment was for palliation only Not primary research (letter) Trial protocol (no data presented) Retrospective study Non-comparative study Not primary research (narrative review) Systematic review that does not meet review protocol, use for cross checking Article not in English Systematic review that does not meet review protocol - use for cross checking Systematic review that does not meet review protocol (Include retrospective studies) Used for cross checking Incorrect comparison (open vs laparoscopic surgery following stent placement) 44

45 Evidence tables, review question 1 Appendix G: Evidence tables, review question 1 Bibliographic reference Study type Aim Patient characteristics Alcantara M, Serra-Aracil X, Falco J et al. (2011) Prospective, controlled, romized study of intraoperative colonic lavage versus stent placement in obstructive left-sided colonic cancer. World Journal of Surgery 35: Romised controlled trial To compare short-term results long-term outcomes of patients who underwent intraoperative colonic lavage with primary anastomosis with those who had stent placement prior to scheduled surgery for obstructive left sided colonic cancer. Inclusion criteria: - Aged Complete intestinal obstruction due to tumour in left colon confirmed by abdominal CT Exclusion criteria: - Unresectable lesion - Severe ischemia or cecal perforation, - Faecal or advanced purulent peritonitis - Hemodynamic instability during surgery - Immunodepressed state - Septic shock Baseline characteristics: Stenting Sex 5M/10F 7M/6F Age mean (sd) 71.9 (8.96) (9) Emergency surgery ASA criteria I-II (5) III (8) IV (2) I-II (1), III (9), IV (3) Pathological staging II (2) III (11) IV (2) II (5) III (6) IV (2) Obstruction subsequently found to be not due to colorectal cancer, N Not reported Not reported Intervention Comparison Attrition: One patient left the trial early from the emergency surgery group. Stent placement followed by surgery 5-7 days later (left or sigmoid colectomy or high anterior resection). Emergency intraoperative colonic lavage surgery (left or sigmoid colectomy, high anterior resection or Hartmann s procedure). Number of Patients Stenting: 15 Emergency surgery: 13 45

46 Evidence tables, review question 1 Bibliographic reference Length of follow up Location Outcomes measures effect size Alcantara M, Serra-Aracil X, Falco J et al. (2011) Prospective, controlled, romized study of intraoperative colonic lavage versus stent placement in obstructive left-sided colonic cancer. World Journal of Surgery 35: Up to 60 months (mean 37.6 months, sd 16.08). It is unclear whether the lower mean follow up time was due to the trial ending early Spain Intention to treat analysis Total hospital stay, median (interquartile range) Cumulative survival at end of 60 months follow up (extracted by reviewer from Kaplan Meier curve) Metastatic Cancer recurrence (at any time in follow up period), number of participants Success of procedure (defined as relief from obstruction using initially allocated treatment) Stenting (15) Emergency surgery (13) 8 days (3) 10 days (10) - 59% 70% - **No complications for either procedure reported, so assumed successful Effect size (calculated by reviewer where possible) 7 2 Relative risk = 3.03 (95% CI ) 15** 13** Relative risk = % CI ) Mortality: Kaplan meier curve plotted Log rank test for Kaplan meier survival curve reported as p=0.843, no further details reported Other outcomes reported but not extracted here: POSSUM risk scoring system, operation time, overall complication, global surgical space infection, superficial, deep, organ space, morbidity, anastomotic leakage, seroma, ileus, eviseration, reoperation, hospital mortality, economic cost, local recurrence Source of funding Comments Parc Tauli Foundation - Trial was closed early due to excess morbidity in emergency surgery group - Romisation was via sealed envelopes. - Unclear how choice of surgical procedure was made but probably surgeon s choice. - Concealment of allocation not clear 46

47 Evidence tables, review question 1 Bibliographic reference Alcantara M, Serra-Aracil X, Falco J et al. (2011) Prospective, controlled, romized study of intraoperative colonic lavage versus stent placement in obstructive left-sided colonic cancer. World Journal of Surgery 35: No blinding - Insufficient sample size for precise estimates of outcomes (partly due to early ending of trial) - Unclear how hospital stay was assessed, over what time period. - Interquartile range not adequately reported (reported as single figure rather than extent of quartiles reported explicitly. No report of overall effect size or statistical comparison. - Unclear how hospital stay was assessed, over what time period. Bibliographic reference Study type Aim Patient characteristics Cheung HYS, Chung CC, Tsang WWC et al. (2009) Endolaparoscopic approach vs conventional open surgery in the treatment of obstructing left-sided colon cancer: a romized controlled trial. Archives of Surgery (Chicago, Ill.: 1960) 144: Tung KLM, Cheung HYS, Ng LWC et al. (2013) Endo-laparoscopic approach versus conventional open surgery in the treatment of obstructing left-sided colon cancer: long-term follow-up of a romized trial. Asian Journal of Endoscopic Surgery 6: Romised controlled trial To compare self-exping metal stents with emergency open surgery in the treatment of obstructing left-sided colon cancer. Inclusion criteria: - Left-sided colon cancer - Clinical features of colonic obstruction - Aged 18+ Exclusion criteria: - Unfit for surgery - Previous laparotomy - Palpable tumour on abdominal examination Baseline characteristics: Stenting Sex 12M/12F 14M/10F Emergency surgery BMI median (range) 24 ( ) 23.9 ( ) Age median (range) 68.5 (27-86) 64.5 (39-68) Pathological staging I (0) II (7) III (8) IV (9) I (1) II (7) III (13) IV (3) 30 day mortality Reported in methods but not results Reported in methods but not results 47

48 Evidence tables, review question 1 Bibliographic reference Cheung HYS, Chung CC, Tsang WWC et al. (2009) Endolaparoscopic approach vs conventional open surgery in the treatment of obstructing left-sided colon cancer: a romized controlled trial. Archives of Surgery (Chicago, Ill.: 1960) 144: Intervention Comparison Tung KLM, Cheung HYS, Ng LWC et al. (2013) Endo-laparoscopic approach versus conventional open surgery in the treatment of obstructing left-sided colon cancer: long-term follow-up of a romized trial. Asian Journal of Endoscopic Surgery 6: Obstruction subsequently found to be not due to colorectal cancer, N Not reported Not reported Attrition: One patient from emergency surgery group withdrew consent after surgery was excluded. One patient from the stenting group was excluded because of liver metastasis found after stenting. Stenting followed by laparoscopic-assisted colectomy within 2 weeks Emergency open surgery (the Hartmann procedure, primary anastomosis after either subtotal or total colectomy or segmental colectomy with on-table lavage as judged by surgeon) Number of Patients Intervention: 25 Comparison: 25 Length of follow up Location Outcomes measures effect size Unclear follow up for Cheung 2009, Median follow up of months for emergency surgery stenting, respectively. China Intention to treat analysis Outcome Colonic stenting (n=24) Emergency surgery (n=24) Statistical comparison Total hospital stay (median, range) 13.5 (7-29) 14 (7-55) Mann Whitney U test, p=0.7 Permanent stoma, number of patients Success of procedure (defined as successful relief from obstruction by initially allocated method) Effect size (calculated by reviewer where possible) 6 0 Fisher exact, p=0.03 Relative risk=0.84 (95% CI ) 20 24* None reported Relative risk=0.84 (95% CI ) - Cumulative survival 60 months (Kaplan Meier analysis) *Not reported explicitly, but evident from study flow chart 48% 27% Log rank test, p=

49 Evidence tables, review question 1 Bibliographic reference Cheung HYS, Chung CC, Tsang WWC et al. (2009) Endolaparoscopic approach vs conventional open surgery in the treatment of obstructing left-sided colon cancer: a romized controlled trial. Archives of Surgery (Chicago, Ill.: 1960) 144: Tung KLM, Cheung HYS, Ng LWC et al. (2013) Endo-laparoscopic approach versus conventional open surgery in the treatment of obstructing left-sided colon cancer: long-term follow-up of a romized trial. Asian Journal of Endoscopic Surgery 6: Source of funding Outcomes reported but not extracted here: Operative time, operative blood loss, lymph node harvest number, pain relief required, anastomotic leakage, chest infection, intra-abdominal sepsis, other morbidities, successful 1 stage operation, Maximum pain score, recurrence rate in those with successful tumor removal following initial treatment, disease free survival Not reported Comments - Rom allocation by computer - Concealment of allocation not fully described but probably occurred. - No blinding of patients or clinicians, however impact of absence of blinding of reported outcomes on the reported outcomes likely to be small. - Different surgical procedures between groups (stenting was not the only difference). The stenting group underwent laparoscopic surgery whereas the emergency surgery group underwent open surgery) - Unclear how hospital stay was assessed, over what time period. - No effect size estimate for hospital stay outcome. Bibliographic reference Study type Aim Patient characteristics Ghazal AH, El-Shazly WG, Bessa SS et al. (2013) Colonic endolumenal stenting devices elective surgery versus emergency subtotal/total colectomy in the management of malignant obstructed left colon carcinoma. Journal of Gastrointestinal Surgery : Official Journal of the Society for Surgery of the Alimentary Tract 17: Romised controlled trial To compare the procedures of endoscopic stenting followed by elective colectomy versus total abdominal colectomy ileorectal anastomosis for acute obstructed carcinoma of the left colon. Inclusion criteria: - Acute left-sided colonic obstruction confirmed by abdominal CT. Exclusion criteria: - Distal rectal cancer less than 8cm from the anal verge. - Signs of peritonitis - Presence of metastatic disease 49

50 Evidence tables, review question 1 Bibliographic reference Ghazal AH, El-Shazly WG, Bessa SS et al. (2013) Colonic endolumenal stenting devices elective surgery versus emergency subtotal/total colectomy in the management of malignant obstructed left colon carcinoma. Journal of Gastrointestinal Surgery : Official Journal of the Society for Surgery of the Alimentary Tract 17: Baseline characteristics: Stenting Emergency surgery Statistical comparison (unclear test types) Sex 12M/18F 11M/19F p=0.79 Age range Pathological staging I (6) II (19) III (5) I (7) II (19) III (4) p=0.845, p=0.92, p=0.97 Obstruction subsequently found to be not due to colorectal cancer, N Not reported Not reported - Intervention Comparison Attrition: 1 participant was excluded from the stenting group due to unsuccessful stent placement. No other dropouts are reported. Stenting followed by elective resection (left hemicolectomy or anterior resection) in the following 7-10 days Total abdominal colectomy ileorectal anastomosis Number of Patients Stenting: 30 Emergency surgery: 30 Length of follow up Location Outcomes measures effect size 6-40 months (median 18 months both groups) Egypt Per protocol analysis Metastatic recurrence (any time during follow up) Median hospital stay Success of procedure (defined as relief of obstruction using initially allocated Stenting Emergency surgery Statistical comparison 50 Effect size (calculated by reviewer where possible 3 (n=29) 3 (n=30) None reported Relative risk= 1.03 (95% CI ) 13 days (n=29) 8 days (n=30) Mann Whitney U test p= (n=30) 30 (n=30) None reported Relative risk = 0.97 (95% -

51 Evidence tables, review question 1 Bibliographic reference Ghazal AH, El-Shazly WG, Bessa SS et al. (2013) Colonic endolumenal stenting devices elective surgery versus emergency subtotal/total colectomy in the management of malignant obstructed left colon carcinoma. Journal of Gastrointestinal Surgery : Official Journal of the Society for Surgery of the Alimentary Tract 17: treatment) CI ) Source of funding Outcomes reported but not extracted here: Operation time, operative blood loss, patients requiring transfusion, postoperative complications, bowel frequency Not stated Comments - Romisation via pseudorom number generator - Adequate description of allocation concealment - Different surgical procedures used for the two groups (stenting was not the only difference). The stenting group underwent a left hemicolectomy or anterior resection, whereas the emergency surgery group underwent a total abdominal colectomy ileorectal anastomosis. - Per protocol analysis, however intention treat analysis would give very similar results as only one participant did not receive romised intervention. - No measure of variability for hospital stay outcome, no estimate of effect size. - Unclear how hospital stay was assessed, over what time period. Bibliographic reference Study type Aim Patient characteristics Ho KS, Quah HM, Lim JF et al. (2012) Endoscopic stenting elective surgery versus emergency surgery for leftsided malignant colonic obstruction: a prospective romized trial. International journal of colorectal disease 27: Romised controlled trial To evaluate the role of colonic stenting as a bridge to surgery in acutely obstructed left-sided colon cancer. Inclusion criteria: - Acute intestinal obstruction (diagnosed by clinical symptoms radiologically) secondary to left-sided colon cancer (diagnosed using abdominal CT or sigmoidoscopy) Exclusion criteria: - Obstruction due to non-colonic malignancy - Suspected peritonitis or bowel perforation Attrition: One patient in the stenting arm was excluded after romisation because he/she developed peritonitis before stenting. Baseline characteristics: 51

52 Evidence tables, review question 1 Bibliographic reference Intervention Comparison Ho KS, Quah HM, Lim JF et al. (2012) Endoscopic stenting elective surgery versus emergency surgery for leftsided malignant colonic obstruction: a prospective romized trial. International journal of colorectal disease 27: Colonic stenting (n=20) Emergency surgery (n=19) Age (years) 68 (range 51-85) 65 (range 49-84) Sex 13M/7F 9M/10F Stage of tumour II (7) III (10) IV (15) II (6) III (5) IV (7) Obstruction subsequently found to be not due to colorectal cancer, N Not reported Stenting followed by elective surgery 9-38 days later (surgery at surgeon s choice) Emergency surgery (surgery at surgeon s choice) Number of Patients Stenting: 21 Emergency surgery: 19 Length of follow up Location Outcomes measures effect size Unclear Singapore Intention to treat analysis Not reported Outcome Colonic stenting (n=20) Emergency surgery (n=19) Effect size (calculated by reviewer where possible) Permanent stoma (stoma present 1 year postoperatively) 1 2 Relative risk=0.47 (95% CI ) Mortality (time point unclear) 0 3 Relative risk=0.14 (95% CI ) Total hospital stay, median (range) Success of procedure (defined as relief from obstruction using initially allocated method) *No failures reported, but not explicitly stated 14 (7-41) 13 (7-41) * Relative risk=0.71 (95% CI ) Outcomes reported but not extracted here: Stoma formation, complication rate, time to bowel function return, duration of surgery, length of incision, bowel frequency, time in critical care, total cost 52

53 Evidence tables, review question 1 Bibliographic reference Source of funding Ho KS, Quah HM, Lim JF et al. (2012) Endoscopic stenting elective surgery versus emergency surgery for leftsided malignant colonic obstruction: a prospective romized trial. International journal of colorectal disease 27: Per protocol analysis also presented Not stated Comments - Romised via opaque sealed envelopes - Unclear length of follow up - Sample size insufficient for precise estimate of effects for rare outcomes (mortality, permanent stoma formation) - Unclear how hospital stay was assessed, over what time period. - No effect size estimate for hospital stay outcome. Bibliographic reference Study type Aim Patient characteristics Pirlet IA, Slim K, Kwiatkowski F et al. (2011) Emergency preoperative stenting versus surgery for acute left-sided malignant colonic obstruction: a multicenter romized controlled trial. Surgical Endoscopy 25: Romised controlled trial To compare outcomes of emergency surgery alone with emergency stenting as a bridge to surgery. Inclusion criteria: - Acute left-sided malignant large bowel obstruction confirmed by contrast enema, CT scan or colonoscopy. - Aged 18+ Exclusion criteria: - Signs of perforation - Stage IV tumour - Pregnant - Unfit for either strategy Baseline characteristics: Colonic stenting (n=30) Emergency surgery (n=30) Age (mean, years) 70.4 (sd 10.3) 74.7 (sd 11.3) 53

54 Evidence tables, review question 1 Bibliographic reference Pirlet IA, Slim K, Kwiatkowski F et al. (2011) Emergency preoperative stenting versus surgery for acute left-sided malignant colonic obstruction: a multicenter romized controlled trial. Surgical Endoscopy 25: Sex 16M/14F 13M/17F p-possum (measure of preoperative complications) mean Obstruction subsequently found to be not due to colorectal cancer, n 24.2 (sd 7.6) 21 (sd 7.2) 1 (excluded) (3.3%) 2 (excluded) (6.7%) Total 3/60 (5%) Intervention Comparison Attrition: 2 were excluded from the stenting arm (1 benign lesion, 1 mistaken level of obstruction). 4 were excluded from the emergency surgery arm (2 protocol violations, 1 mistaken level of obstruction, 2 benign lesions) Stent placement followed by elective surgery within same hospitalisation period (procedure choice of surgeon) Emergency surgery (laparotomy, procedure choice of surgeon) Number of Patients Stent: 30 Emergency surgery: 30 Length of follow up Location Outcomes measures effect size Unclear (states that length of follow up was different in different centres) France (9 centres) Intention to treat analysis Outcome Colonic stenting (n=30) Emergency surgery (n=30) Effect size (calculated by reviewer where possible) Permanent stoma 9 8 Relative risk=1.13 (95% CI ) Total hospital stay, median (range) Success of procedure (defined as relief from obstruction using initially allocated method) 23 (9-27) 17 (7-126) Relative risk=0.43 (95% CI ) Outcomes reported but not extracted here: Procedure duration, technical success, complications after primary surgery, mortality during hospital stay, total stoma formation Source of funding Not stated 54

55 Evidence tables, review question 1 Bibliographic reference Pirlet IA, Slim K, Kwiatkowski F et al. (2011) Emergency preoperative stenting versus surgery for acute left-sided malignant colonic obstruction: a multicenter romized controlled trial. Surgical Endoscopy 25: Comments - Unclear length of follow up - Romisation via website. - Allocation concealment not adequately described. - No blinding of patients or clinicians, however impact of absence of blinding of reported outcomes on the reported outcomes likely to be small. - Unclear how hospital stay was assessed, over what time period. - No effect size estimate for hospital stay outcome. woah - Trial ended early due to high technical failure rate for stent placement (53.3%) Bibliographic reference Study type Aim Patient characteristics van Hooft JE, Bemelman WA, Oldenburg B et al. (2011) Colonic stenting versus emergency surgery for acute leftsided malignant colonic obstruction: a multicentre romised trial. The Lancet Oncology 12: Romised controlled trial To establish whether colonic stenting has better health outcomes than emergency surgery for acute bowel obstruction due to malignant colon obstruction. Inclusion criteria: - Total or subtotal acute left-sided colonic obstruction (clinical signs lasting for less than 1 week, dilation of colon on plain radiograph or contrast enhanced CT) - Presumed to be caused by colonic malignancy - Aged 18+ Exclusion criteria: - Signs of peritonitis, perforation, fever, sepsis - Physical status of 4 or 5 according to American Society of Anesthesiologists - Tumour margin <10cm from anal verge - Inability to complete quality of life measures Attrition: - 1 patient refused emergency surgery after romisation. - 5 from stenting group 1 from emergency surgery group withdrew consent following initial treatment (included in analysis until consent withdrawn) Baseline characteristics: Colonic stenting (n=47) Emergency surgery (n=51) Age (years) Mean=70 4 (sd=11 9) Mean=71 4 (sd=9 7) 55

56 Evidence tables, review question 1 Bibliographic reference Intervention Comparison van Hooft JE, Bemelman WA, Oldenburg B et al. (2011) Colonic stenting versus emergency surgery for acute leftsided malignant colonic obstruction: a multicentre romised trial. The Lancet Oncology 12: Sex 24M/23F 27M/24F ASA classification Unknown (1) 1 (16) 2 (24) 3 (6) Severity of obstruction Unknown (1) Incomplete (13) Complete (33) Obstruction subsequently found to be not due to colorectal cancer, N Unknown (1) 1 (17) 2 (27) 3 (6) Unknown (1) Incomplete (14) Complete (36) 4 (8.5%) 4 (7.8%) Total 8/98 (8.2%) Colonic stenting (within 24hrs of romisation) as a bridge to elective surgery (5 days to 4 weeks later) Emergency surgery (within 24hrs of romisation). Surgery according to conventional stards. Number of Patients Intervention: 47 Comparison: 50 Length of follow up Location Outcomes measures effect size 6 months Netherls Intention to treat analysis Outcome Colonic stenting (n=47) Emergency surgery (n=51) Relative risk (95% CI) 30-day mortality (0 28 to 2 98) Overall (6 month) mortality (0 40 to 2 12) Stoma rate at latest follow up (0 85 to 1 59) Success of procedure (defined as relief from obstruction using originally allocated method) 33 51* Calculated by reviewer 0.70 (0.58 to 0.85) *Not explicitly reported, but assumed as no failures reported. Colonic stenting Emergency surgery Between group difference (adjusted for baseline, 95% CI)* Baseline (n=40) Follow up (n=39) Baseline (n=42) Follow up (n=44) 56

57 Evidence tables, review question 1 Bibliographic reference van Hooft JE, Bemelman WA, Oldenburg B et al. (2011) Colonic stenting versus emergency surgery for acute leftsided malignant colonic obstruction: a multicentre romised trial. The Lancet Oncology 12: Global health status, EORTC- QLQ-C30 (mean) 34.0 (sd 23.2) 63.0 (sd 28.7) 42.5 (sd 28.0) 61.4 (sd 21.9) -4.7 (-14.8 to 5.5) Gastrointestinal problems, EORTC-QLQ- C30 (mean) (n=39) (n=38) (n=40) (n=44) 49.9 (15.3) *Estimated marginal mean with baseline values as covariates (13.9) 40.9 (20.1) 15.7 (13.4) 1.2 ( ) Outcomes reported but not extracted here: Morbidity, Other functional symptom scales for quality of life measure, stoma rate after initial intervention Source of funding None Comments - Romisation via computer-generated lists - Adequate description of concealment - Patient physician not blinded. Impact of absence of blinding on mortality, stoma rate success of procedure likely to be small. Impact on quality of life bowel function outcomes potentially serious. - Unclear type of surgical procedure carried out for two groups, how this was decided. - Insufficient sample size for adequate precision on infrequent outcomes (mortality, permanent stoma rate) 57

58 Evidence tables, review question 1 58

59 Forest plots, review question 1 Appendix H: GRADE profiles, review question 1 Table 3: Outcome: quality of life Quality assessment Number of patients Effect Study id or number of studies Design Risk of bias Inconsistency Indirectness Imprecision I=Stenting EORTC-QLQ-C30 Cancer related quality of life, global health status, 6 month follow up 59 C=Emergency surgery Between group difference, adjusted for baseline (95% CI) Van Hooft 2011 RCT serious a n/a no serious serious b (-14.8 to 5.5) low (a) No blinding of participants or clinicians (b) 95% confidence intervals encompass no effect clinically significant harm of stenting (EORTC manual suggests change of corresponds to a moderate change as perceived by patients). Table 4: Outcome: bowel function Quality assessment Number of patients Effect Study id or number of studies Design Risk of bias Inconsistency Indirectness Imprecision I=Stenting EORTC-QLQ-C38 Colorectal specific quality of life, gastrointestinal problems, 6 month follow up C=Emergency surgery Between group difference, adjusted for baseline (95% CI) Van Hooft 2011 RCT serious a n/a no serious no serious (-5.2 to 6.6) moderate (a) No blinding of participants or clinicians. Table 5: Outcome: permanent stoma Quality assessment Number of patients Effect Study id or number of studies Design Risk of bias Inconsistency Indirectness Imprecision Stenting Emergency surgery Relative risk (95% CI) 3 a RCT no no serious no serious serious c 37/97 44/ (0.66 to 1.18) moderate Quality Quality Quality

60 Forest plots, review question 1 Quality assessment Number of patients Effect Study id or number of studies Design Risk of bias Inconsistency Indirectness Imprecision Stenting serious b Emergency surgery Relative risk (95% CI) Cheung RCT very n/a no serious serious e 6/24 0/ (0.77 to ) low 2009 serious d (a) Ho 2012, Pirlet 2011, van Hooft 2011 (b) Not downgraded despite lack of blinding because unlikely to have serious impact on this outcome. (c) 95% confidence intervals incorporate no effect clinically significant harms. (d) Surgery type for stenting emergency surgery groups differed in the study protocol (not at choice of surgeon). Also unclear over what period hospital stay was measured, whether it related only to colorectal-related stays. (e) 95% confidence intervals incorporate no effect clinically significant benefits. Table 6: Outcome: mortality Quality assessment Number of patients Effect Study id or number of studies 30-day Mortality van Hooft 2011 Design RCT Risk of bias Inconsistency Indirectness Imprecision I=Stenting no n/a no serious very serious b serious a Mortality assessed at end of follow up (unclear time point) C=Emergency surgery Relative risk (95% CI) Quality 5/47 5/ (0.28 to 2.98) low Relative risk Ho 2012 RCT serious c n/a no serious very serious b 0/20 3/ (0.01 to 2.47) very low Kaplan Meier cumulative survival, 60 months Alcantara 2011 Cheung 2009 Cumulative survival RCT serious d n/a no serious very serious e I=59% C=70% Log rank test: p=0.843 RCT very n/a no serious very serious e I=48% C=27% serious f Log rank test: p=0.076 (a) Not downgraded despite lack of blinding because unlikely to have serious impact on this outcome. (b) 95% confidence intervals incorporate both clinically significant benefits harms. (c) Time over which mortality was estimated was not reported. (d) Insufficient details of Kaplan Meier analysis reported. (e) No estimate of either effect size or variability reported. (f) Surgery type for stenting emergency surgery groups differed in the study protocol (not at choice of surgeon). Quality very low very low 60

61 Forest plots, review question 1 Table 7: Outcome: success of procedure (defined as successful treatment of initial obstruction following initial intervention) Quality assessment Number of patients Effect Study id or number of studies Design Risk of bias Inconsistency Indirectness Imprecision Stenting Emergency surgery Relative risk (95% CI) 4 a RCT serious b serious c no serious serious d 74/ / (0.47 to 1.05) very low Cheung 2009 RCT very n/a no serious serious f serious e Quality 20/24 24/ (0.69 to 1.01) very low Ghazal RCT very n/a no serious serious f 29/30 30/ (0.88 to 1.06) very low 2013 serious e (a) Alcantara 2011, Ho 2012, Pirlet 2011, van Hooft 2011 (b) Success of procedure not directly reported for most studies, but inferred by reviewer from reported accounts of procedures. (c) High heterogeneity (I2=92%) with non-overlapping confidence intervals. (d) 95% confidence intervals incorporate clinically significant harm no effect. (e) Surgery type for stenting emergency surgery groups differed in the study protocol (not at choice of surgeon). (f) Low event rates (<4 per study) mean 95% confidence intervals may be misleading. Table 8: Outcome: hospital stay Quality assessment Number of patients Effect Study id or number of studies Alcantara 2011 Cheung 2009 Ghazal 2013 Design Risk of bias Inconsistency Indirectness Imprecision I=Stenting C=Emergency surgery Median hospital stay (days) RCT serious a n/a no serious very serious b I=8 (IQR,3) C=10 (IQR,10) *No statistical test of difference between groups RCT RCT very n/a no serious very serious b serious c very n/a no serious very serious b serious c I=13.5 (range,7 to 29) C=14 (range, 7 to 55) Mann Whitney U: p= I=13, C=8 Mann Whitney U: p=0.102 Ho 2012 RCT serious a n/a no serious very serious b I=14 (range, 7 to 41) C=13 (range, 7 to 41) Quality very low very low very low very low 61

62 Forest plots, review question 1 Quality assessment Number of patients Effect Study id or number of studies Design Risk of bias Inconsistency Indirectness Imprecision I=Stenting C=Emergency surgery Median hospital stay (days) *No statistical test of difference between groups Pirlet 2011 RCT serious a n/a no serious very serious b I=23 (range, 9 to 27) C=17 (range, 7 to 126) *No statistical test of difference between groups Quality very low (a) Unclear over what period hospital stay was measured, whether it related only to colorectal-related stays (b) No estimate of effect size given, no estimate of the variability of the effect. (c) Surgery type for stenting emergency surgery groups differed in the study protocol (not at choice of surgeon). Also unclear over what period hospital stay was measured, whether it related only to colorectal-related stays. Table 9: Outcome: metastatic recurrence Quality assessment Number of patients Effect Study id or number of studies Design Risk of bias Inconsistency Indirectness Imprecision Stenting Metastatic recurrence during follow up (median follow up 18 months) Ghazal 2013 Emergency surgery Relative risk (95% CI RCT serious a n/a no serious serious b 3/29 3/ (0.76 to 12.1) low Metastatic recurrence during follow up (mean follow up 37.6 months) Relative risk (95% CI Alcantara RCT no n/a no serious very serious d 7/15 2/ (0.73 to 10.0) low 2011 serious c (a) Surgery type for stenting emergency surgery groups differed in the study protocol (not at choice of surgeon). (b) 95% confidence intervals incorporate both no effect clinically significant benefits. (c) Not downgraded despite lack of blinding as unlikely to have serious impact on this outcome. (d) 95% confidence intervals incorporate both clinically significant benefits harms. Quality 62

63 Forest plots, review question 1 Appendix I: Forest plots, review question 1 Figure 2: Forest plot showing meta-analysis for permanent stoma formation outcome, review question 1 Figure 3: Forest plot showing meta-analysis for success of procedure outcome, review question 1 63

64 Economic search strategy, review question 1 Appendix J: Economic search strategy, review question 1 Databases that were searched, together with the number of articles retrieved from each database are shown in Table 10. The MEDILINE search strategy is shown in Table 11. The same strategy was translated for the other databases listed. Table 10: Economic search summary Database Date searched Number retrieved NHS EED (Wiley) 12/03/ MEDLINE (Ovid) 12/03/ MEDLINE In-Process (Ovid) 12/03/ EMBASE (Ovid) 12/03/ HEED 12/03/ Table 11: Economic search strategy (MEDLINE) Line number Search term Number retrieved 1 exp Colorectal Neoplasms/ ((colorect* or colon* or rectal* or rectum* or bowel*) adj4 (cancer* or neoplas* or oncolog* or malignan* or tumor* or tumour* or carcinoma* or adenocarcinoma*)).tw or Intestinal Obstruction/ ((colon* or bowel* or intestin*) adj4 (obstruct* or block*)).tw or/ or exp Stents/ (stent* or sems).tw or Colectomy/ ((colon* or bowel* or intestin*) adj4 (resection or remov*)).tw (colectomy or colectomies).tw or/ or animals/ not human/ not limit 18 to english language Economics/ exp "Costs Cost Analysis"/ Economics, Dental/ exp Economics, Hospital/ exp Economics, Medical/ Economics, Nursing/ Economics, Pharmaceutical/

65 Economic search strategy, review question 1 Line number Search term Number retrieved 27 Budgets/ exp Models, Economic/ Markov Chains/ Monte Carlo Method/ Decision Trees/ econom$.tw cba.tw cea.tw cua.tw markov$.tw (monte adj carlo).tw (decision adj3 (tree$ or analys$)).tw (cost or costs or costing$ or costly or costed).tw (price$ or pricing$).tw budget$.tw expenditure$.tw (value adj3 (money or monetary)).tw (pharmacoeconomic$ or (pharmaco adj economic$)).tw or/ "Quality of Life"/ quality of life.tw "Value of Life"/ Quality-Adjusted Life Years/ quality adjusted life.tw (qaly$ or qald$ or qale$ or qtime$).tw disability adjusted life.tw daly$.tw Health Status Indicators/ (sf36 or sf 36 or short form 36 or shortform 36 or sf thirtysix or sf thirty six or shortform thirtysix or shortform thirty six or short form thirtysix or short form thirty six).tw. 56 (sf6 or sf 6 or short form 6 or shortform 6 or sf six or sfsix or shortform six or short form six).tw. 57 (sf12 or sf 12 or short form 12 or shortform 12 or sf twelve or sftwelve or shortform twelve or short form twelve).tw. 58 (sf16 or sf 16 or short form 16 or shortform 16 or sf sixteen or sfsixteen or shortform sixteen or short form sixteen).tw. 59 (sf20 or sf 20 or short form 20 or shortform 20 or sf twenty or sftwenty or shortform twenty or short form twenty).tw (euroqol or euro qol or eq5d or eq 5d).tw (qol or hql or hqol or hrqol).tw (hye or hyes).tw health$ year$ equivalent$.tw utilit$.tw (hui or hui1 or hui2 or hui3).tw disutili$.tw

66 Economic search strategy, review question 1 Line number Search term 67 rosser.tw quality of wellbeing.tw quality of well-being.tw qwb.tw. 159 Number retrieved 71 willingness to pay.tw stard gamble$.tw time trade off.tw time tradeoff.tw tto.tw or/ or

67 Economic review flowchart, review question 1 Appendix K: Economic review flowchart, review question 1 Search retrieved 1428 articles 1409 excluded based on title/abstract 19 full-text articles examined 17 excluded based on full text article 2 included studies Figure 4: Economic review flow chart, review question 1 67

68 Review protocol, review question 2 Appendix L: Economic excluded studies, review question 1 Reference Reason for exclusion Binkert CA, Ledermann H, Jost R et al. (1998) Acute colonic obstruction: clinical aspects cost-effectiveness of preoperative palliative treatment with self-exping metallic stents--a preliminary report. Radiology 206: Castelli C (2007) Cost-effectiveness analysis in colorectal cancer using a semi-markov model. Statistics in Medicine 26: Guest JF, Ruiz FJ, Tang R et al. (2005) Cost implications of postsurgical morbidity following blood transfusion in cancer patients undergoing elective colorectal resection: An evaluation in the US hospital setting. Current Medical Research Opinion 21: Koperna T (2003) Cost-effectiveness of defunctioning stomas in low anterior resections for rectal cancer: a call for benchmarking. Archives of Surgery 138: Maclean A (2006) Colonic stent vs. emergency surgery for management of acute left-sided malignant colonic obstruction: A decision analysis - Commentary. Diseases of the Colon Rectum 49: Miller AR (2000) Quality of life cost effectiveness analysis of therapy for locally recurrent rectal cancer. Diseases of the Colon Rectum Osman, Rashid, Sathananthan et al. (2000) The cost effectiveness of self-exping metal stents in the management of malignant leftsided large bowel obstruction. Colorectal disease: the Official Journal of the Association of Coloproctology of Great Britain Irel 2: Park KC (2001) Decision analysis for the cost-effective management of recurrent colorectal cancer. Annals of Surgery 2333:310-9 Siddiqui A, Khelwal N, Anthony T et al. (2007) Colonic stent versus surgery for the management of acute malignant colonic obstruction: a decision analysis. Alimentary Pharmacology Therapeutics 26: Siddiqui A, Khelwal N, Antony T et al. (2008) Colonic stent surgery for the management of acute malignant colonic obstruction: A decision analysis (Alimentary Pharmacology Therapeutics (2007) 26, 10, ( )). Alimentary Pharmacology Therapeutics 27: 448. Siddiqui A, Spechler SJ, Huerta S (2007) Surgical bypass versus endoscopic stenting for malignant gastroduodenal obstruction: a decision analysis. Digestive Diseases Sciences 52: Targownik LE, Spiegel BM, Sack J et al. (2004) Colonic stent vs. emergency surgery for management of acute left-sided malignant colonic obstruction: a decision analysis. Gastrointestinal Endoscopy 60: Van Den Brink M (2004) Cost-utility analysis of preoperative radiotherapy in patients with rectal cancer undergoing total mesorectal excision: a study of the Dutch colorectal cancer group. Journal of Clinical Oncology 22: Varadarajulu S, Roy A, Lopes T et al. (2011) Endoscopic stenting versus surgical colostomy for the management of malignant colonic 68 Costing only, comparing costs in palliative intervention. Not relevant costs of 5 years follow-up after curative resection. Not relevant additional costs for transfusion surgical site infection. Costing only, comparing costs of stoma resection. Commentary only. No comparator, not comparing with stenting. Costing only, comparing costs of interventions. Not relevant about preoperative scanning. Paper retracted. Paper retracted. Not relevant about costs for duodenal obstruction. Costing only, comparing costs of interventions. Not relevant about preoperative therapy, costing only. Costing only, comparing costs from MediCare in US.

69 Review protocol, review question 2 Reference obstruction: comparison of hospital costs clinical outcomes. Surgical Endoscopy 25: Xinopoulos D, Dimitroulopoulos D, Theodosopoulos T et al. (2004) Palliation of inoperable malignant colonic obstruction. Comparison cost effectiveness analysis between stent placement stoma creation. Annals of Gastroenterology 17: Xinopoulos D, Dimitroulopoulos D, Theodosopoulos T et al. (2004) Stenting or stoma creation for patients with inoperable malignant colonic obstructions? Results of a study cost-effectiveness analysis. Surgical Endoscopy 18: Reason for exclusion About palliation, comparing costs of interventions only. Costing only, comparing costs for palliation. 69

70 Economic summary table of included studies, review question 1 Appendix M: Economic summary table of included studies, review question 1 Study Govindar ajan et al Population Hypothetical 70 year old male with emergent malignant left colonic obstruction secondary to left-sided colon cancer with no evidence of metastatic disease Comparato rs Costs Effects Emergency surgery Emergency colonic stenting as a bridge to definitive surgery CAD$25,737 CAD$21, QALM 43.9 QALM Incremental costs - CAD$-3, Incremen tal effects ICER Uncertainty QALM Dominant An alternative scenario analysis where the patient s physiologic status was minimally impaired by the large-bowel obstruction remained dominant with a reduced incremental benefit of 1.4 QALM cost savings of CAD$5,551. A series of one-way sensitivity analyses were conducted. Values at which stenting is no longer the most effective strategy are 91% probability of initial stent placement failure (base-case 3.1%), 51% probability of stent perforation (base-case 3.8%), 91% probability of stent migration (base-case 7.6%). Applicability limitations Partially applicable with serious limitations. Effects are expressed as Quality Adjusted Life Months derived direct elicitation using the stard gamble method in another study rather than Quality Adjusted Life Years using the EQ-5D. Costs are based on the Canadian healthcare system. Details of the distributions used in the probabilistic

71 Economic summary table of included studies, review question 1 Study Population Comparato rs Costs Effects Incremental costs Incremen tal effects ICER Uncertainty Applicability limitations sensitivity analysis are not provided. Discounting was applied at 3% rather than NICE s reference case of 3.5%. Singh et al Hypothetical 70 year old individual presenting with acute colonic obstruction Resective surgery Diverting colostomy CAD$13,820 CAD$11, operations per patient 44% temporary stoma 14% permanent stoma 11% mortality 1.90 operations per patient 100% temporary stoma 14% permanent stoma 13% diverting colostomy Dominated Reference Probabalistic sensitivity analysis not conducted. One-way sensitivity analysis was conducted. Resective surgery becomes less expensive than colonic surgery if: more than 80% of resective surgery patients obtain primary anastomosis at the time of tumour resection; cost of stent placement increases to CAD$3,240; fewer than 50% of patients undergo a second operation to reverse colostomy; or less than 70% or stent placements are successful. Quality of life not part of model so results are not reported in terms of QALYs. Costs are based on the Canadian healthcare system. Six month time horizon does not account for long-term health outcomes. Probabilistic sensitivity analysis has not been conducted. 71

72 Economic summary table of included studies, review question 1 Study Population Comparato rs Costs Effects Incremental costs Incremen tal effects ICER Uncertainty Applicability limitations Colonic stenting CAD$13, operations per patient 7% temporary stoma 2% permanent stoma 5% mortality CAD$1,313 Reported in proportion s only CAD$1,415 per temporary stoma prevented CAD$1,516 per operation prevented CAD$10,79 1 per permanent stoma prevented CAD$15,73 4 per death averted (a) CAD: Canadian dollars (b) QALM: Quality adjusted life months, a measure of health effects developed by Govindarajan unique to their study (c) EQ-5D: European Quality of Life 5 Dimensions multi-attribute utility instrument validated generic measure of health outcomes 72

73 Economic evidence tables, review question 1 Appendix N: Economic evidence tables, review question 1 Bibliographic reference Study design Govindarajan A, Naimark D, Coburn NG et al. (2007) Use of colonic stents in emergent malignant left colonic obstruction: a Markov chain Monte Carlo decision analysis. Diseases of the Colon Rectum 50: Type of Analysis Model structure Cycle length Time horizon Perspective Source of base-line data Source of effectiveness data Source of utility data Source of cost data Currency unit Cost-utility analysis Markov Chain Monte Carlo Decision Analysis Monthly Lifetime Cost year 2006 Discounting Canadian provincial healthcare payer (although this is not explicitly stated) Epidemiological data literature review Stent placement probabilities derived from systematic review. Remaining probabilities from literature review. Published survival models for tumour recurrence survival Direct elicitation using stard gamble from a separate study Ontario Case Costing Project, literature expert opinion Canadian dollars (CAD) Results were discounted at 3%. It is not clear if costs effects were discounted on an individual basis from year to year Patient characteristics 70 year old male with complete emergent malignant left colonic obstruction secondary to left-sided colon cancer with no evidence of metastatic disease. American Society of Anesthesiology (ASA) score of 3. Second base case as a scenario analysis where the patient s physiologic status is minimally impaired by the bowel obstruction has an ASA score of 2. Sample size Age Gender Subgroup analysis Not stated 70 years old Male No subgroup analysis performed 73

74 Economic evidence tables, review question 1 Bibliographic reference Interventions Govindarajan A, Naimark D, Coburn NG et al. (2007) Use of colonic stents in emergent malignant left colonic obstruction: a Markov chain Monte Carlo decision analysis. Diseases of the Colon Rectum 50: Emergency stenting as a bridge to elective surgery Surgery which may be elective or emergent may obtain primary anastomosis or formation of colostomy Outcome measures results Outcome measures Results Acute mortality Stenting Surgery Permanent colostomy Stenting Surgery Recurrence Stenting Surgery Life expectancy Stenting Surgery Quality adjusted life expectancy Stenting Surgery Cost Stenting Surgery ICER Stenting compared to surgery One-way sensitivity analysis: Threshold at which stenting is no longer most effective: Probability of initial stent placement failure Probability of stent perforation Probability of stent migration 15% 34% 12% 17% 40% 39.8% 115 months 92.4 months 45.9 QALM a 34.7 QALM CAD$21,974 CAD$21,448 Dominant 91% (base case 3.1%) 51% (base case 3.8%) 91% (base case 7.6%) 74

75 Economic evidence tables, review question 1 Bibliographic reference Govindarajan A, Naimark D, Coburn NG et al. (2007) Use of colonic stents in emergent malignant left colonic obstruction: a Markov chain Monte Carlo decision analysis. Diseases of the Colon Rectum 50: Threshold at which stenting is no longer the less costly strategy: Probability of initial stent placement failure Probability of stent perforation Probability of stent migration Daily hospital cost after stent placement Daily hospital cost after cancer resection Cost of stent apparatus Length of stay after successful stent insertion Additional length of stay for emergency surgery (compared with elective surgery) Probabilistic sensitivity analysis: Based on a willingness to pay of CAD$20,000/QALY, the authors state there was a 98% probability that stenting was the more effective strategy, 94% probability that it was both more effective less costly, 99.6% probability it was the most cost-effective decision. It is unknown how this was derived when QALYs were not used as a health outcome 64% (base case 3.1%) 75% (base case 3.8%) 50% (base case 7.6%) CAD$2,174 (base-case 799) CAD$562 (base-case 1176) CAD$5,864 (base-case 2100) 8.2 days (base-case 3) 3.3 days (base-case 7) Comments Partially applicable with serious limitations. Effects are expressed as Quality Adjusted Life Months derived direct elicitation using the stard gamble method in another study rather than Quality Adjusted Life Years using the EQ-5D. Costs are based on the Canadian healthcare system. Details of the distributions used in the probabilistic sensitivity analysis are not provided. Discounting was applied at 3% rather than NICE s reference case of 3.5%. Conflicts No conflicts of were reported. (a) QALM: Quality adjusted life months. This is a measure of health effects adjusted for quality of life unique to the present study. 75

76 Economic evidence tables, review question 1 Bibliographic reference Study design Singh H, Latosinsky S, Spiegel BMR et al. (2006) The cost-effectiveness of colonic stenting as a bridge to curative surgery in patients with acute left-sided malignant colonic obstruction: a Canadian perspective. Canadian Journal of Gastroenterology = Journal Canadien de Gastroenterologie 20: Type of Analysis Model structure Time horizon Perspective Source of base-line data Source of effectiveness data for resective surgery Source of effectiveness data for Cost-effectiveness analysis Not specified, presumably simple decision tree Six months Canadian provincial health plan All base-case scenario probabilities were taken from various literature sources. Emergency surgery perioperative mortality: 10% Elective resection perioperative mortality: 4% Secondary reanastomosis perioperative mortality: 1% Probability of obtaining resection primary anastomosis on emergent basis: 59% Probability of secondary reanastomosis after emergency Hartmann s procedure: 75% After negative computed tomography, probability of finding unresectable disease on laparotomy: 5% Colonic stent placement: - Clinical success 88% - Uncomplicated clinical failure 8% - Perforation rate 3.5% - Procedure-related death 0.5% Rate of obstruction or migration of the colonic stent over six months: 24% 4% risk of developing an anastomotic leak requiring another operation for colostomy obtained from literature. 41% chance that primary anastomosis is not feasible a Hartmann s procedure is performed from an unknown source. 25% chance that a patient would not undergo colostomy closure reanastomsis due to severe comorbid illness from literature. All patients immediately receive a diverting colostomy elective resective surgery primary anastomosis four weeks later according to the base-case 76

77 Economic evidence tables, review question 1 Bibliographic reference Singh H, Latosinsky S, Spiegel BMR et al. (2006) The cost-effectiveness of colonic stenting as a bridge to curative surgery in patients with acute left-sided malignant colonic obstruction: a Canadian perspective. Canadian Journal of Gastroenterology = Journal Canadien de Gastroenterologie 20: diverted colostromy parameters outlines above according to literature sources. Source of effectiveness data for colonic stenting Source of cost data Currency unit Cost year 2004 Discounting Effectiveness of colonic stenting from literature sources noted in the basecase above. Costs for physician services were obtained from the 2004 Manitoba Health Services Insurance Plan Physician s Manual. Costs of inpatient hospital services were obtained from the 1994 cost list for Manitoba Health Services inflated to 2004 dollars using the GDP price index inflator. Canadian dollars Not applied due to short timeframe Patient characteristics Interventions 70 year old individual (sex unspecified) with significant yet nonterminal medical comorbidities who presented with acute colonic obstruction was found on an urgently computed tomography scan to have a left colonic mass located proximal to the rectum, dilation of the proximal colon no evidence of metastatic disease. Resective surgery Diverting colostomy Colonic stenting Outcome measures results Outcome measures Results Acute mortality Resective surgery Diverting colostomy Colonic stenting Proportion with permanent stoma Resective surgery Diverting colostomy Colonic stenting 77 11% 13% 5% 14% 14% 2% Proportion with temporary stoma Resective surgery 44%

78 Economic evidence tables, review question 1 Bibliographic reference Singh H, Latosinsky S, Spiegel BMR et al. (2006) The cost-effectiveness of colonic stenting as a bridge to curative surgery in patients with acute left-sided malignant colonic obstruction: a Canadian perspective. Canadian Journal of Gastroenterology = Journal Canadien de Gastroenterologie 20: Diverting colostomy Colonic stenting Mean number of operations per patient Resective surgery Diverting colostomy Colonic stenting Total cost Resective surgery Diverting colostomy Colonic stenting 100% 7% CAD$13,820 CAD$11,851 CAD$13,164 Incremental cost effectiveness ratio of colonic stenting compared to diverting colostomy (resective surgery is dominated): Temporary stoma prevented Operation prevented Permanent stoma prevented Death prevented CAD$1,415 CAD$1,516 CAD$15,734 Probabilistic sensitivity analysis Not conducted One-way sensitivity analysis Resective surgery becomes less expensive than colonic surgery if: - more than 80% of resective surgery patients obtain primary anastomosis at the time of tumour resection - cost of stent placement increases to CAD$3,240 - fewer than 50% of patients undergo a second operation to reverse 78

79 Economic evidence tables, review question 1 Bibliographic reference Comments Singh H, Latosinsky S, Spiegel BMR et al. (2006) The cost-effectiveness of colonic stenting as a bridge to curative surgery in patients with acute left-sided malignant colonic obstruction: a Canadian perspective. Canadian Journal of Gastroenterology = Journal Canadien de Gastroenterologie 20: colostomy less than 70% or stent placements are successful Quality of life not part of model so results are not reported in terms of QALYs. Costs are based on the Canadian healthcare system. Six month time horizon does not account for long-term health outcomes. Probabilistic sensitivity analysis has not been conducted. Conflicts Dr Laura Targownik is supported by the Rudy Falk Clinician Scientist Award. This work was funded by an unrestricted grant from Boston Scientific Inc. (a) ASA: American Society of Anesthesiology (b) CAD: Canadian dollars 79

80 Review protocol, review question 2 Appendix O: Review protocol, review question 2 Details Review Question Objectives Type of Review Language Study Design Status Population What is the most effective treatment for early rectal cancer? Screening for bowel cancer has led to the diagnosis of more cases of early stage rectal cancer. The stard treatment for rectal cancer is radical bowel resection. However, for early rectal cancer, local excision or ablative therapies may be as effective, with the benefit of reduced post-operative complications. The aim of this review is to compare the effectiveness of local excision, brachytherapy, bowel resection for early rectal cancer. Intervention English only Systematic reviews, Romised controlled trials, Non-romised controlled studies, Prospective comparative observational studies, Retrospective comparative observational studies A stepwise approach will be used (see: Other criteria for inclusion/exclusion, below) Published papers (full text only) Adults (aged 18+) with early rectal cancer ( T1 or T2, N0, M0). Intervention Comparator Outcomes Subgroups: Tumour location (high, mid or low rectum) Tumour stage: T1 (SM1,2 or 3, Haggitt level 1,2,3 or 4) or T2 Presence or absence of lymphovascular invasion Presence or absence of factors reducing fitness for surgery (e.g. comorbidities, frailty) Presence or absence of poor differentiation Transanal endoscopic microsurgery Transanal minimally invasive surgery (TAMIS) Transanal endoscopic operation Endoscopic mucosal resection Brachytherapy (also known as contact radiotherapy or papillon treatment) Glove port rectal surgery Transanal resection Any of the above with additional pre-operative radiotherapy or radio chemotherapy Bowel resection (including abdominoperineal excision, anorectal excision, anterior resection, Single incision larparoscopic surgery (SILS) rectal operation) Any of the above interventions Listed in order of importance: Local cancer recurrence Mortality (measured at any time between 30 days 3 years**), Permanent stoma formation (equal ranking) Metastatic cancer recurrence Quality of life Bowel function Sexual dysfunction 80

81 Review protocol, review question 2 Other criteria for inclusion / exclusion of studies Details **Modified post-hoc to include mortality at all later time points, due to lack of mortality data between 30 days 3 years. For each combination of comparison outcome, we will search for evidence using a step-wise approach based on the following hierarchy of evidence. If no evidence or evidence that is insufficient to support a recommendation is found following each step, we will proceed to the next level of evidence: Systematic reviews* Romised controlled trials Non-romised controlled studies Prospective comparative observational studies Retrospective comparative observational studies *Systematic reviews must have the same inclusion exclusion criteria as defined in this protocol, meet the quality stards defined in the NICE clinical guidelines methods hbook. Search strategies Review strategies Exclude: Narrative reviews, non-comparative studies, case series, case reports Search filters will be applied to limit the search to romised controlled trials comparative observational studies. Data on all included studies will be extracted into evidence tables (where data on whether participants were identified via screening is available, this will be extracted) Where statistically possible, a meta-analytical approach will be used to give an overall summary effect. All important outcomes from the evidence will be presented in GRADE profiles or modified profiles further summarized in evidence statements 81

82 Search strategy, review question 2 Appendix P: Search strategy, review question 2 Databases that were searched, together with the number of articles retrieved from each database are shown intable 12: Clinical search summary. The MEDLINE search strategy is shown in Table 13. The same strategy was translated for the other databases listed. Table 12: Clinical search summary Database Date searched Number retrieved CDSR (Wiley) 28/04/ Database of Abstracts of Reviews of Effects DARE (Wiley) 28/04/ HTA database (Wiley) 28/04/ CENTRAL (Wiley) 28/04/ MEDLINE (Ovid) 28/04/ MEDLINE In-Process (Ovid) 28/04/ EMBASE (Ovid) 28/04/ PsycINFO (Ovid) 28/04/ PubMed 28/04/ Table 13: Clinical search terms (MEDLINE) Line number Search term Number retrieved 1 exp Colorectal Neoplasms/ ((colorect* or rectal* or rectum* or bowel*) adj4 (cancer* or neoplas* or oncolog* or malignan* or tumor* or tumour* or carcinoma* or adenocarcinoma*)).tw or/ ((Transanal* or trans-anal*) adj4 (microsurg* or operation or resection*)).tw. 5 (TEMS or TEM or TEO).tw (Endoscop* adj4 (mucosal* or submucosal*)).tw Brachytherapy/ brachytherap*.tw papillon*.tw ((therap* or radiotherap* or radioisotope* or radiation) adj4 (interstitial or plaque or implant or surface or intracavit* or contact)).tw. 11 (curietherap* or endocurietherap*).tw ((bowel* or abdominoperineal or anorectal or anterior or anteroposterior) adj4 (excision* or remov* or resection*)).tw. 13 (glove* adj4 port*).tw ((single adj1 incision adj1 laparoscopic adj1 surg*) or SILS).tw or/

83 Search strategy, review question 2 Line number Search term 83 Number retrieved 17 animals/ not human/ not limit 18 to english language Observational Study as Topic/ Observational Study/ Epidemiologic Studies/ exp Case-Control Studies/ exp Cohort Studies/ Cross-Sectional Studies/ Comparative Study.pt case control$.tw case series.tw (cohort adj (study or studies)).tw cohort analy$.tw (follow up adj (study or studies)).tw (observational adj (study or studies)).tw longitudinal.tw prospective.tw retrospective.tw cross sectional.tw or/ Meta-Analysis.pt Meta-Analysis as Topic/ Review.pt exp Review Literature as Topic/ (metaanaly$ or metanaly$ or (meta adj3 analy$)).tw (review$ or overview$).ti (systematic$ adj5 (review$ or overview$)).tw ((quantitative$ or qualitative$) adj5 (review$ or overview$)).tw ((studies or trial$) adj2 (review$ or overview$)).tw (integrat$ adj3 (research or review$ or literature)).tw (pool$ adj2 (analy$ or data)).tw (hsearch$ or (h adj3 search$)).tw (manual$ adj3 search$).tw or/ animals/ not humans/ not Romized Controlled Trial.pt Controlled Clinical Trial.pt Clinical Trial.pt exp Clinical Trials as Topic/ Placebos/ Rom Allocation/ Double-Blind Method/ Single-Blind Method/ 18889

84 Search strategy, review question 2 Line number Search term Number retrieved 62 Cross-Over Studies/ ((rom$ or control$ or clinical$) adj3 (trial$ or stud$)).tw (rom$ adj3 allocat$).tw placebo$.tw ((singl$ or doubl$ or trebl$ or tripl$) adj (blind$ or mask$)).tw (crossover$ or (cross adj over$)).tw or/ animals/ not humans/ not or 53 or

85 Review flowchart, review question 2 Appendix Q: Review flowchart, review question 2 Figure 5: Clinical review flowchart, review question 2 85

86 Excluded studies, review question 2 Appendix R: Excluded studies, review question 2 Reference Reason for exclusion Allaix ME, Arezzo A, Giraudo G et al. (2012) Transanal endoscopic microsurgery vs. laparoscopic total mesorectal excision for T2N0 rectal cancer. Journal of Gastrointestinal Surgery: Official Journal of the Society for Surgery of the Alimentary Tract 16: Balani A, Turoldo A, Braini A et al. (2000) Local excision for rectal cancer. Journal of Surgical Oncology 74: Barendse RM, van den Broek FJC, van Schooten J et al. (2012) Endoscopic mucosal resection vs transanal endoscopic microsurgery for the treatment of large rectal adenomas. Colorectal disease: the Official Journal of the Association of Coloproctology of Great Britain Irel 14: e191-e196. Barendse RM, van den Broek FJC, Dekker E et al. (2011) Systematic review of endoscopic mucosal resection versus transanal endoscopic microsurgery for large rectal adenomas. Endoscopy 43: Barendse RM, Oors JM, Graaf EJR et al. (2013) The effect of endoscopic mucosal resection transanal endoscopic microsurgery on anorectal function. Colorectal Disease 15: e534-e541. Beck DE, Reickert CA, Margolin DA et al. (2006) Local recurrence, distant recurrence survival of rectal cancer. Ochsner Journal 6: Bentrem DJ, Okabe S, Wong WD et al. (2005) T1 adenocarcinoma of the rectum: transanal excision or radical surgery? Annals of Surgery 242: Borschitz T, Wachtlin D, Mohler M et al. (2008) Neoadjuvant chemoradiation local excision for T2-3 rectal cancer. Annals of Surgical Oncology 15: Bujko K, Richter P, Kolodziejczyk M et al. (2009) Preoperative radiotherapy local excision of rectal cancer with immediate radical re-operation for poor responders. Radiotherapy Oncology: Journal of the European Society for Therapeutic Radiology Oncology 92: Bujko K, Richter P, Smith FM et al. (2013) Preoperative radiotherapy local excision of rectal cancer with immediate radical re-operation for poor responders: a Population does not match review protocol (T2N0 patients included initially, but some found to have T3 tumours or lymph node involvement N1 following surgery - outcomes for these patients were not reported separately) Observational study of local excision vs major surgery, but outcomes for types of local excision specified in review protocol (transanal excision, transanal endoscopic microsurgery endoscopic excision) not reported separately Incorrect population (patients with adenoma) Systematic review that does not match review protocol (population is patients with adenomas) Incorrect population (patients with adenoma) Population does not match review protocol (patients with stage 1-4 cancer includes, outcomes not reported separately for each intervention stage) Population does not match review protocol (Radical resection group included patients with lymph node metastasis, outcomes for these patients were not reported separately) Systematic review that does not match review protocol (includes patients with T3 tumours) Intervention comparator do not match review protocol (compared radiotherapy with radiochemotherapy) Intervention comparator do not match review protocol (compared radiotherapy with 86

87 Excluded studies, review question 2 Reference prospective multicentre study. Radiotherapy oncology: Journal of the European Society for Therapeutic Radiology Oncology 106: Caricato M, Borzomati D, Ausania F et al. (2006) Complementary use of local excision transanal endoscopic microsurgery for rectal cancer after neoadjuvant chemoradiation. Surgical Endoscopy 20: Chorost MI, Petrelli NJ, McKenna M et al. (2001) Local excision of rectal carcinoma. The American Surgeon 67: Coatmeur O, Truc G, Barillot I et al. (2004) Treatment of T1- T2 rectal tumors by contact therapy interstitial brachytherapy. Radiotherapy Oncology: Journal of the European Society for Therapeutic Radiology Oncology 70: Da Rocha JJR, Feres O (2008) Transanal endoscopic operation. A new proposal. Acta Cirurgica Brasileira 23: Dafnis G, Pahlman L, Raab Y et al. (2004) Transanal endoscopic microsurgery: clinical functional results. Colorectal Disease: the Official Journal of the Association of Coloproctology of Great Britain Irel 6: de Anda EH, Lee SH, Finne CO et al. (2004) Endorectal ultrasound in the follow-up of rectal cancer patients treated by local excision or radical surgery. Diseases of the Colon Rectum 47: de Graaf EJR, Doornebosch PG, Tollenaar RAEM et al. (2009) Transanal endoscopic microsurgery versus total mesorectal excision of T1 rectal adenocarcinomas with curative intention. European Journal of Surgical Oncology: the Journal of the European Society of Surgical Oncology the British Association of Surgical Oncology 35: Doornebosch PG, Tollenaar RAEM, Gosselink MP et al. (2007) Quality of life after transanal endoscopic microsurgery total mesorectal excision in early rectal cancer. Colorectal Disease: the Official Journal of the Association of Coloproctology of Great Britain Irel 9: Doornebosch PG, Tollenaar RAEM, de Graaf EJR (2009) Is the increasing role of Transanal Endoscopic Microsurgery in curation for T1 rectal cancer justified? A systematic review. Acta Oncologica (Stockholm, Sweden) 48: Endreseth BH, Myrvold HE, Romundstad P et al. (2005) Transanal excision vs. major surgery for T1 rectal cancer. Diseases of the Colon Rectum 48: Fichera A, Allaix ME (2014) Paradigm-shifting new evidence for treatment of rectal cancer. Journal of Gastrointestinal Reason for exclusion radiochemotherapy) Population does not match review protocol (patients with stage II III disease were included, outcomes were not reported separately for patients with disease of different stages) Intervention comparator did not match review protocol (compared transanal excision with without post-operative radio or chemotherapy) Combination of intervention comparator do not match review protocol Non comparative study Population does not match review protocol (included patients with adenoma, comparative outcomes in review protocol were not reported for patients with T1/T2 tumours separately) Population does not match review protocol (radical surgery group included patients with stage II III disease, outcomes were not reported separately for different disease stages) Population does not match review protocol (absence of lymph node metastases only criteria for transanal endoscopic microsurgery group, not total mesorectal excision group) Population does not match review protocol (the total mesorectal excision group included patients with Stage II cancers T3 tumours, outcomes for these patients were not reported separately) Systematic review that does not match review protocol (does not include all specified interventions) Population does not match review protocol (N1 cancers included, outcomes for these cancers are not reported separately) Not primary research (narrative 87

88 Excluded studies, review question 2 Reference Surgery: Official Journal of the Society for Surgery of the Alimentary Tract 18: Garcia-Aguilar J (2013) Transanal endoscopic microsurgery following neoadjuvant chemoradiation therapy in rectal cancer: A word of caution about patient selection? Diseases of the Colon Rectum 56: 1-3. Gerard JP, Ortholan C, Benezery K et al. (2008) Contact X- ray therapy for rectal cancer: experience in Centre Antoine- Lacassagne, Nice, International Journal of Radiation Oncology, Biology, Physics 72: Gornicki A, Richter P, Polkowski W et al. (2013) Anorectal sexual functions after preoperative radiotherapy fullthickness local excision of rectal cancer. European journal of surgical oncology : the Journal of the European Society of Surgical Oncology the British Association of Surgical Oncology Hahnloser D, Wolff BG, Larson DW et al. (2005) Immediate radical resection after local excision of rectal cancer: an oncologic compromise? Diseases of the Colon Rectum 48: Han Y, He YG, Lin MB et al. (2012) Local resection for rectal tumors: comparative study of transanal endoscopic microsurgery vs. conventional transanal excision - the experience in China. Hepato-gastroenterology 59: Heintz A, Morschel M, Junginger T (1998) Comparison of results after transanal endoscopic microsurgery radical resection for T1 carcinoma of the rectum. Surgical Endoscopy 12: Hurlstone DP, Sers DS (2006) Further evidence to support the safety efficacy of endoscopic mucosal resection for Paris type 0-II, Is laterally spreading tumors of the colorectum in Western cohorts [1]. Endoscopy 38: Ishikawa K, Arita T, Shimoda K et al. (2005) Usefulness of transanal endoscopic surgery for carcinoid tumor in the upper middle rectum. Surgical Endoscopy 19: Jeon JH, Cheung DY, Lee SJ et al. (2014) Endoscopic resection yields reliable outcomes for small rectal neuroendocrine tumors. Digestive Endoscopy Johnston CF, Tomlinson G, Temple LK et al. (2013) The management of patients with T1 adenocarcinoma of the low rectum: a decision analysis. Diseases of the Colon Rectum 56: Kudo S (1993) Endoscopic mucosal resection of flat depressed types of early colorectal cancer. Endoscopy 25: Langer C, Liersch T, Suss M et al. (2003) Surgical cure for early rectal carcinoma large adenoma: transanal endoscopic microsurgery (using ultrasound or electrosurgery) Reason for exclusion review) Not primary research (Editorial) Observations study of contact radiotherapy with without surgery or external beam radiotherapy, but treatments not compared in the same populations (treatment depended on tumour stage) Intervention did not match review protocol (Outcomes were reported for local excision performed by different methods grouped together) Intervention did not match review protocol (different types of local excision grouped together outcomes not reported separately) Population does not match review protocol (patients with adenomas other benign lesions were included, outcomes were not reported separately for these patients) Intervention does not match review protocol (local excision was carried out by either transanal excision or transanal endoscopic microsurgery, outcomes were not reported separately for the two procedures) Not primary research (letter/comment) Population does not match review protocol (no information about TNM classification given) Population does not match review protocol (patients with neuroendocrine tumours) Decision model including systematic review that does not match review protocol Not primary research (instructional article) Population does not match review protocol (patients with adenomas other benign lesions were 88

89 Excluded studies, review question 2 Reference compared to conventional local radical resection. International Journal of Colorectal Disease 18: Lebedyev A, Tulchinsky H, Rabau M et al. (2009) Long-term results of local excision for T1 rectal carcinoma: the experience of two colorectal units. Techniques in Coloproctology 13: Lezoche E, Guerrieri M, Paganini AM et al. (1998) Transanal endoscopic microsurgical excision of irradiated nonirradiated rectal cancer. A 5-year experience. Surgical Laparoscopy & Endoscopy 8: Lin GL, Meng WCS, Lau PYY et al. (2006) Local resection for early rectal tumours: Comparative study of transanal endoscopic microsurgery (TEM) versus posterior transsphincteric approach (Mason's operation). Asian Journal of Surgery / Asian Surgical Association 29: Marks JH, Valsdottir EB, DeNittis A et al. (2009) Transanal endoscopic microsurgery for the treatment of rectal cancer: comparison of wound complication rates with without neoadjuvant radiation therapy. Surgical Endoscopy 23: Middleton PF, Sutherl LM, Maddern GJ (2005) Transanal endoscopic microsurgery: a systematic review. Diseases of the Colon Rectum 48: Moore JS, Cataldo PA, Osler T et al. (2008) Transanal endoscopic microsurgery is more effective than traditional transanal excision for resection of rectal masses. Diseases of the Colon Rectum 51: Myint AS (2013) Contact radiotherapy for elderly patients with early low rectal cancers. British Journal of Hospital Medicine (London, Engl: 2005) 74: Nash GM, Weiser MR, Guillem JG et al. (2009) Long-term survival after transanal excision of T1 rectal cancer. Diseases of the Colon Rectum 52: Olsheski M, Schwartz D, Rineer J et al. (2013) A populationbased comparison of overall disease-specific survival following local excision or abdominoperineal resection for stage I rectal adenocarcinoma. Journal of Gastrointestinal Cancer 44: Ortholan C, Romestaing P, Chapet O et al. (2012) Correlation in rectal cancer between clinical tumor response after neoadjuvant radiotherapy sphincter or organ preservation: 10-year results of the Lyon R romized trial. International Journal of Radiation Oncology, Biology, Physics 83: e165-e171. Pakkastie T, Jarvinen HJ (1997) Local excision as an option in the treatment of low rectal carcinoma. Annales Chirurgiae et Gynaecologiae 86: Reason for exclusion included, outcomes were not reported separately for these patients) Outcomes specified in review protocol not reported separately for transanal excision transanal endoscopic microsurgery groups Transanal endoscopic microsurgery with without radiotherapy not compared on same population (radiotherapy for more advanced disease only) Population does not match review protocol (includes patients with T0 or Tis tumour as well as T1, does not present outcomes separately) Population does not match review protocol (patients with T0 T3 tumours were included outcomes were not reported separately for patients with different tumour classifications) Systematic review that does not match the review protocol (includes patients with adenomas) Population does not match the review protocol (included patients with adenomas T3 tumours, did not report outcomes separately for patients with different tumour classifications) Not primary research (narrative review) Population does not match review protocol (patients with lymph node metastasis were included in the radical resection group, outcomes for these patients were not reported separately) Insufficient detail of 'local excision' intervention: all types of local excision grouped together in reporting of outcomes Population does not match review protocol (included patients with T3 N1 tumours, results not reported separately for patients with different tumour classifications) Population does not match review protocol (included patients with Dukes stage A-C disease, outcomes not reported separately for patients with different tumour 89

90 Excluded studies, review question 2 Reference Perez RO, Habr-Gama A, Sao Juliao GP et al. (2011) Transanal endoscopic microsurgery for residual rectal cancer after neoadjuvant chemoradiation therapy is associated with significant immediate pain hospital readmission rates. Diseases of the Colon Rectum 54: Praveen CR (2011) Transanal endoscopic microsurgery: Where it sts as of today? World Journal of Laparoscopic Surgery 4: Ptok H, Marusch F, Meyer F et al. (2007) Oncological outcome of local vs radical resection of low-risk pt1 rectal cancer. Archives of Surgery 142: Ramirez JM, Aguilella V, Valencia J et al. (2011) Transanal endoscopic microsurgery for rectal cancer. Long-term oncologic results. International Journal of Colorectal Disease 26: Sajid MS, Farag S, Leung P et al. (2014) Systematic review meta-analysis of published trials comparing the effectiveness of transanal endoscopic microsurgery radical resection in the management of Early Rectal Cancer. Colorectal Disease 16: Savage AP, Reece-Smith H, Faber RG (1994) Survival after peranal abdominoperineal resection for rectal carcinoma. The British Journal of Surgery 81: Sengupta S, Tjra JJ (2001) Local excision of rectal cancer: what is the evidence? Diseases of the Colon Rectum 44: Serra-Aracil X, Mora-Lopez L, Alcantara-Moral M et al. (2014) Atypical indications for transanal endoscopic microsurgery to avoid major surgery. Techniques in Coloproctology 18: Serra-Aracil X, Mora-Lopez L, Alcantara-Moral M et al. (2014) Transanal endoscopic microsurgery with 3-D (TEM) or high-definition 2-D transanal endoscopic operation (TEO) for rectal tumors. A prospective, romized clinical trial. International Journal of Colorectal Disease 29: Sgourakis G, Lanitis S, Gockel I et al. (2011) Transanal endoscopic microsurgery for T1 T2 rectal cancers: a meta-analysis meta-regression analysis of outcomes. The American Surgeon 77: Soetikno RM, Gotoda T, Nakanishi Y et al. (2003) Endoscopic mucosal resection. Gastrointestinal Endoscopy 57: Suppiah A, Maslekar S, Alabi A et al. (2008) Transanal endoscopic microsurgery in early rectal cancer: time for a trial? Colorectal disease: the official journal of the Association of Coloproctology of Great Britain Irel 10: Tanaka S, Haruma K, Oka S et al. (2001) Clinicopathologic features endoscopic treatment of superficially spreading colorectal neoplasms larger than 20 mm. Gastrointestinal Reason for exclusion stages) Population does not match review protocol (comparator group included patients with benign rectal polyps, carcinoids stromal tumours) Systematic review that does not match review protocol (includes patients with adenomas) Interventions do not match review protocol (outcomes for transanal excision Transanal endoscopic microsurgery are grouped not reported separately) Interventions comparators did not match review protocol (all patients received TEMs, then a subgroup received radical resection based on histological results) Systematic review that does not match review protocol (only includes subset of interventions) - use for cross checking Population does not match review protocol (included patients with locally advanced metastatic disease) Not primary research (Narrative review) Population does not match review protocol (includes patients with benign lesions neuroendocrine tumours) Population does not match review protocol (includes patients with adenomas, does not report outcomes separately for these patients) Systematic review that does not match review protocol - used for cross checking Systematic review that does not meet required quality stards (only MEDLINE searched) - use for cross checking Systematic review that does not meet quality stards (only MEDLINE Pubmed searched) - use for cross checking Population does not match review protocol (included patients with adenoma, did not report 90

91 Excluded studies, review question 2 Reference Endoscopy 54: Tanaka S, Haruma K, Oh E et al. (2000) Conditions of curability after endoscopic resection for colorectal carcinoma with submucosally massive invasion. Oncology Reports 7: van den Broek FJC, de Graaf EJR, Dijkgraaf MGW et al. (2009) Transanal endoscopic microsurgery versus endoscopic mucosal resection for large rectal adenomas (TREND-study). BMC Surgery 9: 4. Velnic D, Tomicic M, Rukavina J et al. (1998) Comparison of minimally invasive radical operations in the management of early rectal carcinoma. Croatian Journal of Gastroenterology Hepatology 7: Wentworth S, Russell GB, Tuner II et al. (2005) Long-term results of local excision with without chemoradiation for adenocarcinoma of the rectum. Clinical Colorectal Cancer 4: Winde G, Schmid KW, Reers B et al. (1996) [Microsurgery in prospective comparison with conventional transanal excision or anterior rectum resection in adenomas superficial carcinomas]. Langenbecks Archiv für Chirurgie.Supplement.Kongressb.Deutsche Gesellschaft für Chirurgie.Kongress 113: Winde G, Herwig R, Nottberg H et al. (1996) Controlled romized comparison on transanal endoscopic microsurgery anterior resection for pt1-rectal cancer. Endoskopie Heute. 9: Wu Y, Wu YY, Li S et al. (2011) TEM conventional rectal surgery for T1 rectal cancer: a meta-analysis. Hepatogastroenterology 58: Zieren J, Paul M, Menenakos C (2007) Transanal endoscopic microsurgery (TEM) vs. radical surgery (RS) in the treatment of rectal cancer: indications, limitations, prospectives. A review. Acta gastro-enterologica Belgica 70: Reason for exclusion outcomes separately for different tumour types) Endoscopic mucosal resection surgical resection not compared on outcomes specified in review protocol Population does not match review protocol (patients with adenomas) Population does not match review protocol (included patients with Tis tumours did not report outcomes separately by tumour classification) Population does not match review protocol (included patients with Tis T3 tumours did not report outcomes separately for patients with different tumour classifications) Article not in English Article not in English Systematic review that does not match review protocol - used for cross checking Article not obtainable (likely to be narrative review from abstract) 91

92 Evidence tables, review question 2 Appendix S: Evidence tables, review question 2 S.1 Romised controlled trials Bibliographic reference Study type Aim Patient characteristics Chen Yy, Liu Zh, Zhu K et al. (2013) Transanal endoscopic microsurgery versus laparoscopic lower anterior resection for the treatment of T1-2 rectal cancers. Hepato-gastroenterology 60: Romised controlled trial To compare the surgical oncological effectiveness safety of transanal endoscopic microsurgery (TEMS) laparoscopic anterior resection in T1-2 rectal cancer patients. Inclusion criteria: - T1-2 N0 M0 - Tumour located 6-11cm from anal verge - Moderately or highly differentiated (determined histologically) - Acceptable physical tolerance on preoperative assessment Exclusion criteria: - Previous lower abdominal or pelvic surgery - Not meeting above criteria Baseline characteristics: TEMS Laparoscopic resection Statistical test Sex 14M/16F 17M/13F Fishers exact test, p=0.133 Age mean (sd) 68.8 (5.3) 66.2 (7.7) Fishers exact test, p=0.606 Tumour size (sd) 2.3 cm (0.5) 2.8 cm (0.6) Independent t test, p<0.001 Tumour distance from anal verge (sd) Preoperative tumour staging, number of participants 7.8 cm (1.6) 8.1 cm (1.3) Independent t test, p=0.429 T1,24 T2,6 T1,22 T2,8 Fishers exact test, p=

93 Evidence tables, review question 2 Bibliographic reference Chen Yy, Liu Zh, Zhu K et al. (2013) Transanal endoscopic microsurgery versus laparoscopic lower anterior resection for the treatment of T1-2 rectal cancers. Hepato-gastroenterology 60: Postoperative tumour staging, number of participants Pathological type, n High differentiation, 26 Moderate differentiation, 4 Poor differentiation, 0 Mucinous, 0 T1,22 T2,8 T1,22 T2, 8 Fishers exact test, p=1.0 High differentiation, 26 Moderate differentiation, 3 Poor differentiation, 1 Mucinous,0 Fishers exact test, p=0.565 Lymphovascular invasion, 4 7 Fishers exact test, p=0.506 Intervention Comparison Attrition: Two patients romised to TEMS converted to laparoscopic resection were excluded from analysis. TEMS. No routine post-operative adjuvant treatment according to risk factors. Laparoscopic anterior resection. Adjuvant chemotherapy (FOLFOX-4 regimen) if considered high risk following surgery (poorly differentiated tumor or lymphovascular invasion) occurred in 8 out of 30 patients. Number of Patients TEMS: 30 Laparoscopic resection: 30 Length of follow up TEMs mean: 18.0 months (sd 2.6) Laparoscopic resection mean: 17.5 months (sd 2.2) Location Outcomes measures effect size China Two patients romised to TEMs converted to larparoscopic resection were excluded from analysis (per protocol analysis) Local recurrence (any time in follow up period), n Metastatic recurrence (any time in follow up period), n TEMS (28) Laparoscopic resection (30) Statistical test Relative risk (95 % CI) Calculated by reviewer for dichotomous outcomes 2 0 Fishers exact, p= ( ) 0 0 Fishers exact, p=1 not estimable Mortality at 1 year, n 0 0 Fishers exact, p=1 not estimable Mortality (any time in 0 0 not estimable 93

94 Evidence tables, review question 2 Bibliographic reference Chen Yy, Liu Zh, Zhu K et al. (2013) Transanal endoscopic microsurgery versus laparoscopic lower anterior resection for the treatment of T1-2 rectal cancers. Hepato-gastroenterology 60: follow up period) Source of funding Other outcomes reported but not extracted here: Length of hospital stay, conversion rate, en bloc resection rate, operative duration, volume of blood loss, blood transfusion, major operative events, time to restart off bed activities, anal incontinence, time to bowel movement, time to oral intake, postoperative complication frequency Shanghai Municipal Department of Health Comments - Per protocol analysis - Significantly smaller initial tumour size in TEMS group, - Postoperative adjuvant treatment given in resection group if high risk, but not TEMS group, so introducing bias favouring the resection group. - No details of romisation process given - Allocation concealment unclear - No blinding Lezoche et al. 2005, 2008, 2012 (Communication with authors confirmed articles report the same trial) Bibliographic reference Study type Aim Patient characteristics Lezoche E, Guerrieri M, Paganini AM et al. (2005) Transanal endoscopic versus total mesorectal laparoscopic resections of T2-N0 low rectal cancers after neoadjuvant treatment: a prospective romized trial with a 3-years minimum follow-up period. Surgical Endoscopy 19: Romised controlled trial To compare transanal endoscopic microsurgery (TEMS) laparoscopic resection in the treatment of T2-N0 low rectal cancer Inclusion criteria: - T2 N0 M0 tumour stage - Tumour location within 6cm of anal verge - Well (G1) or moderately well (G2) differentiated tumour - Diameter no larger than 3cm Exclusion criteria: - Not meeting criteria above - Patient older than 70 years or with compromised general condition 94

95 Evidence tables, review question 2 Lezoche et al. 2005, 2008, 2012 (Communication with authors confirmed articles report the same trial) Baseline characteristics: TEMS Laparoscopic resection Sex 12M/8F 13M/7F Age median (IQR) 68 (64-70) 67 (62-68) Intervention Comparison Attrition: 2 patients romised to laparoscopic TME dropped out elected to have open surgery Chemoradiotherapy (50.4 Gy 200mg per m2 per day 5-fluorouracil over 5 weeks) followed by TEMS Chemoradiotherapy (as above) followed by laparoscopic resection (Miles procedure or low anterior) Number of Patients TEM: 20 Laparoscopic resection: 20 Length of follow up Location Outcomes measures effect size TEMS follow up median (IQR): 52 months (43-58), Laparoscopic resection follow up median (IQR): 67 months (53-72). Follow up started at date of treatment ended on 1 st Sept 2003 Italy Permanent stoma formation, number of participants Metastatic Cancer recurrence (assessed at median follow up period of 56 months matching procedure across groups unclear), number of participants Local Cancer recurrence (assessed at median follow up period of 56 months matching procedure across groups unclear), number of participants TEMS (20) Laparoscopic resection (20) Relative risk (95 % CI) Calculated by reviewer for dichotomous outcomes ( ) ( ) ( ) Mortality (during follow up ( ) 95

96 Evidence tables, review question 2 Lezoche et al. 2005, 2008, 2012 (Communication with authors confirmed articles report the same trial) period), number of participants Probability of survival estimated at 77.6 months (Kaplan Meier) 0.95 ( ) 0.83 (95% CI ) - Source of funding Comments Other outcomes reported but not extracted here: Intraoperative programme change, median hospital stay, conversion to open surgery, temporary stoma formation, duration of operation, blood loss, no. of patients receiving transfusion, no. of patients receiving analgesia, post-operative complications, Probability of local or metastatic recurrence estimated at 77.6 months. Not stated - Significantly longer median follow up in laparoscopic resection group - Method for matching follow up period for assessing local metastatic recurrence unclear - Romisation was via rom number generator table - Concealment of allocation not clear - No blinding - Insufficient sample size for precise estimates of rare outcomes (recurrence, mortality) - Not explicitly stated, but likely to be per protocol analysis as inclusion criteria include criteria that would not be know until after surgery (e.g. differentiation). Bibliographic reference Study type Aim Patient characteristics Lezoche G, Baldarelli M, Guerrieri M et al. (2008) A prospective romized study with a 5-year minimum follow-up evaluation of transanal endoscopic microsurgery versus laparoscopic total mesorectal excision after neoadjuvant therapy. Surgical endoscopy 22: Romised controlled trial To compare transanal endoscopic microsurgery (TEMS) laparoscopic resection in the treatment of T2-N0 low rectal cancer Inclusion criteria: - T2 N0 M0 tumour stage - Tumour location within 6cm of anal verge - Well (G1) or moderately well (G2) differentiated tumour - Diameter no larger than 3cm 96

97 Evidence tables, review question 2 Lezoche et al. 2005, 2008, 2012 (Communication with authors confirmed articles report the same trial) - Minimum follow up period of 5 years (unclear how many patients did not meet this criteria retrospectively) Exclusion criteria: - Not meeting criteria above Baseline characteristics: TEMS Laparoscopic resection Sex 23/12F 20M/15F Age median (IQR) 67 (61-70) 65 (60-69) Intervention Comparison Attrition: Not specified Chemoradiotherapy (50.4 Gy 200mg per m2 per day 5-fluorouracil over 5 weeks) followed by TEMS Chemoradiotherapy (as above) followed by laparoscopic resection (Miles procedure or low anterior) Number of Patients TEM: 35 Laparoscopic resection: 35 Length of follow up TEMS follow up median (IQR): 84 months (71-97), Laparoscopic resection follow up median (IQR): 84 months (76-96). Minimum follow up period of 5 years. Location Outcomes measures effect size Italy Permanent stoma formation, number of participants Metastatic Cancer recurrence (any time in follow up period), number of participants Local Cancer recurrence (any time in follow up period), number of TEMS (35) Laparoscopic resection (35) Relative risk (95 % CI) Calculated by reviewer for dichotomous outcomes ( ) ( ) ( ) 97

98 Evidence tables, review question 2 Lezoche et al. 2005, 2008, 2012 (Communication with authors confirmed articles report the same trial) participants Mortality (assessed at 30 days), number of participants Probability of survival estimated at end of follow up period (Kaplan Meier) 0 0 not estimable 0.95 (95% CI ) 0.94 (95% CI ) - Source of funding Other outcomes reported but not extracted here: Intraoperative programme change, median Hospital stay, conversion to open surgery, temporary stoma formation, duration of operation, blood loss, no. of patients receiving transfusion, no. of patients receiving analgesia, post-operative complications, Probability of local or metastatic recurrence estimated at end of follow up Not stated Comments - Romisation unclear ( The patients were romized casually to one of two procedures, TEMS or laparoscopic resection, via a drawing protocol. ) - Concealment of allocation not clear - No blinding - Insufficient sample size for precise estimates of rare outcomes (recurrence, mortality) Bibliographic reference Study type Aim Patient characteristics Lezoche E, Baldarelli M, Lezoche G et al. (2012) Romized clinical trial of endoluminal locoregional resection versus laparoscopic total mesorectal excision for T2 rectal cancer after neoadjuvant therapy. The British journal of surgery 99: Romised controlled trial To compare transanal endoscopic microsurgery (TEMS) laparoscopic total mesorectal excision (TME) in the treatment of non-advanced low rectal cancer Inclusion criteria: - T2 N0 M0 tumour stage - American Society of Anesthesiologists fitness grade I-II - Superior margin of tumour within 6cm of anal verge - Histologically confirmed well (G1) or moderately well (G2) differentiated tumour - Diameter no larger than 3cm Exclusion criteria: 98

99 Evidence tables, review question 2 Lezoche et al. 2005, 2008, 2012 (Communication with authors confirmed articles report the same trial) - Not meeting criteria above - Tumour with lymphovascular or perineural invasion Baseline characteristics: TEMS TME Sex 30M/20F 34M/16F Age median (IQR) 66 (58-70) 66 (60-69) Follow up median (IQR) 9.6 years ( ) 9.6 years ( ) Intervention Comparison Number of Patients TEM: 50 TME: 52 Attrition: 2 patients romised to laparoscopic TME dropped out elected to have open surgery Chemoradiotherapy (50.4 Gy 200mg per m2 per day 5-fluorouracil over 5 weeks) followed by TEMS Chemoradiotherapy (as above) followed by laparoscopic TME Length of follow up Minimum 5 years, TEMS follow up median (IQR): 9.6 years ( years), TME follow up median (IQR): 9.6 years ( ) Location Outcomes measures effect size Italy Described as intention to treat analysis (see comments) Permanent stoma formation, number of participants Metastatic Cancer recurrence (during follow up period), number of participants Local Cancer recurrence (during follow up period), number of participants TEMS (50) TME (50) Relative risk (95 % CI) Calculated by reviewer for dichotomous outcomes ( ) ( ) ( ) Mortality (during follow up ( ) 99

100 Evidence tables, review question 2 Lezoche et al. 2005, 2008, 2012 (Communication with authors confirmed articles report the same trial) period), number of participants Probability of cancer-related survival at end of follow up (unclear time point) (Kaplan Meier) 72% (95% CI 56-81) 80% (95% CI 62-90) - Kaplan Meier plot for probability of local or metastatic recurrence (not extracted here as not plotted separately for local metastatic recurrence). Kaplan Meier plot for cancer-related survival. Log rank test p= Source of funding Comments Other outcomes reported but not extracted here: Intraoperative programme change, Median hospital stay, Conversion to open surgery, temporary stoma formation, duration of operation, blood loss, no. of patients receiving transfusion, no. of patients receiving analgesia, post-operative complications, cancer-related mortality Not stated - Similar length of follow up for both groups - Romisation was via sealed envelopes. - Concealment of allocation not clear - No blinding - Insufficient sample size for precise estimates of rare outcomes (recurrence) - Unclear analysis type: described as intention to treat, but some patients in TME group converted to open procedure during surgery but were still included in the TME group. However, some of the inclusion criteria include things that could not be known until after surgery, for example differentiation, so not clear how this was addressed. Communication with the authors confirmed that these three studies report the same trial. However, there are inconsistencies in the reporting of inclusion exclusion criteria, the methods for romisation across the three articles. Bibliographic reference Winde G, Nottberg H, Keller R et al. (1996) Surgical cure for early rectal carcinomas (T1). Transanal endoscopic microsurgery vs. anterior resection. Diseases of the colon rectum 39:

101 Evidence tables, review question 2 Bibliographic reference Study type Aim Patient characteristics Winde G, Nottberg H, Keller R et al. (1996) Surgical cure for early rectal carcinomas (T1). Transanal endoscopic microsurgery vs. anterior resection. Diseases of the colon rectum 39: Romised controlled trial To compare local resection using transanal endoscopic microsurgery to anterior resection for early rectal cancer. Inclusion criteria: - T1 tumour stage Exclusion criteria: - Strong general contraindication to surgery - Severe infection - Severe metabolic disorder - Poorly differentiated tumour Baseline characteristics: TEMS Anterior resection Statistical test Sex (M:F ratio) Age mean (range) 63.7 (36-90) 60.9 (47-81) Welch s t test t=0.8, p=0.428 Tumour location (low, middle, upper rectum) 7,12,5 8,11,7 Unpaired t test t=0.17 p=0.87 (unclear how t test used to analyse these data) Intervention Comparison Number of Patients Attrition: Two patients were excluded from the TEMS group after romisation due to incorrect T staging discovered after surgery. TEMS Anterior resection (open laparotomy).tumours of the upper rectum via anterior resection, the middle or lower rectum by low anterior resection or coloanal anastomosis. TEMS=26 Anterior resection=26 Length of follow up TEMS mean: 40.9 months (sd 24.6) Anterior resection mean: 45.8 months (sd 24.6) Location Outcomes measures effect size Germany Per protocol analysis: Two patients were excluded from the TEMS group after romisation due to incorrect TNM staging discovered after surgery. TEMS (24) Anterior resection (26) Relative risk (95 % CI) 101

102 Evidence tables, review question 2 Bibliographic reference Winde G, Nottberg H, Keller R et al. (1996) Surgical cure for early rectal carcinomas (T1). Transanal endoscopic microsurgery vs. anterior resection. Diseases of the colon rectum 39: Calculated by reviewer for dichotomous outcomes Local recurrence, n ( ) Metastatic recurrence, n ( ) 30 day mortality, n 0 0 not estimable Mortality (any time during follow up), n ( ) Log rank test comparison of survival curves, chi squared=0.0002, p=0.99 Source of funding Other outcomes reported but not extracted here: Length of hospital stay, operation time, blood loss, post-operative analgesic dem, complication rates Not specified Comments - Romisation was by a number table - Allocation concealment unclear - No blinding - Insufficient sample size for rare outcomes (mortality, recurrence) S.2 Observational studies Bibliographic reference Study type Aim Patient characteristics Christoforidis D, Cho HM, Dixon MR et al. (2009) Transanal endoscopic microsurgery versus conventional transanal excision for patients with early rectal cancer. Annals of surgery 249: Retrospective observational study To compare transanal endoscopic microsurgery (TEMS) to conventional transanal excision (TAE) for stage I rectal cancer. Inclusion criteria: - T1-2 N0 M0 rectal cancer Exclusion criteria: - Patients undergoing fulgurations, endoscopic snare excisions, transanal excisions performed as a complement to a margin-positive snare excision if no residual cancer was found in the specimen. - Synchronous colorectal tumours 102

103 Evidence tables, review question 2 Bibliographic reference Christoforidis D, Cho HM, Dixon MR et al. (2009) Transanal endoscopic microsurgery versus conventional transanal excision for patients with early rectal cancer. Annals of surgery 249: Recurrent rectal tumours - Tumours treated with neoadjuvant therapy - Histologically non-adenomatous tumours - Patients undergoing immediate salvage surgery - Patients with follow up time less than 3 months Baseline characteristics: TEMS (42) TAE (129) Fisher exact test Sex (M/F, n) 28/14 71/ Age median (range) 70 (40-91) 74 (30-95) Unsuitable for major surgery (n) Tumour diameter (median, range) Distance from anal verge (median, range) 14 28/102# cm (1-9) 3 cm (1-12) cm (4-14) 5 cm (0-12) Tumour classification (n) T1: 27 T2: 15 T1:72 T2: Mucinous features (n) 2/41# 11/122# Poorly differentiated (n) 3/41# 6/120# Lymphovascular invasion (n) 5/35# 16/93# #denominator reported when data was not available for all participants Intervention Comparison Number of Patients Attrition: TEMS + considered for adjuvant therapy if adverse histological features (positive margins, T2 stage, poor differentiation, lymphovascular invasion) Conventional TAE + considered for adjuvant therapy if adverse histological features (criteria as above) TEMS=42 TAE=129 Length of follow up TEMS: median 60 months (range ) TAE: median 45 months (range 7-133) Location Outcomes measures effect size USA 103

104 Evidence tables, review question 2 Bibliographic reference Christoforidis D, Cho HM, Dixon MR et al. (2009) Transanal endoscopic microsurgery versus conventional transanal excision for patients with early rectal cancer. Annals of surgery 249: year local recurrence rate, Kaplan Meier estimate 5 year survival, Kaplan Meier estimate TEMS (42) TAE (129) Statistical test 15.4 (95% CI ) 29.1 ( ) Log rank test (95% CI ) 66.0 ( ) Log rank test Population high tumour height (>=5cm from anal verge) 5 year local recurrence rate, Kaplan meier estimate 5 year survival, Kaplan Meier estimate TEMS >= 5cm from anal verge (38) TAE >= 5cm from anal verge (69) 15.9 (95% CI ) 24.0 ( )************* None 79.2 (95% CI ) 72.3 ( ) None Statistical test Source of funding Other outcomes reported but not extracted here: number of positive resection margins, complications after surgery, disease-free survival, recurrence survival for T1 T2, high low tumours also compared but not separately for each procedure, multivariate analysis of factors affecting local recurrence, disease-free survival overall survival Not specified Comments - Distance from anal verge significantly higher in TEMS group (but a separate subgroup analysis was done) - Retrospective study - No details on how choice of procedure was made Bibliographic reference Study type Aim Patient characteristics Lee W, Lee D, Choi S et al. (2003) Transanal endoscopic microsurgery radical surgery for T1 T2 rectal cancer: Retrospective study. Surgical Endoscopy Other Interventional Techniques 17: Retrospective observational study (review of patient records) To compare the results of TEM radical surgery in patients with T1 T2 rectal cancer. Allocation to groups: For T2, radical surgery was considered first TEM only considered when radical surgery was refused or patients were unsuitable. For T1 with favourable histology, TEM was considered first radical surgery only performed when patients chose it. 104

105 Evidence tables, review question 2 Bibliographic reference Lee W, Lee D, Choi S et al. (2003) Transanal endoscopic microsurgery radical surgery for T1 T2 rectal cancer: Retrospective study. Surgical Endoscopy Other Interventional Techniques 17: Inclusion criteria: - T1 or T2 cancer with no evidence of lymph node metastasis - 15cm from the anal verge Exclusion criteria: (formulated by reviewer from list of exclusions with reasons) - Preoperative radio or chemotherapy - Positive resection margin - Poorly differentiated or mucinous tumour - Other simultaneous cancer - Follow up loss Baseline characteristics: TEMS (74) TME (100) T- test Sex M/F, (n) 37/37 51/49 ns Age mean (sd) 61.1 (11.2) 57.7 (11.8) ns Distance from anal verge, mean (sd) 6.7 cm (3.2) 7.5 cm (4.0) ns Size (sd) 23.5 mm (9.5) 37.8 mm (15.3) p<0.05 Tumour stage T1: 52 T2: 22* T1: 17 T2: 83* - *Inconsistency between text table 1, figures in text reported as these add up to the total N for each group. Attrition: 2 patients from the TEMS group 7 from the radical surgery group were reported as lost to follow up. Intervention Comparison Number of Patients TEMS: 74 TME: 100 Transanal endoscopic microsurgery (TEMS, full thickness excision including perirectal fat with 1cm resection margin) Total mesorectal excision (TME) Length of follow up TEM (mean,sd): 31 months (17.2) TME (mean, sd): 34.6 months (19.4) Location USA 105

106 Evidence tables, review question 2 Bibliographic reference Outcomes measures effect size Lee W, Lee D, Choi S et al. (2003) Transanal endoscopic microsurgery radical surgery for T1 T2 rectal cancer: Retrospective study. Surgical Endoscopy Other Interventional Techniques 17: TEMS (74) TME (100) Statistical test (unclear test type) T1 (Kaplan Meier analysis) n=52 n=17 5 year Local recurrence, % 4.1% 0% p= year survival, % 100% 92.9% p=0.07 T2 (Kaplan Meier analysis) n=22 n=83 5 year Local recurrence, % 19.5% 9.4% p= year survival, % 94.7% 96.1% p=0.48 Source of funding Outcomes reported but not extracted here: Complication rate, disease free survival Not stated Comments - TEMS patients were more likely to have T1 tumour smaller tumour (size of tumour not reported separately for T1 T2 tumours for each group) - Unclear statistical analysis (comparison of recurrence survival) Bibliographic reference Study type Aim Patient characteristics Lezoche E, Paganini AM, Fabiani B et al. (2014) Quality-of-life impairment after endoluminal locoregional resection laparoscopic total mesorectal excision. Surgical Endoscopy Other Interventional Techniques 28: Retrospective observational study (using prospective register of data) To compare the short medium term quality of life for patients with early low rectal cancer who have undergone transanal endoscopic microsurgery (TEMS) or laparoscopic total mesorectal excision Allocation to groups: Patients received written information about the two procedures expressed a choice of treatment. Inclusion criteria: - T1 N0 rectal cancer - American Society of Anaesthesiologists grade 1 or 2. Exclusion criteria: - T2 or T3 tumour, lymph node involvement, distant metastasis or local recurrence 106

107 Evidence tables, review question 2 Bibliographic reference Lezoche E, Paganini AM, Fabiani B et al. (2014) Quality-of-life impairment after endoluminal locoregional resection laparoscopic total mesorectal excision. Surgical Endoscopy Other Interventional Techniques 28: Previous anorectal or abdominal surgery - Neoadjuvant or adjuvant radiochemotherapy or ileostomy - Associated pathology that could compromise quality of life - Patients with a stoma Baseline characteristics: TEMS (17) TME (18) Sex M/F (n) 7/10 8/10 Age median (range) 67.5 (37-88) 65.8 (39-83) Distance from anal verge, mean (range) 5.5 cm (1-10) 5.9 cm (3-10) Attrition: TEMS group: 3 out of those meeting the inclusion criteria did not return questionaires up to 12 months following surgery TME group: 2 out of those meeting the inclusion criteria did not return questionaires up to 12 months following surgery Intervention Comparison Number of Patients Length of follow up Location Outcomes measures effect size Transanal endoscopic microsurgery (endoluminal locoregional resection removing mucosa, submucosa, muscolaris propria adjacent mesorectal fat) Laparoscopic total mesorectal excision TEMS: 20 (3 loss to follow up) TME: 20 (2 loss to follow up) 12 months Italy Data in table below extracted by reviewer from graph. Reported as Means (+/- 1 stard deviation). The authors did not carry out statistical comparison between groups (Only across time points for each group, the time points compared for this comparison are unclear from the text, therefore are not reported). 95% confidence intervals were calculated by the reviewer from the reported sample sizes stard deviations. Time point TEMS (17) TME (18) Quality of life EORTC QLQ-CR38 (Cancer- mean sd 95% CI mean sd 95% CI Pre treatment month

108 Evidence tables, review question 2 Bibliographic reference Lezoche E, Paganini AM, Fabiani B et al. (2014) Quality-of-life impairment after endoluminal locoregional resection laparoscopic total mesorectal excision. Surgical Endoscopy Other Interventional Techniques 28: specific) Gastrointestinal 3 months problems 6 months Quality of life EORTC QLQ-CR30 (Colorectalspecific) Global health status Pre treatment month months months Source of funding Outcomes reported but not extracted here: Quality of life subscales Not stated Comments - Overall quality of life for EOTRC QLQ-CR30 not reported - Patients with a stoma were excluded. Having a stoma has potential impact on quality of life that may cause between group differences if there were different stoma rates. - No estimate of effect sizes or comparison across groups. Baseline differences in groups not accounted for at subsequent time points. Bibliographic reference Study type Aim Patient characteristics Palma P, Horisberger K, Joos A et al. (2009) Local excision of early rectal cancer: is transanal endoscopic microsurgery an alternative to radical surgery? Revista espanola de enfermedades digestivas : organo oficial de la Sociedad Espanola de Patologia Digestiva 101: Retrospective observational study (of prospectively collected database) To evaluate the safety oncological outcomes of transanal endoscopic microsurgery excision compared with radical surgery in the treatment of T1 low-risk rectal cancer. Allocation to groups: Based on patient preference. Inclusion criteria: - T1 N0 rectal cancer - Well or moderately well-differentiated Exclusion criteria: - Lymphovascular or neuronal invasion 108

109 Evidence tables, review question 2 Bibliographic reference Palma P, Horisberger K, Joos A et al. (2009) Local excision of early rectal cancer: is transanal endoscopic microsurgery an alternative to radical surgery? Revista espanola de enfermedades digestivas : organo oficial de la Sociedad Espanola de Patologia Digestiva 101: Baseline characteristics: TEMS (34) Radical surgery (17) Statistical test (unclear test type) Sex M/F (n) Not specified Not specified Age mean (sd) 68.4 (10.7) 65.6 (9.7) p=0.369 Distance from anal verge, mean (sd) 10.9 cm (3.5) 8.9 cm (3.2) p=0.45 Tumour size (sd) 5.5 cm 2 (4.5) 5.5 cm 2 (5.3) p=0.756 Intervention Comparison Attrition: No patients were lost to follow up. Number of Patients TEMS: 34 Radical surgery: 17 Transanal endoscopic microsurgery (TEMS, full wall thickness excision with attempted margin of 1cm) Radical surgery (Total mesorectal excision, anterior resection or Hartmann procedure) Length of follow up TEMS: Median 86.5 months (range ) Radical surgery: 93.0 months (range ) Location Outcomes measures effect size Spain Local recurrence at any time in follow up period, n Metastatic recurrence at any time in follow up period, n Mortality at any time in follow up period, n TEMS (34) Radical surgery (17) Statistical test (unclear test type) Relative risk (95 % CI) calculated by reviewer for dichotomous outcomes 2 0 p= ( ) 2 0 p= ( ) 6 3 p= ( ) 109

110 Evidence tables, review question 2 Bibliographic reference Palma P, Horisberger K, Joos A et al. (2009) Local excision of early rectal cancer: is transanal endoscopic microsurgery an alternative to radical surgery? Revista espanola de enfermedades digestivas : organo oficial de la Sociedad Espanola de Patologia Digestiva 101: Outcomes reported but not extracted here: Operating time, blood loss, time of hospitalisation, complication rate Source of funding Not stated Comments - Sample size too small to allow sufficient precision for rare outcomes (mortality recurrence). Bibliographic reference Study type Aim Patient characteristics Saraste D, Gunnarsson U, Janson M (2013) Local excision in early rectal cancer-outcome worse than expected: a population based study. European Journal of Surgical Oncology : the Journal of the European Society of Surgical Oncology the British Association of Surgical Oncology 39: Retrospective observational study (using prospective register of data) To determine whether local excision provides long-term survival equivalent to total mesorectal excision for stage 1 cancer, particularly for elderly patients. All cases of stage 1 rectal cancer at centre for 11 year period were included. Inclusion criteria: - T1-T2 N0 M0 rectal cancer Exclusion criteria: - All patients treated for stage I rectal cancer were included in the overall analysis. Only local excision by endoscopic resection, transanal excision or transanal endoscopic microsurgery are reported here. Baseline characteristics: Not reported separately for each group Attrition: Data on type of local excision was available for 81% of patients who underwent local excision Intervention Comparison Transanal endoscopic microsurgery (TEMS), endoscopic resection, transanal excision (TAE), anterior resection, abdominoperineal resection, Hartmanns procedure Any of above Number of Patients transanal endoscopic microsurgery (TEMS): 98 endoscopic resection: 55 transanal excision: 210 anterior resection:

111 Evidence tables, review question 2 Bibliographic reference Length of follow up Location Outcomes measures effect size Saraste D, Gunnarsson U, Janson M (2013) Local excision in early rectal cancer-outcome worse than expected: a population based study. European Journal of Surgical Oncology : the Journal of the European Society of Surgical Oncology the British Association of Surgical Oncology 39: abdominoperineal resection: 982 hartmanns procedure: years Sweden Kaplan Meier analysis was used to estimate 5 year survival. Overall (all causes of mortality) relative (mortality due to disease) mortality are reported. Anterior resection (1947) Abdominoperineal resection (982) Hartmanns procedure (253) Endoscopic resection (55) Transanal excision, TAE (210) Transanal endoscopic microsurgery, TEMS (98) Overall 5 year survival (cumulative probability, 95% CI) Relative 5 year survival (cumulative probability, 95% CI) 0.8 ( ) 0.95 ( ) 0.75 ( ) 0.57 ( ) 0.89 ( ) 0.77 ( ) 0.57 ( ) 0.76 ( ) 0.61 ( ) 0.82 ( ) 0.56 ( ) 0.75 ( ) Source of funding Outcomes reported but not extracted here: Multivariate analysis of risk factors affecting survival, subgroup analysis by age Stockholm city council, Karolinska Institute, the Bengt Ihre Foundation Comments - Observational study with little reporting of baseline characteristics means we must be very cautious in interpreting these results. The groups may have differed substantially in their baseline characteristics (for example, frailer patients might have undergone less invasive surgery), this could account for differences in survival across procedures. The substantial differences between overall relative survival supports this idea. 111

112 GRADE profiles, review question 2 Appendix T: GRADE profiles, review question 2 T.1 Transanal endoscopic microsurgery vs radical bowel resection Table 14: Outcome: local recurrence Quality assessment Number of patients Effect Study id or number of studies Design Risk of bias Inconsistency Indirectness Imprecision I=TEMS C=Resection Population: T1 mean follow up TEMS 40.9 months Resection 45.8 months Winde 1996 RCT Population: T1 Kaplan meier 5 year local recurrence rate no n/a no serious very serious b serious a 1/24 (4%) Relative risk (95% CI) 0/26 (0%) 3.24 (0.14 to 75.9) low Cumulative recurrence rate Lee 2003 Observational serious c n/a no serious very serious d I=4.1%, C=0%, p=0.94 (unclear test type) Population: T1 mean follow up TEMS 86.5 months Resection 93.0 months Palma 2009 Observational no serious n/a no serious very serious b 2/34 (6%) Population: T1/T2 median follow up TEMS 18 months Resection 17.5 months Chen 2013 RCT very serious e n/a no serious very serious b Population: T2 Kaplan meier 5 year local recurrence rate 2/28 (7%) Relative risk (95% CI) Quality very low 0/17 (0%) 2.57 (0.13 to 50.7) very low Relative risk (95% CI) 0/30 (0%) 5.34 (0.27 to 106.7) very low Cumulative recurrence rate Lee 2003 Observational serious c n/a no serious very serious d I=19.5%, C=9.4%, p=0.035 (unclear test type) (a) Not downgraded despite lack of blinding as unlikely to have serious impact on this outcome. (b) 95% confidence intervals incorporate both clinically significant benefit harm. (c) Patients in TEMS group were more likely to have a smaller tumour than those in the resection group. (d) No estimate of effect size associated variability reported. (e) Patients in resection group received adjuvant chemotherapy if considered high risk following surgery. Patients in the TEMS group did not. very low 112

113 GRADE profiles, review question 2 Table 15: Outcome: mortality Quality assessment Number of patients Effect Study id or number of studies Design Population: T1 Kaplan meier 5 year survival Risk of bias Inconsistency Indirectness Imprecision TEMS Resection Cumulative survival rate Lee 2003 Observational serious a n/a no serious very serious b I=100%, C=92.9%, p=0.07 (unclear test type) Population: T1 mean follow up TEMS 86.5 months Resection 93.0 months Palma 2009 Observational no serious Population: T2 Kaplan meier 5 year survival n/a no serious very serious c 2/34 (6%) Relative risk (95% CI) Quality very low 0/17 (0%) 1.00 (0.07 to 16.3) very low Cumulative recurrence rate Lee 2003 Observational serious a n/a no serious very serious b I=94.7%, C=96.1%, p=0.48 (unclear test type) (a) Patients in TEMS group were more likely to have a smaller tumour than those in the resection group. (b) No estimate of effect size associated variability reported. (c) 95% confidence intervals incorporate both clinically significant benefit harm. Table 16: Outcome: permanent stoma Not reported Table 17: Outcome: metastatic recurrence Quality assessment Number of patients Effect Study id or number of studies Design Risk of bias Inconsistency Indirectness Imprecision TEMS Resection Relative risk (95% CI) Population: T1 mean follow up TEMS 40.9 months Resection 45.8 months Winde 1996 RCT no n/a no serious very serious b serious a Population: T1 mean follow up TEMS 86.5 months Resection 93.0 months Palma 2009 Observational no serious 0/24 (0%) n/a no serious very serious b 2/34 (6%) Population: T1/T2 median follow up TEMS 18 months Resection 17.5 months 1/26 (4%) 0.36 (0.02 to 8.43) low very low Quality 0/17 (0%) 2.57 (0.13 to 50.7) very low 113

114 GRADE profiles, review question 2 Quality assessment Number of patients Effect Study id or number of studies Design Risk of bias Inconsistency Indirectness Imprecision TEMS Resection Relative risk (95% CI) Chen 2013 RCT very n/a no serious very serious d 0/28 0/30 (0%) Not estimable (0 serious c (0%) events in each arm) (a) Not downgraded despite lack of blinding as unlikely to have serious impact on this outcome. (b) 95% confidence intervals incorporate both clinically significant benefit harm. (c) Patients in resection group received adjuvant chemotherapy if considered high risk following surgery. Patients in the TEMS group did not. (d) Effect size not estimable. Quality very low Table 18: Outcome: quality of life Quality assessment Number of patients Effect Study id or number of studies Design Population: T1 EORTC QLQ-CR30 Global health status Lezoche 2014 Risk of bias Inconsistency Indirectness Imprecision TEMS Resection Mean scores (95% CI) Observational serious a n/a no serious very serious b Pre-treatment: TEMS: 10.6 (6.9 to 14.3) Resection: 8.6 (5.1 to 12.1) 1 month: TEMS: 8.6 (4.9 to 12.3) Resection: 7.9 (4.8 to 10.8) 3 months: TEMS: 10.4 (5.6 to 15.2) Resection: 7.9 (4.7 to 11.1) 6 months: TEMS: 10.2 (6.6 to 13.8) Resection: 10.6 (7.3 to 13.9) No statistical comparisons (a) Patients with a stoma were excluded. Having a stoma has potential impact on quality of life that may cause between group differences if there were different stoma rates. (b) No estimate of effect sizes or comparison across groups. Baseline differences in groups not accounted for at subsequent time points. No statistical comparison between groups Quality very low 114

115 GRADE profiles, review question 2 Table 19: Outcome: bowel function Quality assessment Number of patients Effect Study id or number of studies Design Risk of bias Inconsistency Indirectness Imprecision TEMS Resection Mean scores (95% CI) Population: T1 EORTC QLQ-CR38 Gastrointestinal problems symptom scale Lezoche 2014 Observational serious a n/a no serious very serious b Pre-treatment: TEMS 6.6 (5.6 to 7.6) Resection: 8.3 (5.5 to 11.1) 1 month: TEMS 6.6 (8.4 to 16.2) Resection: 10.6 (4.3 to 16.9) 3 months: TEMS: 6.6 (4.0 to 9.2) Resection: 12.3 (8.4 to 16.2) 6 months: TEMS: 6.5 (3.0 to 10.0) Resection: 7.8 (4.1 to 11.5) No statistical comparisons Quality very low (a) Patients with a stoma were excluded. Having a stoma has potential impact on bowel function that may cause between group differences if there were different stoma rates. (b) No estimate of effect sizes or comparison across groups. Baseline differences in groups not accounted for at subsequent time points. No statistical comparisons. Table 20: Outcome: sexual dysfunction Not reported T.2 Chemoradiation with transanal endoscopic microsurgery (TEMS) vs chemoradiation with radical bowel resection Table 21: Outcome: local recurrence Quality assessment Number of patients Effect Quality 115

116 GRADE profiles, review question 2 Study id or number of studies Design Risk of bias Inconsistency Indirectness Imprecision Population: T2, local recurrence at median follow up 56 months Lezoche RCT very n/a no serious very serious b serious a Population: T2, local recurrence at median follow up 84 months Lezoche Chemoradiation + TEMS Chemoradiation+ resection Local recurrence (number) Relative risk (95% CI) 1/20 (5%) 1/20 (5%) 1.00 (0.06 to 16.44) very low Chemoradiation + TEMS Chemoradiation+ resection Relative risk (95% CI) RCT serious c n/a no serious very serious b 2/35 (6%) 1/35 (3%) 2.06 (0.18 to 23.8) very low Population: T2, local recurrence at median follow up 9.6 years Chemoradiation + TEMS Chemoradiation+ resection Relative risk (95% CI) Lezoche RCT serious c n/a no serious very serious b 4/50 (8%) 3/50 (6%) 1.36 (0.29 to 6.43) very low (a) Method for matching follow up period across groups unclear. Unclear romisation method exclusion criteria as reported differently in different reports of the same study. Not downgraded despite lack of blinding, as unlikely to have a serious impact on this outcome. (b) 95% confidence intervals incorporate clinically significant harms benefits. (c) Unclear romisation as reported differently in different reports of the same study. Not downgraded despite lack of blinding, as unlikely to have a serious impact on this outcome. Table 22: Outcome: mortality Quality assessment Number of patients Effect Study id or number of studies Design Population: T2, 30-day mortality Lezoche Risk of bias Inconsistency Indirectness Imprecision I=Chemoradiation + TEMS C=Chemoradiation + resection Mortality Relative risk (95% CI) RCT serious a n/a no serious very serious b 0/35 (0%) 0/35 (0%) Not estimable (0 events in each arm) Population: T2, Mortality at median follow up of 56 months Lezoche RCT very n/a no serious very serious d serious c Population: T2, Mortality at median follow up of 9.6 years Relative risk (95% CI) Quality very low 1/20 (5%) 2/20 (10%) 0.47 (0.04 to 5.69) very low Chemoradiation + TEMS Chemoradiation+ resection Relative risk (95% CI)

117 GRADE profiles, review question 2 Quality assessment Number of patients Effect Study id or number of studies Lezoche Design Risk of bias Inconsistency Indirectness Imprecision I=Chemoradiation + TEMS RCT serious a n/a no serious very serious d 10/50 (20%) Population: T2, Kaplan Meier cumulative probability of survival at end of follow up (unclear time point) C=Chemoradiation + resection Mortality Quality 7/50 (14%) 1.54 (0.53 to 4.42) very low Cumulative survival (95% CI) Lezoche RCT very n/a no serious very serious f I=72% (56 to 81) very low serious d C=80% (62 to 90) (a) Unclear romisation method exclusion criteria as reported differently in different reports of the same study. Not downgraded despite lack of blinding, as unlikely to have a serious impact on this outcome. (b) Effect size associated variability not estimable (c) Unclear how groups were matched to ensure equal median follow up period. Unclear romisation method exclusion criteria as reported differently in different reports of the same study. Not downgraded despite lack of blinding, as unlikely to have a serious impact on this outcome. (d) 95% confidence intervals incorporate substantial clinical harms benefits. (e) Mortality estimated at unclear timepoint. Unclear romisation method exclusion criteria as reported differently in different reports of the same study. Not downgraded despite lack of blinding, as unlikely to have a serious impact on this outcome. (f) Effect size associated variability not reported. Table 23: Outcome: permanent stoma Quality assessment Number of patients Effect Study id or number of studies Design Risk of bias Inconsistency Indirectness Imprecision Chemoradiation + TEMS Chemoradiation + Resection Relative risk (95% CI) Lezoche RCT serious a no serious no serious no serious 0/50 (0%) 12/50 (24%) 0.04 (0.00 to 0.66) moderate (a) Unclear romisation method exclusion criteria as reported differently in different reports of the same study. Not downgraded despite lack of blinding, as unlikely to have a serious impact on this outcome. Table 24: Outcome: metastatic recurrence Quality assessment Number of patients Effect Quality Study id or number of studies Design Risk of bias Inconsistency Indirectness Imprecision Population: T2, metastatic recurrence at median follow up 56 months Chemoradiation + TEMS Chemoradiation+ resection Metastatic recurrence Relative risk (95% CI) Quality 117

118 GRADE profiles, review question 2 Quality assessment Number of patients Effect Quality Study id or number of studies Lezoche Design RCT Risk of bias Inconsistency Indirectness Imprecision very n/a no serious very serious b serious a Population: T2, metastatic recurrence at median follow up 84 months Lezoche Chemoradiation + TEMS Chemoradiation+ resection Metastatic recurrence 1/20 (5%) 1/20 (5%) 1.00 (0.14 to 7.39) very low Chemoradiation + TEMS Chemoradiation+ resection Relative risk (95% CI) RCT serious c n/a no serious very serious b 1/35 (3%) 1/35 (3%) 1.00 (0.06 to 16.65) very low Population: T2, metastatic recurrence at median follow up 9.6 years Chemoradiation + TEMS Chemoradiation+ resection Relative risk (95% CI) Lezoche RCT serious c n/a no serious very serious b 2/50 (4%) 2/50 (4%) 1.00 (0.14 to 7.39) very low (a) Unclear procedure for matching follow up period across groups. Unclear romisation method exclusion criteria as reported differently in different reports of the same study. Not downgraded despite lack of blinding, as unlikely to have a serious impact on this outcome. (b) 95% confidence intervals encompass clinically significant harms benefits. (c) Unclear romisation method exclusion criteria as reported differently in different reports of the same study. Not downgraded despite lack of blinding, as unlikely to have a serious impact on this outcome. Table 25: Outcome: quality of life Not reported Table 26: Outcome: bowel function Not reported Table 27: Outcome: sexual dysfunction Not reported 118

119 GRADE profiles, review question 2 T.3 Transanal endoscopic microsurgery vs transanal excision Table 28: Outcome: local recurrence Quality assessment Number of patients Effect Study id or number of studies Design Risk of bias Inconsistency Indirectness Imprecision I=TEMS Population: T1/T2, tumour, all tumour distances from anal verge Cumulative Kaplan-meier recurrence rate at 5 years Christoforidis 2009 Observational very n/a no serious very serious b serious a C=Transanal excision Cumulative recurrence rate (95% CI) I=15.4% (6.5 to 33.7) C=29.1% (21.1 to 38.2) Log rank test: p=0.108 Quality very low Population: T1/T2, Subgroup of above: Tumour => 5cm from anal verge Cumulative Kaplan-meier recurrence rate at 5 years Christoforidis 2009 Cumulative recurrence rate (95% CI) Observational serious c n/a no serious very serious d I=15.9% (1.1 to 47.5) C=24.0% (14.7 to 17.5) very low (a) TEMS groups had significantly higher tumour height than transanal excision group. No details on how interventions were chosen for each patient. (b) No effect size associated variability reported. (c) No baseline information available for this subgroup separately. No details on how interventions were chosen for each patient. (d) No effect size associated variability reported. 95% confidence intervals inconsistent with effect estimate. Table 29: Outcome: mortality Quality assessment Number of patients Effect Study id or number of studies Design Risk of bias Inconsistency Indirectness Imprecision I=TEMS Population: T1/T2, tumour, all tumour distances from anal verge Cumulative Kaplan-meier survival at 5 years Christoforidis 2009 Observational very n/a no serious very serious b serious a C=Transanal excision Cumulative 5 year survival (95% CI) I=79.9% (60.1 to 90.6) C=66.0% (55.4 to 74.7) Quality very low 119

120 GRADE profiles, review question 2 Quality assessment Number of patients Effect Study id or number of studies Design Risk of bias Inconsistency Indirectness Imprecision I=TEMS C=Transanal excision Cumulative 5 year survival (95% CI) Quality Population: T1/T2, tumour => 5cm from anal verge Cumulative Kaplan-meier survival at 5 years Christoforidis 2009 Observational serious c n/a no serious very serious b I=79.2% (58.8 to 87.2) C=72.3% (58.3 to 82.2) (a) TEMS groups had significantly higher tumour height than transanal excision group. No details on how interventions were chosen for each patient. (b) No effect size associated variability reported. (c) No baseline information available for this subgroup separately. No details on how interventions were chosen for each patient. very low Table 30: Outcome: permanent stoma formation Not reported Table 31: Outcome: metastatic recurrence Not reported Table 32: Outcome: quality of life Not reported Table 33: Outcome: bowel function Not reported Table 34: Outcome: sexual dysfunction Not reported 120

121 TEMS Transanal excision, TAE Endoscopic resection, ER Hartmanns procedure, HP Abdominoperineal resection, APR Anterior resection, AR Clinical guideline Colorectal cancer GRADE profiles, review question 2 T.4 Endoscopic resection vs transanal endoscopic microsurgery vs transanal excision vs radical bowel resection Table 35: Outcome: local recurrence Not reported Table 36: Outcome: mortality Quality assessment Number of patients Effect Study id or number of studies Design Risk of bias Inconsistency Indirectness Imprecision Quality Population: T1/T2, tumour Cumulative Kaplan-meier 5 year relative survival at 5 years Kaplan Meier Relative probability 5 year survival (95% CI) Saraste 2013 Observational very n/a no serious very serious b serious a AR=0.95 (0.92 to 0.97) APR=0.89 (0.85 to 0.93) HP=0.77 (0.69 to 0.87) ER=0.82 (0.73 to 0.91) TAE=0.82 (0.73 to 0.91) TEMS=0.75 (0.62 to 0.88) very low No statistical comparisons (a) Baseline characteristics not reported separately for each group, so substantial risk that groups may differ in prognosis before treatment. (b) No effect size accompanying variability reported. Table 37: Outcome: permanent stoma formation Not reported 121

122 GRADE profiles, review question 2 Table 38: Outcome: metastatic recurrence Not reported Table 39: Outcome: quality of life Not reported Table 40: Outcome: bowel function Not reported Table 41: Outcome: sexual dysfunction Not reported 122

123 Economic search strategy, review question 2 Appendix U: Economic search strategy, review question 2 Databases that were searched, together with the number of articles retrieved from each database are shown in Table 42. The MEDLINE search strategy is shown in Table 43.The same strategy was translated for the other databases listed. Table 42: Economic search summary Database Date searched Number retrieved NHS EED (Wiley) 30/04/ MEDLINE (Ovid) 30/04/ MEDLINE In-Process (Ovid) 30/04/ EMBASE (Ovid) 30/04/ HEED 30/04/ Table 43: Economic search strategy (MEDLINE) Line number Search term 123 Number retrieved 1 exp Colorectal Neoplasms/ ((colorect* or rectal* or rectum* or bowel*) adj4 (cancer* or neoplas* or oncolog* or malignan* or tumor* or tumour* or carcinoma* or adenocarcinoma*)).tw or/ ((Transanal* or trans-anal*) adj4 (microsurg* or operation or resection*)).tw. 5 (TEMS or TEM or TEO).tw (Endoscop* adj4 (mucosal* or submucosal*)).tw Brachytherapy/ brachytherap*.tw papillon*.tw ((therap* or radiotherap* or radioisotope* or radiation) adj4 (interstitial or plaque or implant or surface or intracavit* or contact)).tw. 11 (curietherap* or endocurietherap*).tw ((bowel* or abdominoperineal or anorectal or anterior or anteroposterior) adj4 (excision* or remov* or resection*)).tw. 13 (glove* adj4 port*).tw ((single adj1 incision adj1 laparoscopic adj1 surg*) or SILS).tw or/ animals/ not human/ not limit 18 to english language Economics/ exp "Costs Cost Analysis"/ Economics, Dental/ exp Economics, Hospital/ exp Economics, Medical/ 13541

124 Economic search strategy, review question 2 Line number Search term Number retrieved 25 Economics, Nursing/ Economics, Pharmaceutical/ Budgets/ exp Models, Economic/ Markov Chains/ Monte Carlo Method/ Decision Trees/ econom$.tw cba.tw cea.tw cua.tw markov$.tw (monte adj carlo).tw (decision adj3 (tree$ or analys$)).tw (cost or costs or costing$ or costly or costed).tw (price$ or pricing$).tw budget$.tw expenditure$.tw (value adj3 (money or monetary)).tw (pharmacoeconomic$ or (pharmaco adj economic$)).tw or/ "Quality of Life"/ quality of life.tw "Value of Life"/ Quality-Adjusted Life Years/ quality adjusted life.tw (qaly$ or qald$ or qale$ or qtime$).tw disability adjusted life.tw daly$.tw Health Status Indicators/ (sf36 or sf 36 or short form 36 or shortform 36 or sf thirtysix or sf thirty six or shortform thirtysix or shortform thirty six or short form thirtysix or short form thirty six).tw. 56 (sf6 or sf 6 or short form 6 or shortform 6 or sf six or sfsix or shortform six or short form six).tw. 57 (sf12 or sf 12 or short form 12 or shortform 12 or sf twelve or sftwelve or shortform twelve or short form twelve).tw. 58 (sf16 or sf 16 or short form 16 or shortform 16 or sf sixteen or sfsixteen or shortform sixteen or short form sixteen).tw. 59 (sf20 or sf 20 or short form 20 or shortform 20 or sf twenty or sftwenty or shortform twenty or short form twenty).tw (euroqol or euro qol or eq5d or eq 5d).tw (qol or hql or hqol or hrqol).tw (hye or hyes).tw health$ year$ equivalent$.tw utilit$.tw

125 Economic search strategy, review question 2 Line number Search term 65 (hui or hui1 or hui2 or hui3).tw disutili$.tw rosser.tw quality of wellbeing.tw quality of well-being.tw qwb.tw. 160 Number retrieved 71 willingness to pay.tw stard gamble$.tw time trade off.tw time tradeoff.tw tto.tw or/ or

126 Economic review flowchart, review question 2 Appendix V: Economic review flowchart, review question 2 Figure 6: Economic review flowchart, review question 2 126

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