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Colorectal cancer (update) [C3] Optimal surgical technique for rectal cancer
NICE guideline TBC Evidence reviews July 2019
Draft for Consultation
These evidence reviews were developed by the National Guideline Alliance hosted by the Royal College of Obstetricians and Gynaecologists
DRAFT FOR CONSULTATION Efective treatment for early cancer
Disclaimer The recommendations in this guideline represent the view of NICE, arrived at after careful consideration of the evidence available. When exercising their judgement, professionals are expected to take this guideline fully into account, alongside the individual needs, preferences and values of their patients or service users. The recommendations in this guideline are not mandatory and the guideline does not override the responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or their carer or guardian. Local commissioners and/or providers have a responsibility to enable the guideline to be applied when individual health professionals and their patients or service users wish to use it. They should do so in the context of local and national priorities for funding and developing services, and in light of their duties to have due regard to the need to eliminate unlawful discrimination, to advance equality of opportunity and to reduce health inequalities. Nothing in this guideline should be interpreted in a way that would be inconsistent with compliance with those duties. NICE guidelines cover health and care in England. Decisions on how they apply in other UK countries are made by ministers in the Welsh Government, Scottish Government, and Northern Ireland Executive. All NICE guidance is subject to regular review and may be updated or withdrawn.
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DRAFT FOR CONSULTATION Optimal surgical technique for rectal cancer
Contents Optimal surgical technique for rectal cancer ...... 6 Review question ...... 6 Introduction ...... 6 Summary of the protocol ...... 6 Methods and process ...... 7 Clinical evidence ...... 7 Summary of clinical studies included in the evidence review ...... 8 Quality assessment of clinical studies included in the evidence review 15 Economic evidence ...... 16 Economic model ...... 16 Evidence statements ...... 20 The committee’s discussion of the evidence ...... 27 References ...... 32 Appendices ...... 36 Appendix A – Review protocol ...... 36 Review protocol for review question: What is the optimal surgical technique for rectal cancer? ...... 36 Appendix B – Literature search strategies ...... 41 Literature search strategies for review question: What is the optimal surgery for rectal cancer? ...... 41 Appendix C – Clinical evidence study selection ...... 44 Clinical study selection for review question: What is the optimal surgery for rectal cancer? ...... 44 Appendix D – Clinical evidence tables ...... 45 Clinical evidence tables for review question: What is the optimal surgery for rectal cancer? ...... 45 Appendix E – Forest plots...... 131 Forest plots for review question: What is the optimal surgery for rectal cancer? ...... 131 Appendix F – GRADE tables ...... 156 GRADE tables for review question: What is the optimal surgery for rectal cancer? ...... 156 Appendix G – Economic evidence study selection ...... 176 Economic evidence study selection for review question: What is the optimal surgical technique for rectal cancer? ...... 176 Appendix H – Economic evidence tables ...... 177 Economic evidence study selection for review question: What is the optimal surgical technique for rectal cancer? ...... 177
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DRAFT FOR CONSULTATION Optimal surgical technique for rectal cancer
Appendix I – Economic evidence profiles ...... 178 Economic evidence profiles for review question: What is the optimal surgical technique for rectal cancer? ...... 178 Appendix J – Economic analysis ...... 179 Economic evidence analysis for review question: What is the optimal surgical technique for rectal cancer? ...... 179 Appendix K – Excluded studies ...... 193 Excluded clinical studies for review question: What is the optimal surgical technique for rectal cancer? ...... 193 Appendix L – Research recommendations ...... 220 Research recommendations for review question: What is the optimal surgical technique for rectal cancer? ...... 220
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DRAFT FOR CONSULTATION Optimal surgical technique for rectal cancer
1 Optimal surgical technique for rectal 2 cancer 3 This evidence review supports recommendations 1.3.6 to 1.3.9.
4 Review question 5 What is the optimal surgical technique for rectal cancer?
6 Introduction 7 Over the last couple of decades, laparoscopic surgery, a minimally invasive surgical 8 technique, has become more and more common in rectal cancer surgery, offering an 9 alternative to the conventional open surgical technique. In recent years manual 10 laparoscopic surgery has been challenged by robotic surgery and transanal total 11 mesorectal excision (TaTME) has been suggested as a surgical technique when 12 performing anterior resection. The aim of this review is to compare the clinical and 13 cost effectiveness of different surgical techniques in treating non-metastatic rectal 14 cancer.
15 Summary of the protocol 16 Please see Table 1 for a summary of the population, intervention, comparison and 17 outcomes (PICO) characteristics of this review.
18 Table 1: Summary of the protocol (PICO table) Population Adults with non-metastatic rectal cancer • T1-2 N1-2 • T3 N any • T4 N any • M0 Intervention Surgical resection (for example abdominoperineal resection [APR] or low anterior resection [LAR]) • Open • Laparoscopic • Robotic • Transanal total mesorectal excision (TaTME; only anterior resection) Comparison Surgical techniques compared to each other
Outcomes Critical • Overall survival • Quality of life o Overall o Sexual function o Bladder function • Resection margins Important • Local recurrence • Length of hospital stay
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DRAFT FOR CONSULTATION Optimal surgical technique for rectal cancer
• 90-day mortality • Treatment-related complications: o Anastomotic leak (only relevant in anterior resection) o Surgical site infection o Blood loss 1 APR: abdominoperineal resection; LAR: lower anterior resection; TNM: cancer classification system, 2 standing for tumour, nodal and metastasis stages. 3 For further details see the review protocol in appendix A.
4 Methods and process 5 This evidence review was developed using the methods and process described in 6 Developing NICE guidelines: the manual 2014. Methods specific to this review 7 question are described in the review protocol in appendix A. 8 Declarations of interest were recorded according to NICE’s 2014 conflicts of interest 9 policy until 31 March 2018. From 1 April 2018, declarations of interest were recorded 10 according to NICE’s 2018 conflicts of interest policy. Those interests declared until 11 April 2018 were reclassified according to NICE’s 2018 conflicts of interest policy (see 12 Register of Interests).
13 Clinical evidence
14 Included studies 15 Thirty-seven publications from 17 RCTs and 9 cohort studies were included in this 16 review (ACOSOG Z6051 trial [Fleshman 2015; Fleshman 2018]; ALaCaRT trial 17 [Stevenson 2015; Stevenson 2018]; Arteaga Gonzalez 2006; Bordeaux trial [Denost 18 2018; Pontallier 2016]; Braga 2007; Buonpane 2017; CLASICC trial [Green 2013; 19 Guillou 2005; Jayne 2005; Jayne 2010; Quah 2002]; COLOR II trial [Andersson 20 2014; Andersson 2013; Bonjer 2015; van der Pas 2013]; Corbellini 2016; COREAN 21 trial [Jeong 2014; Kang 2010]; Ielpo 2017; Ishibe 2017; Kim 2016; Kim 2017a; Kim 22 2017b; Law 2017; Liang 2011; Lujan 2011; Ng 2008; Ng 2009; Ng 2014; Park 2015; 23 ROLARR trial [Jayne 2017]; Rouanet 2018; Yoo 2015; Zhou 2004). 24 The included studies are summarised in Table 2. 25 Fourteen RCTs (24 publications) compared laparoscopic surgery to open surgery in 26 people with rectal cancer (comparison 1) (ACOSOG Z6051 trial [Fleshman 2015; 27 Fleshman 2018]; ALaCaRT trial [Stevenson 2015; Stevenson 2018]; Arteaga 28 Gonzalez 2006; Braga 2007; CLASICC trial [Green 2013; Guillou 2005; Jayne 2005; 29 Jayne 2010; Quah 2002]; COLOR II trial [Andersson 2014; Andersson 2013; Bonjer 30 2015; van der Pas 2013]; COREAN trial [Jeong 2014; Kang 2010]; Ishibe 2017; 31 Liang 2011; Lujan 2011; Ng 2008; Ng 2009; Ng 2014; Zhou 2004)). 32 Three cohort studies compared robotic surgery to open surgery in people with rectal 33 cancer (comparison 2) (Buonpane 2017; Corbellini 2016; Kim 2016). 34 Two RCTs and 8 cohort studies compared robotic surgery to laparoscopic surgery in 35 people with rectal cancer (comparison 3) (Corbellini 2016; Ielpo 2017; Kim 2016; Kim 36 2017a; Kim 2017b; Law 2017; Park 2015; ROLARR trial [Jayne 2017]; Rouanet 37 2018; Yoo 2015).
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DRAFT FOR CONSULTATION Optimal surgical technique for rectal cancer
1 One RCT (3 publications) compared TaTME to laparoscopic anterior resection in 2 people with rectal cancer (comparison 4) (Bordeaux’ trial [Denost 2017; Denost 2018; 3 Pontallier 2016]). 4 See the literature search strategy in appendix B and study selection flow chart in 5 appendix C.
6 Excluded studies 7 Studies not included in this review with reasons for their exclusions are provided in 8 appendix K.
9 Summary of clinical studies included in the evidence review 10 Summaries of the studies that were included in this review are presented in Table 2.
11 Table 2: Summary of included studies Intervention/Compa Outcomes Study Population rison Comparison 1: Laparoscopic versus open surgery ACOSOG N=486 Everyone received • Positive Z6051 trial preoperative therapy. resection Adenocarcinoma of the margins (Fleshman rectum within 12 cm of the Laparoscopic • Local or 2015; Fleshman anal verge; clinical stage II, surgery included locoregional 2018) IIA, or IIB; ≥18 years of age; 17% hand-assisted recurrence BMI <34; ECOG performance laparoscopic surgery • Length of RCT score <3 and 14% robot- hospital stay assisted • Operative laparoscopic surgery. USA mortality
• Anastomotic ~75-80% LAR leak ~20-25% APR • Blood loss
ALaCaRT trial N=475 ~50% received • Overall preoperative survival (Stevenson Adenocarcinoma of the radiotherapy • Positive 2015; rectum within 15 cm of the resection Stevenson anal verge; ≥18 years of age; ~90% LAR margins 2018) life expectancy of >12 weeks; ~10% APR • Local or adequate performance locoregional RCT status; no comorbidity or recurrence condition that would preclude
the use of either form of Australia surgery
Arteaga N=40 Preoperative • Positive Gonzalez 2006 radiotherapy: T3 or resection Rectal carcinoma <15 cm T4 middle and margins RCT from the anal verge lower third tumours • Length of or mesorectal hospital stay adenopathy without Spain ~25% TNM stage I • Anastomotic distant metastases leak • Blood loss ~50% LAR
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Intervention/Compa Outcomes Study Population rison ~25% APR ~25% Hartmann Braga 2007 N=168 Preoperative • Positive chemoradiotherapy: resection RCT Adenocarcinoma of the preoperative T3 margins cancers rectum; ≥18 years of age; • Local or
Italy suitable for elective surgery locoregional ~90% LAR recurrence
~30% Duke’s stage I ~10% APR • Length of hospital stay • Operative mortality • Anastomotic leak • Surgical site infection • Blood loss CLASICC trial N=381 Not clear how many • Overall received survival (Green 2013; Rectal or colon cancer preoperative therapy. • Quality of life Guillou 2005; suitable for right • Positive Jayne 2005; melicolectomy, left ~65% AR resection Jayne 2010; hemicolectomy, sigmoid ~25% APR margins Quah 2002) colectomy, anterior resection, ~10% other • Operative or abdominoperineal mortality resection RCT 4% of laparoscopic • Surgical site
surgery and 17% of infection UK (only data on people with open surgery was rectal cancer were palliative surgery considered for this review)
Proportion of the population with T1-2N0M0 cancer (exact proportion not clear)
COLOR II trial N=1,103 Preoperative • Overall radiotherapy: ~60% survival (Andersson A single rectal cancer within Preoperative • Quality of life 2013; 15 cm of the anal verge; no chemotherapy: ~30% • Positive Andersson evidence of distant resection 2014; Bonjer metastases; candidate for ~60% resection with margins 2015; van der elective surgery TME • Local or Pas 2013) ~10% resection with locoregional ~30% clinical stage I partial mesorectal recurrence RCT excision • Length of ~25% APR hospital stay Belgium, ~5% Hartmann • Operative Canada, mortality Denmark, • Anastomotic Germany, the leak Netherlands, Poland, South • Surgical site infection
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Intervention/Compa Outcomes Study Population rison Korea, Spain, Sweden COREAN trial N=340 Everyone received • Overall preoperative survival (Jeong 2014; Mid- or low-rectal cancer; chemoradiotherapy. • Positive Kang 2010) T3N0-2M0; previous resection preoperative ~85-90% LAR margins RCT chemoradiotherapy; 18-80 ~10-15% APR • Local or years of age locoregional recurrence South Korea • Operative mortality • Anastomotic leak Ishibe 2017 N=58 No one received • Overall preoperative therapy. survival RCT Colorectal adenocarcinoma; • Local or ≥75 years of age; clinical ~65% LAR locoregional Japan stage of up to T4a tumours; ~20% high AR recurrence any N stage; no evidence of ~10% APR metastasis; elective surgery (only data on people with rectal cancer was considered for this review)
Note that this study was among people 75 years or older.
Liang 2011 N=343 No one received • Operative preoperative therapy. mortality RCT Rectal cancer; without lung or • Anastomotic liver metastases; BMI ≤30; no ~50% LAR leak China preoperative therapy ~50% APR • Surgical site infection ~5% T1-2N0M0
Lujan 2009 N=204 Preoperative • Overall therapy: ~75% survival RCT Mid and low rectal • Positive adenocarcinoma ~75-80% AR resection Spain ~20-25% APR margins ~10-15% stage I • Local or locoregional recurrence • Length of hospital stay • Operative mortality • Anastomotic leak
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Intervention/Compa Outcomes Study Population rison • Surgical site infection • Blood loss Ng 2008 N=99 No one received • Overall preoperative therapy. survival RCT Low rectal cancer within 5cm • Positive from the anal verge 100% APR resection Hong Kong margins ~17-19% AJCC stage I • Local or locoregional recurrence • Length of hospital stay • Operative mortality • Surgical site infection • Blood loss Ng 2009 N=153 Preoperative • Overall therapy: not reported survival RCT Adenocarcinoma in the upper • Positive rectum (12-15cm from the 100% AR resection Hong Kong anal verge) margins • Local or ~14-17% AJCC stage I locoregional recurrence • Length of hospital stay • Operative mortality • Anastomotic leak • Surgical site infection • Blood loss Ng 2014 N=80 No one received • Overall preoperative therapy. survival RCT Mid and low rectal cancer, • Positive lowest margin of tumour 100% sphincter- resection Hong Kong located between 5 and 12 cm preserving surgery margin from the anal verge • Local or locoregional ~13% AJCC stage I recurrence • Length of hospital stay • Operative mortality • Surgical site infection • Anastomotic leak
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DRAFT FOR CONSULTATION Optimal surgical technique for rectal cancer
Intervention/Compa Outcomes Study Population rison • Blood loss Zhou 2004 N=171 Preoperative • Positive therapy: not reported resection RCT Rectal adenocarcinoma with margins the lowest margin of tumour Laparoscopic • Length of China located under the peritoneal surgery: anal hospital stay reflection and 1.5 cm above sphincter-preserving • Operative the dentate line resection mortality Open surgery: type • Anastomotic ~6% Duke’s stage A of surgery not clear leak • Surgical site infection Comparison 2: Robotic versus open surgery Buonpane 2017 N=16,672 Preoperative • Positive radiotherapy: ~60% resection Retrospective Surgically resected rectal Preoperative margins cohort study cancer chemotherapy: ~60%
This is a 3-arm Data obtained from a national Type of surgery not study oncology database. reported. comparing robotic versus A proportion of the population laparoscopic with T1-2N0M0 (not clear versus open how many) surgery but only
robotic versus open surgery is ~6-10% metastatic disease considered in this review.
USA Corbellini 2016 N=120 Preoperative therapy • Overall recommended to survival Prospective A single rectal cancer within locally advanced • Positive cohort study 12 cm of the anal verge; cancers. resection without evidence of distant margins This is a 3-arm metastases; candidates for ~80-90% AR study elective, good-chance ~10-20% APR comparing surgeries robotic versus laparoscopic ~20-25% pathologic stage I versus open (clinical stage not reported) surgery.
Italy Kim 2016 N=1,628 Preoperative • Overall chemoradiotherapy: survival Prospective Curatively resected 32% robotic surgery, • Quality of life 51% open surgery cohort study adenocarcinoma of the • Positive rectum; stage ≤ III; ECOG resection This is a 3-arm performance status of 0-3; ~85-95% LAR margins study ≤75 years of age ~1-3% AR
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Intervention/Compa Outcomes Study Population rison comparing ~5-10% APR robotic versus ~25% AJCC clinical stage 0-I laparoscopic versus open surgery.
South Korea Comparison 3: Robotic versus laparoscopic surgery Corbellini 2016 N=105 Preoperative therapy • Overall recommended to survival Prospective A single rectal cancer within locally advanced cohort study 12cm from the anal verge; cancers. without evidence of distant This is a 3-arm metastases; candidates for ~90-95% AR study elective, good-chance ~3-10% APR comparing surgeries robotic versus laparoscopic ~25-35% pathologic stage I versus open (clinical stage not reported) surgery. Italy Italy Ielpo 2017 N=198 Preoperative • Overall therapy: ~77% survival Retrospective Rectal cancer; underwent cohort study laparoscopic or robotic ~65-70% LAR surgery; not T4 cancer ~25-30% APR Spain ~5% colo-anal Proportion of population with anastomosis T1-2N0M0 not clear.
Kim 2016 N=1,628 Preoperative • Overall chemoradiotherapy: survival Prospective Curatively resected 32% robotic surgery, • Quality of life 51% open surgery cohort study adenocarcinoma of the • Positive rectum; stage ≤ III; ECOG resection This is a 3-arm performance status of 0-3; ~85-95% LAR margins study ≤75 years of age ~1-3% AR comparing ~5-10% APR robotic versus ~25% AJCC clinical stage 0-I laparoscopic versus open surgery
South Korea Kim 2017a N=163 Preoperative • Quality of life chemoradiotherapy: • Positive RCT Rectal adenocarcinoma ~80% resection within 9 cm from the anal margins South Korea verge; without distant ~95-99% LAR metastasis ~1-3% APR
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Intervention/Compa Outcomes Study Population rison Proportion of population with T1-2N0M0 not clear.
Kim 2017b N=448 Preoperative • Overall chemoradiotherapy: survival Retrospective Rectal adenocarcinoma ~20% • Quality of life cohort study within 15cm of the anal • Positive verge; underwent minimally ~75% LAR resection South Korea invasive surgery for rectal ~2% AR margins cancer ~15% • Length of intersphincteric hospital stay 28% pathologic TNM stage I resection • Anastomotic (clinical stage was not ~5% APR leak reported) • Blood loss
Law 2017 N=391 Preoperative • Overall radiotherapy: ~30- survival Retrospective Rectal cancer within 12cm 40% cohort study from the anal verge; underwent elective radical ~90-95% LAR Hong Kong resection ~5-8% APR ~1-3% Hartmann ~30% stage 0-I
Park 2015 N=217 Preoperative • Overall chemoradiotherapy: survival Prospective Rectal adenocarcinoma; ~11% cohort study underwent low anterior resection by robotic or 100% AR South Korea conventional laparoscopic approach
~30% postoperative pathologic stage I (preoperative/clinical stage not reported)
ROLARR trial N=471 Preoperative • Quality of life radiotherapy or • Positive (Jayne 2017) Adenocarcinoma of the chemoradiotherapy: resection ~46% rectum; fit for resectional margins
RCT surgery • Length of ~65-70% LAR hospital stay ~10% high AR Australia, Proportion of population with • Operative Denmark, T1-2N0M0 not clear. ~20% APR mortality Finland, France, • Anastomotic Germany, Italy, leak Singapore, • Surgical site infection
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Intervention/Compa Outcomes Study Population rison South Korea, UK, US Rouanet 2018 N=400 Laparoscopic TME • Overall (n=200) vs robotic survival TME (n=200) Retrospective Histologically proven cohort study adenocarcinoma located 12 cm from the anal verge who France underwent minimally invasive surgery (laparoscopic or robotic TME), with no previous or concurrent malignancy and no evidence of distant metastasis at time of surgery. Yoo 2015 N=70 Preoperative • Overall chemoradiotherapy: survival Retrospective Rectal cancer <5 cm from the 54% robotic, 27% cohort study anal verge; treated via laparoscopic laparoscopic or robotic South Korea intersphincteric resection 100% intersphincteric Proportion of the population resection with T1-2N0M0 not clear.
~10% with metastatic disease
South Korea Comparison 4: TaTME versus laparoscopic surgery Bourdeaux’ N=100 Preoperative • Overall Trial radiotherapy: ~80- survival Rectal cancer <6 cm from the 90% • Quality of life (Denost 2018; anal verge; suitable for Preoperative • Positive Pontallier 2016) laparoscopic sphincter-saving chemotherapy: ~80% resection resection margins RCT Laparoscopic • Local Small proportion possibly with surgery: sphincter- recurrence preserving resection France T1-2N0M0 but not clear • Length of (~80% T3-4 and ~60% N+) hospital stay • Operative mortality • Anastomotic leak (and/or abscess) 1 AJCC: American Joint Committee on Cancer; APR: abdominoperineal resection; AR: anterior resection; 2 BMI: body mass index; ECOG: Eastern Cooperative Oncology Group; LAR: lower anterior resection; N: 3 number; RCT: randomised controlled trial; T: tumour stage; TaTME: transanal total mesorectal excision: 4 TME: total mesorectal excision; TNM: tumour, node, metastasis staging system 5 See the full evidence tables in appendix D and the forest plots in appendix E.
6 Quality assessment of clinical studies included in the evidence review 7 See the clinical evidence profiles in appendix F.
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1 Economic evidence
2 Included studies 3 A systematic review of the economic literature was conducted but no economic 4 studies were identified which were applicable to this review question.
5 Excluded studies 6 A global search of economic evidence was undertaken for all review questions in this 7 guideline. See Supplement 2 for further information.
8 Economic model 9 An economic analysis was undertaken to estimate the cost-effectiveness of surgical 10 techniques for rectal cancer (see appendix J for the full report of the economic 11 analysis).
12 Methods 13 The analysis was developed in Microsoft Excel® and was conducted from the 14 perspective of the NHS and Personal Social Services (PSS) as outlined in the NICE 15 Reference Case (see Developing NICE guidelines: the manual). The model 16 considered a lifetime horizon with future costs and benefits discounted at a rate of 17 3.5% (as recommended in the NICE reference case).
18 Clinical data and model approach 19 The economic analysis was based on clinical effectiveness data for each of the 20 surgical techniques, which was sourced from the clinical evidence review. However, 21 only the comparison between the open and laparoscopic approach provided 22 sufficient data for all the key outcomes of interest for the economic analysis (overall 23 survival, local recurrence and complications). As a result, a decision was made to 24 separately consider two comparisons in the analysis. In the first, a comparison is 25 made between the open and laparoscopic approach based on evidence from the 26 clinical evidence review. In the second, all four surgical approaches are considered 27 using available data from the clinical evidence review in combination with 28 assumptions to fill in the missing data. The second analysis was therefore considered 29 to be more speculative and the conclusions that can be drawn from the analysis were 30 limited.
31 Costs 32 The costs considered in the model reflect the perspective of the analysis, thus only 33 costs that are relevant to the UK NHS & PSS were included. Where possible, all 34 costs were estimated in 2016/17 prices. 35 The majority of costs were sourced from NHS reference costs 2016/17 by applying 36 tariffs associated with the appropriate Healthcare Resource Groups (HRG) code. 37 However, note that the cost of the surgical procedure in NHS reference costs (FF31: 38 complex large intestine procedures, 19 years and over) is the same regardless of the 39 approach taken. Therefore, this cost was not estimated using the procedure code 40 from NHS reference costs and an alternative approach was adopted in order to 41 differentiate the various surgical techniques.
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DRAFT FOR CONSULTATION Optimal surgical technique for rectal cancer
1 Surgical equipment costs were estimated using data from a cost-effectiveness 2 analysis of surgical approaches in prostate cancer (Ramsay 2012), with costs inflated 3 to 2016 prices. Equipment costs were estimated to be £1,502, £1,605, £4,628 and 4 £1,815 for the open, laparoscopic, robotic and TaTME approaches, respectively. 5 Operative time costs were estimated using average theatre time estimates reported 6 in Ramsay 2012. A cost for an hour of operating theatre time was sourced from the 7 cost-effectiveness analysis from Ramsay 2012 and inflated to 2016 prices (£1,266). 8 Length of stay costs were estimated using data on the length of stay in hospital 9 following each procedure from the studies included in the clinical evidence review 10 combined with the cost of an excess bed day from NHS reference costs 2016/17. 11 Complication costs were estimated using the different costs associated with 12 complication and co-morbidity (CC) scores for the surgical procedure from NHS 13 reference costs. The difference between CC score 0-2 and an average of the other 14 CC scores associated with complex large intestine procedures (FF31) was used as 15 an estimate of complication costs. 16 Systemic chemotherapy costs were estimated assuming that patients would be 17 treated with 6 cycles of FOLFIRI or FOLFOX. The chemotherapy delivery costs were 18 sourced from NHS Reference Costs 2015/16 (assuming day case delivery) and drug 19 costs were sourced from eMit. 20 The cost of palliative care was estimated using estimates from a costing report by the 21 Nuffield Trust (Georghiou 2014). A cost of £7,287 was applied based on the average 22 resource use of patients with cancer in the last three months of life.
23 Health-related quality of life 24 As recommended in the NICE reference case, the model estimates effectiveness in 25 terms of quality adjusted life years (QALYs). These are estimated by combining life 26 year estimates with quality of life (QoL) values associated with being in a particular 27 health state. 28 QoL data for all comparisons were sourced from Rao 2017, a cost-effectiveness 29 analysis that estimated QoL for recurrences (0.78) and for being recurrence free 30 (0.86).
31 Base case results 32 The base case results of the analysis, based on the point estimates of the model 33 inputs, are shown in Table 15 and Table 16 for the two-way and four-way comparison 34 respectively. The results of the two-way comparison show the laparoscopic approach 35 to be more effective (1.26 QALYs) and less costly than the open approach (£921) 36 and it is therefore dominant. These results are driven by improvements in overall 37 survival which are clinically significant. 38 In the four-way comparison, alternative approaches were compared using a net 39 monetary benefit approach assuming a threshold of £20,000 per QALY. The results 40 show the TaTME approach to be the least costly approach. All other strategies are 41 found to be more costly and less effective than TaTME and are therefore dominated. 42 Consequently, net monetary benefit was negative for all other interventions. However 43 it should be noted for TaTME that the results are driven by improvements in overall 44 survival and recurrence which were based on a hazard ratio for which the 95% 45 confidence interval passed the line of no effect. It is therefore plausible that TaTME 46 may result in lower QALYs and higher costs (through increased recurrence) 47 compared to alternative approaches. These results should therefore be considered 48 speculative.
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DRAFT FOR CONSULTATION Optimal surgical technique for rectal cancer
1 Table 3: Base case results for two-way comparison Strategy Cost QALYs ICER (cost per Total Incremental Total Incremental QALY Open £11,963 - 9.08 - - Laparoscopic £11,042 -£921 10.34 1.26 Dominant 2 ICER: incremental cost-effectiveness ratio; QALYs: quality adjusted life years
3 Table 4: Base case results for four-way comparison Strategy Cost QALYs ICER (cost NMB per QALY Total Incremental Total Incremental TaTME £9,812 - 11.15 - - Laparoscopic £11,042 £1,230 10.34 -0.81 Dominated -£17,395 Open £11,963 £2,151 9.08 -2.07 Dominated -£43,575 Robotic £15,612 £5,800 9.92 -1.24 Dominated -£30,503 4 ICER: incremental cost-effectiveness ratio; QALYs: quality adjusted life years NMB Net monetary 5 benefit
6 Deterministic sensitivity results 7 A series of deterministic sensitivity analyses were conducted, whereby an input 8 parameter is changed, the model is re-run and the new cost-effectiveness result is 9 recorded. This is a useful way of estimating uncertainty and determining the key 10 drivers of the model result. The results of the deterministic sensitivity analyses are 11 presented in Table 5 and Table 6 for the two-way and four-way comparison, 12 respectively. 13 In the two way comparison, it can again be seen that the conclusion of the analysis 14 remains unchanged in the majority of modelled scenarios with the laparoscopic 15 approach found to be cost-effective. Notably this includes a scenario in which only 16 statistically significant effects are modelled. The conclusion of the analysis was found 17 to change when the upper hazard ratio (HR) for overall survival was applied 18 (meaning that overall survival is better with the open approach). 19 In the four way comparison, it can again be seen that the conclusion of the analysis 20 remains unchanged in the majority of modelled scenarios with TaTME found to be 21 cost-effective. However, notably, this does not includes a scenario in which only 22 statistically significant effects are modelled (in which the laparoscopic approach is 23 found to be cost-effective). The laparoscopic approach was also found to be cost- 24 effective when the upper HR for overall survival for TaTME was applied or when 25 overall survival was assumed to be equivalent with laparoscopic and TaTME. The 26 open approach was found to be cost-effective when the upper HR for overall survival 27 for TaTME and the laparoscopic approach was applied.
28 Table 5: Deterministic sensitivity results for two-way comparison Modelled scenario Optimal strategy Base case Laparoscopic Overall survival – lower HR Laparoscopic Overall survival – upper HR Laparoscopic Local recurrence – lower RR Laparoscopic Local recurrence – upper RR Laparoscopic Complications – lower RR Laparoscopic
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Modelled scenario Optimal strategy Complications – upper RR Laparoscopic Statistically significant changes only Laparoscopic Number of robotic procedures per year = 50 Laparoscopic Number of robotic procedures per year = 100 Laparoscopic Number of robotic procedures per year = 200 Laparoscopic Complication costs + 50% Laparoscopic Complication costs - 50% Laparoscopic No systemic chemotherapy costs Laparoscopic No palliative care costs Laparoscopic No recurrence disutility Laparoscopic 1 HR: hazard ratio: RR: relative risk
2 Table 6: Deterministic sensitivity results for four-way comparison Modelled scenario Optimal strategy Base case TaTME Overall survival – lower HR for laparoscopic TaTME Overall survival – upper HR for laparoscopic TaTME Overall survival – lower HR for TaTME TaTME Overall survival – upper HR for TaTME Laparoscopic Overall survival with TaTMEequivalent to laparoscopic Laparoscopic Overall survival – upper HR for TaTME and laparoscopic Open Absolute overall survival with robotic 10% higher TaTME Absolute overall survival with robotic 10% lower TaTME Local recurrence – lower RR for laparoscopic TaTME Local recurrence – upper RR for laparoscopic TaTME Absolute local recurrence with TaTME 10% higher TaTME Absolute local recurrence with TaTME 10% lower TaTME Local recurrence with TaTME equivalent to laparoscopic TaTME Complications – lower RR TaTME Complications – upper RR TaTME Statistically significant changes only Laparoscopic Number of robotic procedures per year = 50 TaTME Number of robotic procedures per year = 100 TaTME Number of robotic procedures per year = 200 TaTME Complication costs + 50% TaTME Complication costs - 50% TaTME No systemic chemotherapy costs TaTME No palliative care costs TaTME No recurrence disutility TaTME 3 HR: hazard ratio; RR: relative risk; TaTME: transanal total mesorectal excision
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DRAFT FOR CONSULTATION Optimal surgical technique for rectal cancer
1 Evidence statements
2 Clinical evidence statements
3 Comparison 1: Laparoscopic versus open surgery
4 Critical outcomes
5 Overall survival 6 • Moderate quality evidence from 9 RCTs (N=2731; median follow-up 3.2 to 9.2 7 years) showed a clinically important improvement in the overall survival of people 8 who underwent laparoscopic surgery for non-metastatic rectal cancer when 9 compared to those who had open surgery.
10 Quality of life 11 • Very low quality evidence from 1 RCT (N=338) showed no clinically important 12 difference in global quality of life at 4 weeks, 6 months or 12 months after surgery 13 (self-assessed using QLQ-C30) between people who underwent laparoscopic or 14 open surgery for non-metastatic rectal cancer. 15 • Very low quality evidence from 1 RCT (N=336) showed no clinically important 16 difference in global health status at 4 weeks, 6 months or 12 months after surgery 17 (self-assessed using EQ-VAS) between people who underwent laparoscopic or 18 open surgery for non-metastatic rectal cancer. 19 • Very low quality evidence from 1 RCT (N=168) showed a clinically importantly 20 higher general health score at 12 months after surgery (self-assessing using SF- 21 36) in people who underwent laparoscopic surgery compared to those who 22 underwent open surgery for non-metastatic rectal cancer. However, at 24 months 23 after surgery there was no difference in the same general health score. 24 • Very low quality evidence from 1 RCT (N=1,103) showed no clinically important 25 difference in sexual functioning at 4 weeks, 6, 12 or 24 months after surgery (self- 26 assessed using QLQ-CR38) between people who underwent laparoscopic or open 27 surgery for non-metastatic rectal cancer. 28 • Very low quality evidence from 1 RCT (N=1,103) showed no clinically important 29 difference in sexual enjoyment at 6, 12 or 24 months after surgery (self-assessed 30 using QLQ-CR38) between people who underwent laparoscopic or open surgery 31 for non-metastatic rectal cancer. 32 • Very low quality evidence from 1 RCT (N=1,103) showed no clinically important 33 difference in sexual problems at 6, 12 or 24 months after surgery (self-assessed 34 using QLQ-CR38) between women who underwent laparoscopic or open surgery 35 for non-metastatic rectal cancer. 36 • Very low quality evidence from 1 RCT (N=46) showed no clinically important 37 difference in overall sexual dysfunction after surgery (self-assessed using FSFI) 38 between women who underwent laparoscopic or open surgery for non-metastatic 39 rectal cancer. 40 • Very low quality evidence from 1 RCT (N=1,103) showed no clinically important 41 difference in sexual problems at 4 weeks, 6, 12 or 24 months after surgery (self- 42 assessed using QLQ-CR38) between men who underwent laparoscopic or open 43 surgery for non-metastatic rectal cancer. 44 • Very low quality evidence from 1 RCT (N=37) showed a clinically important 45 increased risk of overall sexual dysfunction at median 3 years after surgery (self- 46 assessed using IIEF) in previously sexually active men who underwent
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1 laparoscopic surgery compared to those who underwent open surgery for non- 2 metastatic rectal cancer. 3 • Very low quality evidence from 1 RCT (N=82) showed no clinically important 4 difference in perceived severe change in overall level of sexual function after 5 surgery (self-assessed using IIEF) in men who underwent laparoscopic or open 6 surgery for non-metastatic rectal cancer. 7 • Very low quality evidence from 1 RCT (N=1,103) showed no clinically important 8 difference in micturitional symptoms at 4 weeks, 6, 12, or 24 months after surgery 9 (self-assessed using QLQ-CR38) between people who underwent laparoscopic or 10 open surgery for non-metastatic rectal cancer. 11 • Very low quality evidence from 1 RCT (N=148) showed “no differences in bladder 12 function, either in overall score or in individual symptom scores” at 2 weeks, 3, 6, 13 and 18 months after surgery (self-assessed using IPSS and QLQ-CR38) between 14 people who underwent laparoscopic or open surgery for non-metastatic rectal 15 cancer (reported narratively only).
16 Resection margins 17 • Moderate quality evidence from 9 RCTs (N=2,246) showed no clinically important 18 difference in positive CRM (defined as <1 mm, ≤1 mm or not defined) between 19 people who underwent laparoscopic or open surgery for non-metastatic rectal 20 cancer. 21 • Low quality evidence from 1 RCT (N=888) showed no clinically important 22 difference in positive CRM (defined as <2 mm) between people who underwent 23 laparoscopic or open surgery for non-metastatic rectal cancer. 24 • Low quality evidence from 5 RCTs (N=1,347) showed no clinically important 25 difference in positive distal resection margin between people who underwent 26 laparoscopic or open surgery for non-metastatic rectal cancer. 27 • Moderate quality evidence from 1 RCT (N=462) showed no clinically important 28 difference in positive radial resection margin (defined as ≤1 mm) between people 29 who underwent laparoscopic or open surgery for non-metastatic rectal cancer. 30 • Very low quality evidence from 1 RCT (N=40) showed no clinically important 31 difference in positive radial resection margin (defined as ≤2 mm) between people 32 who underwent laparoscopic or open surgery for non-metastatic rectal cancer. 33 Low quality evidence from 1 RCT (N=171) showed that 0 people who underwent 34 either laparoscopic or open surgery for non-metastatic rectal cancer had positive 35 resection margins (defined as “cancer cell found in the cut margins”).
36 Important outcomes
37 Local recurrence 38 • Moderate quality evidence from 3 RCTs (N=701; median follow-up ranging from 39 3.2 to 4 years) showed no clinically important difference in local recurrence free 40 survival between people who underwent laparoscopic or open surgery for non- 41 metastatic rectal cancer. 42 • Low quality evidence from 9 RCTs (N=2,520; median follow-up ranging from 3 to 43 7.5 years) showed no clinically important difference in local or locoregional 44 recurrence rates between people who underwent laparoscopic or open surgery for 45 non-metastatic rectal cancer.
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DRAFT FOR CONSULTATION Optimal surgical technique for rectal cancer
1 Length of hospital stay 2 • Meta-analysis of length of hospital stay showed considerable heterogeneity, 3 therefore, subgroup analysis according to type of surgical resection was done. 4 • Very low quality evidence from 4 RCTs (N=1,750) showed no clinically important 5 difference in mean length of hospital stay between people who underwent 6 laparoscopic or open anterior resection or abdominoperineal resection for non- 7 metastatic rectal cancer. Low quality evidence from one 1 RCT (N=381) showed 8 no clinically important difference in median length of hospital stay between people 9 who underwent laparoscopic or open anterior resection or abdominoperineal 10 resection for non-metastatic rectal cancer. 11 • Low quality evidence from 4 RCTs (N=572) showed a clinically important lower 12 mean length of hospital stay in people who underwent laparoscopic sphincter- 13 preserving surgery compared to open sphincter-preserving surgery for non- 14 metastatic rectal cancer. Moderate quality evidence from 2 RCTs (N=815) showed 15 no clinically important difference in median length of hospital stay in people who 16 underwent laparoscopic or open sphincter-preserving surgery for non-metastatic 17 rectal cancer. 18 • Low quality evidence from 1 RCT (N=99) showed no clinically important difference 19 in mean length of hospital stay in people who underwent laparoscopic or open 20 abdominoperineal surgery for non-metastatic rectal cancer.
21 90-day mortality 22 • Low quality evidence from 4 RCTs (N=2,053) showed no clinically important 23 difference in 30-day mortality between people who underwent laparoscopic or 24 open surgery for non-metastatic rectal cancer. 25 • Moderate quality evidence from 1 RCT (N=340) showed no deaths within 90 days 26 of surgery in people who underwent either laparoscopic or open surgery for non- 27 metastatic rectal cancer. 28 • Low quality evidence from 6 RCTs (N=1,408) showed no clinically important 29 difference in operative mortality (timeframe not defined) between people who 30 underwent laparoscopic or open surgery for non-metastatic rectal cancer.
31 Treatment-related complications: anastomotic leak 32 • Low quality evidence from 10 RCTs (N=2,616) showed no clinically important 33 difference in anastomotic leak between people who underwent laparoscopic or 34 open surgery for non-metastatic rectal cancer.
35 Treatment-related complications: surgical site infection 36 • Low quality evidence from 10 RCTs (N=2,678) showed no clinically important 37 difference in surgical site infection between people who underwent laparoscopic or 38 open surgery for non-metastatic rectal cancer.
39 Treatment-related complications: blood loss 40 • Meta-analysis of blood loss showed considerable heterogeneity, therefore, 41 subgroup analysis according to type of surgical resection was done. 42 • Moderate quality evidence from 3 RCTs (N=695) showed a clinically important 43 lower mean blood loss in people who underwent laparoscopic anterior resection or 44 abdominoperineal resection compared to those who underwent open anterior 45 resection or abdominoperineal resection for non-metastatic rectal cancer. 46 Moderate quality evidence from 1 RCT (N=1,044) showed that the median blood 47 loss was significantly lower in people who underwent laparoscopic anterior
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1 resection or abdominoperineal resection compared to those who underwent open 2 anterior resection or abdominoperineal resection for non-metastatic rectal cancer. 3 • Moderate quality evidence from 4 RCTs (N=572) showed a clinically important 4 lower mean blood loss in people who underwent laparoscopic sphincter- 5 preserving surgery compared to those who underwent open sphincter-preserving 6 surgery for non-metastatic rectal cancer. Moderate quality evidence from 2 RCTs 7 (N=815) showed that the median blood loss was significantly lower in people who 8 underwent laparoscopic sphincter-preserving surgery compared to those who 9 underwent open sphincter-preserving surgery for non-metastatic rectal cancer. 10 • Low quality evidence from 1 RCT (N=99) showed no difference in mean blood loss 11 between people who underwent laparoscopic or open abdominoperineal resection 12 for non-metastatic rectal cancer.
13 Comparison 2: Robotic versus open surgery
14 Critical outcomes
15 Overall survival 16 • Very low quality evidence from 1 prospective and 1 retrospective cohort study 17 (N=1,691) showed no clinically important difference in overall survival at 3 years 18 between people who underwent robotic surgery compared to those who 19 underwent open surgery for non-metastatic rectal cancer.
20 Quality of life 21 • Very low quality evidence from 1 prospective cohort study (N=473) showed a 22 clinically important lower risk of moderate or severe sexual dysfunction in men 65 23 years or younger (self-assessed using VAS) who underwent robotic surgery 24 compared to those who underwent open surgery for non-metastatic rectal cancer. 25 When looking at severe and moderate sexual dysfunction separately, there was 26 no difference in severe sexual dysfunction (VAS 4-5) between the groups but a 27 clinically important lower risk of moderate sexual dysfunction (VAS 2-3) in men 65 28 years or younger who underwent robotic surgery compared to those who 29 underwent open surgery.
30 Resection margins 31 • Very low quality evidence from 1 retrospective cohort study (N=16,672) showed a 32 clinically important lower risk of positive resection margin (not defined) in people 33 who underwent robotic surgery compared to those who underwent open surgery 34 for non-metastatic rectal cancer. 35 • Very low quality evidence from 1 prospective cohort study (N=1,628) showed no 36 clinically important difference in positive CRM (defined as ≤1 mm) between people 37 who underwent robotic or open surgery for non-metastatic rectal cancer. 38 • Very low quality evidence from 1 prospective cohort study (N=120) showed no 39 clinically important difference in R1 resection between people who underwent 40 robotic or open surgery for non-metastatic rectal cancer. 41 • Very low quality evidence from 1 prospective cohort study (N=1,628) showed no 42 clinically important difference in positive distal resection margin (defined as ≤5 43 mm) between people who underwent robotic or open surgery for non-metastatic 44 rectal cancer.
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DRAFT FOR CONSULTATION Optimal surgical technique for rectal cancer
1 Important outcomes
2 Local recurrence 3 No RCT evidence was identified to inform this outcome.
4 Length of hospital stay 5 No RCT evidence was identified to inform this outcome.
6 90-day mortality 7 No RCT evidence was identified to inform this outcome.
8 Treatment-related complications: anastomotic leak 9 No RCT evidence was identified to inform this outcome.
10 Treatment-related complications: surgical site infection 11 No RCT evidence was identified to inform this outcome.
12 Treatment-related complications: blood loss 13 No RCT evidence was identified to inform this outcome.
14 Comparison 3: Robotic versus laparoscopic surgery
15 Critical outcomes
16 Overall survival 17 • Very low quality evidence from 2 prospective and 6 retrospective cohort studies 18 (N=2,771) with median follow-up 3 to 5 years showed no clinically important 19 difference in overall survival between people who underwent robotic or 20 laparoscopic surgery for non-metastatic rectal cancer.
21 Quality of life 22 • Very low quality evidence from 1 RCT (N=139) showed no clinically important 23 difference in global health status at 3 weeks, 3 and 12 months after surgery (self- 24 assessed using QLQ-C30) between people who underwent robotic or 25 laparoscopic surgery for non-metastatic rectal cancer. 26 • Very low quality evidence from 1 RCT (N=139) showed a clinically important better 27 sexual function score at 12 months (self-assessed using QLQ-CR38) in people 28 who underwent robotic surgery compared to those who underwent laparoscopic 29 surgery for non-metastatic rectal cancer. 30 • Very low quality evidence from 1 RCT (N=471) showed no clinically important 31 difference in female sexual function at 6 months (self-assessed using FSFI) 32 between women who underwent robotic or laparoscopic surgery for non- 33 metastatic rectal cancer. 34 • Very low quality evidence from 1 RCT (N=471) showed no clinically important 35 difference in male sexual function at 6 months (self-assessed using IIEF) between 36 men who underwent robotic or laparoscopic surgery for non-metastatic rectal 37 cancer. 38 • Very low quality evidence from 1 RCT (N=471) showed no clinically important 39 difference in bladder function at 6 months (self-assessed using IPSS) between
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DRAFT FOR CONSULTATION Optimal surgical technique for rectal cancer
1 people who underwent robotic or laparoscopic surgery for non-metastatic rectal 2 cancer.
3 Resection margins 4 • Very low quality evidence from 2 RCTs (N=598) showed no clinically important 5 difference in positive CRM (defined as ≤1 mm) between people who underwent 6 robotic or laparoscopic surgery for non-metastatic rectal cancer. 7 • Very low quality evidence from 1 RCT (N=471) showed no clinically important 8 difference in positive distal resection margin between people who underwent 9 robotic or laparoscopic surgery for non-metastatic rectal cancer. In the same trial, 10 no positive proximal resection margins were observed.
11 Important outcomes
12 Local recurrence 13 No RCT evidence was identified to inform this outcome.
14 Length of hospital stay 15 • Very low quality evidence from 2 RCTs (N=610) showed no clinically important 16 difference in length of hospital stay between people who underwent robotic or 17 laparoscopic surgery for non-metastatic rectal cancer.
18 90-day mortality 19 • Very low quality evidence from 1 RCT (N=471) showed no clinically important 20 difference in 30-day mortality between people who underwent robotic or 21 laparoscopic surgery for non-metastatic rectal cancer.
22 Treatment-related complications: anastomotic leak 23 • Very low quality evidence from 2 RCTs (N=500) showed no clinically important 24 difference in anastomotic leak between people who underwent robotic or 25 laparoscopic surgery for non-metastatic rectal surgery.
26 Treatment-related complications: surgical site infection 27 • Very low quality evidence from 1 RCT (N=471) showed no clinically important 28 difference in surgical site infection within 30 days from the operation or between 29 30 days and 6 months from the operations between people wo underwent robotic 30 or laparoscopic surgery for non-metastatic rectal cancer.
31 Treatment-related complications: blood loss 32 • Low quality evidence from 1 RCT (N=139) showed a clinically important higher 33 blood loss in people who underwent robotic surgery compared to those who 34 underwent laparoscopic surgery for non-metastatic rectal cancer.
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DRAFT FOR CONSULTATION Optimal surgical technique for rectal cancer
1 Comparison 4: Transanal total mesorectal excision versus laparoscopic surgery
2 Critical outcomes
3 Overall survival 4 • Low quality evidence from 1 RCT (N=100) showed no clinically important 5 difference in overall survival at 5 years between people who underwent TaTME or 6 laparoscopic anterior resection for non-metastatic rectal cancer.
7 Quality of life 8 • Very low quality evidence from 1 RCT (N=51) showed a clinically important higher 9 rate of maintained sexual activity at median 3.2 years after treatment in previously 10 sexually active people who underwent TaTME compared to those who underwent 11 laparoscopic anterior resection for non-metastatic rectal cancer. 12 • Very low quality evidence from 1 RCT (N=39) showed no clinically important 13 difference in erectile function at median 3.2 years after treatment (self-assessed 14 using IIEF) between men who underwent TaTME or laparoscopic anterior 15 resection for non-metastatic rectal cancer. 16 • Very low quality evidence from 1 RCT (N=37) showed no clinically important 17 difference in ejaculatory function at median 3.2 years after treatment (self- 18 assessed using IIEF) between previously sexually active men who underwent 19 TaTME or laparoscopic anterior resection for non-metastatic rectal cancer. 20 • Very low quality evidence from 1 RCT (N=8) showed no clinically important 21 difference in female sexual function after treatment (self-assessed using FSFI) 22 between previously sexually active female who underwent TaTME or laparoscopic 23 anterior resection for non-metastatic rectal cancer. 24 • Very low quality evidence from 1 RCT (N=72) showed no sclinically important 25 difference in median urinary function quality of life score or median urinary 26 function total score after treatment (self-assessed using IPSS) in people who 27 underwent TaTME or laparoscopic anterior resection for non-metastatic rectal 28 cancer.
29 Resection margins 30 • Low quality evidence from 1 RCT (N=100) showed a clinically important lower risk 31 of R1 resection (defined as positive CRM) in people who underwent TaTME 32 compared to those who underwent laparoscopic anterior resection for non- 33 metastatic rectal cancer. 34 • Low quality evidence from 1 RCT (N=100) showed no clinically important 35 difference in positive distal margin between people who underwent TaTME or 36 laparoscopic anterior resection for non-metastatic rectal cancer.
37 Important outcomes
38 Local recurrence 39 • Low quality evidence from 1 RCT (N=100) showed no clinically important 40 difference in local recurrence at 5 years between people who underwent TaTME 41 or laparoscopic anterior resection for non-metastatic rectal cancer.
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1 Length of hospital stay 2 • Low quality evidence from 1 RCT (N=100) showed no clinically important 3 difference in median length of hospital stay between people who underwent 4 TaTME or laparoscopic anterior resection for non-metastatic rectal cancer.
5 90-day mortality 6 • Low quality evidence from 1 RCT (N=100) showed no clinically important 7 difference in postoperative mortality between people who underwent TaTME or 8 laparoscopic anterior resection for non-metastatic rectal cancer.
9 Treatment-related complications: anastomotic leak 10 • Low quality evidence from 1 RCT (N=100) showed no clinically important 11 difference in anastomotic leak and/or abscess between people who underwent 12 TaTME or laparoscopic anterior resection for non-metastatic rectal cancer.
13 Treatment-related complications: surgical site infection 14 No RCT evidence was identified to inform this outcome.
15 Treatment-related complications: blood loss 16 No RCT evidence was identified to inform this outcome.
17 Comparison 5: Transanal total mesorectal excision versus open surgery 18 No evidence was identified for this comparison.
19 Comparison 6: Transanal total mesorectal excision versus robotic surgery 20 No evidence was identified for this comparison.
21 Economic evidence statements 22 One bespoke economic model developed for this review question taking a UK NHS 23 and PSS perspective and using clinical parameters from the accompanying clinical 24 evidence review suggested that a laparoscopic approach was both cost saving and 25 health improving compared to an open approach. Probabalistic sensitivity analysis 26 concluded this result was robust with a 93% probability of laparoscopic approach 27 being cost effective when QALYs are valued at £20,000 each. A speculative analysis 28 gave very favourable results for TaTME compared to an open, laparoscopic and 29 robotic approaches. However, there was great uncertainty around the inputs for this 30 model and consequently the conclusions with results sensitive to assumptions 31 around overall survival.
32 The committee’s discussion of the evidence
33 Interpreting the evidence
34 The outcomes that matter most 35 Overall survival, quality of life and resection margins were considered critical 36 outcomes for decision making. Overall survival was considered a critical outcome 37 because ultimately the aim of cancer treatment is to improve survival. From the 38 patient’s perspective it is also critical to consider the effect on quality of life. Quality of 39 life in terms of sexual function and bladder function were of particular interest to this 40 review because of the potential effects that the different surgical techniques might
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1 have on these. Impaired sexual function and bladder function can both have a 2 significant impact on a person’s quality of life. Resection margins were considered a 3 critical outcome because a cancer-positive resection margin is a predictor for cancer 4 recurrence. 5 Local recurrence, length of hospital stay, mortality within 90 days of surgery and 6 treatment-related complications were considered important outcomes.
7 The quality of the evidence 8 Evidence was available for the comparison of laparoscopic versus open surgery 9 (comparison 1), robotic versus open surgery (comparison 2), robotic versus 10 laparoscopic surgery (comparison 3), and transanal total mesorectal excision 11 (TaTME) versus laparoscopic surgery (comparison 4). No evidence was identified for 12 the comparison of TaTME versus open surgery or of TaTME versus robotic surgery. 13 Evidence was available for all of the outcomes for comparison 1. The quality of the 14 clinical evidence was assessed using GRADE and varied from low to moderate 15 quality. For comparison 2, evidence was available for all critical outcomes but no 16 evidence was available for important outcomes (local recurrence, length of hospital 17 stay, 90-day mortality, and treatment–related complications). The quality of the 18 evidence was assessed using GRADE and was of very low quality. For comparison 3 19 evidence was available for all outcomes except local recurrence and for comparison 20 4 evidence was available for all outcomes except surgical site infection and blood 21 loss. The quality of the evidence for these comparisons was assessed using GRADE: 22 for comparison 3 the evidence was mostly of very low quality and varied from very 23 low to low and for comparison 4 it was mostly of low quality, varying from very low to 24 low quality. 25 The main reasons for downgrading the quality of evidence were population 26 indirectness, imprecision of the effect estimate, and risk of bias due to lack of 27 blinding. 28 Some of the studies included a proportion of participants with early rectal cancer (T1- 29 2, N0, M0) or metastatic rectal cancer which were out of the scope for this review and 30 the quality of evidence was therefore downgraded for population indirectness. 31 For some outcomes, there was considerable uncertainty in the effect estimate due to 32 the small number of participants or low number of events, in which case the evidence 33 was downgraded for imprecision. 34 Blinding of personnel, patients and outcome assessors was generally not done or not 35 possible to do. Lack of blinding might influence outcome measurement, particularly 36 for outcomes that are subjective in nature. Therefore, for subjective outcomes such 37 as quality of life, the quality of evidence was downgraded due to risk of detection 38 bias.
39 Benefits and harms 40 Over time, minimally invasive surgical techniques, including laparoscopic surgery, 41 have been developed in order to lower operative complications and adverse events 42 and speeding up recovery without compromising the long-term effectiveness of 43 surgery on survival and disease recurrence. Laparoscopic surgery for rectal cancer is 44 commonly used in current practice alongside open surgery and the choice of 45 technique is sometimes dependent on the skills and experience of the surgeon rather 46 than the clinical effectiveness or appropriateness of either technique.
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DRAFT FOR CONSULTATION Optimal surgical technique for rectal cancer
1 Clinical evidence on the long-term effectiveness of laparoscopic surgery compared to 2 open surgery indicated an overall survival benefit with laparoscopic surgery with no 3 clinically important difference in local recurrence rates. 4 The committee also considered the short-term effectiveness of laparoscopic surgery 5 compared to open surgery. No overall difference was observed in positive resection 6 margins. However, the committee discussed that there can be a long learning curve 7 for laparoscopic surgery, which might be reflected in the results for resection margin 8 and operative complications seen in some of the trials. The expectation is that the 9 clinical effectiveness and safety of laparoscopic technique is now better than when 10 most of the trials were conducted. 11 In general, there was no difference in length of hospital stay; however, a clinically 12 important lower mean length of hospital stay was observed in people who underwent 13 laparoscopic compared to open sphincter-preserving surgery for non-metastatic 14 rectal cancer. No clinically important difference was observed in respect of quality of 15 life, operative mortality, or anastomotic leak. As the committee expected, mean or 16 median blood loss was lower in the laparoscopic group compared to the open group. 17 However, the committee agreed that in some cases open surgery is the most 18 appropriate approach because of clinical or technical reasons. For example, scarring 19 from previous abdominal or pelvic surgeries might make open surgery more feasible. 20 Open surgery might also be more appropriate for technically demanding resection of 21 adjacent organs or structures in locally advanced tumours. 22 In recent years robotic surgery has been introduced as another way of performing 23 laparoscopic surgery. The robots are expensive but their technical advantages 24 compared to the manual laparoscopic surgery include, for example, better 25 visualisation, better freedom of movement, lack of tremor, and better ergonomics. 26 Some clinical evidence was available comparing the robotic technique to either open 27 or laparoscopic technique in rectal cancer surgery. 28 Low quality observational evidence was available comparing robotic surgery to open 29 surgery. No difference was observed in overall survival. One study suggested a lower 30 risk of positive resection margin with robotic approach, although two other studies 31 found no difference between the groups. One study found less sexual dysfunction in 32 men who underwent robotic surgery. 33 Robotic technique was compared to manual laparoscopic technique in one RCT and 34 a few low quality observational studies. Overall, the evidence did not show the 35 robotic approach to be better than manual laparoscopic approach. There was no 36 difference in overall survival, overall quality of life, bladder function, resection 37 margins, length of hospital stay, operative mortality, or anastomotic leak. One study 38 showed better sexual function in the robotic group compared to manual laparoscopic 39 group at 1 year after surgery. 40 TaTME is another relatively novel surgical approach to treat rectal cancers. TaTME 41 has been suggested as a particularly useful approach in cancers in the low rectum in 42 male patients because of the anatomical challenges of open or laparoscopic 43 technique in this area, however, the evidence on this is lacking. The evidence base 44 for this technique is small and the findings were statistically underpowered, therefore, 45 the committee was not able to determine if TaTME is a clinically effective surgical 46 technique to treat rectal cancer. 47 The committee was aware of the NICE interventional procedures guidance on 48 transanal total mesorectal excision of the rectum (IPG514). The committee was also 49 aware that TaTME has been suspended in Norway due to increased local recurrence
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DRAFT FOR CONSULTATION Optimal surgical technique for rectal cancer
1 rates. Increased complication rates have also been attributed to TaTME, however, it 2 is not impossible that these complications could happen in any operation in the 3 pelvis. There is currently not enough evidence to show neither benefit nor harm from 4 TaTME compared to more established techniques. COLOR III trial is currently 5 recruiting patients to compare TaTME to laparoscopic technique. 6 After reviewing the clinical evidence on the different surgical techniques, the 7 committee concluded that the clinical short- and long-term outcomes of laparoscopic 8 technique were similar or better than of the open technique (although as discussed in 9 certain cases the open approach is better) and that there seemed to be no difference 10 between manual laparoscopic and robotic laparoscopic techniques. The committee 11 agreed that in addition to the clinical effectiveness it is important to consider the costs 12 of these difference techniques in order to assess which technique is the most cost 13 effective approach in rectal cancer surgery. 14 The evidence showed no clinical benefit, clinically important higher blood loss but no 15 other clinically important differences in complications no clinically important 16 difference in complications (length of hospital stay, 90-day mortality, anastomotic 17 leak, and surgical site infection) from the robotic technique. The committee 18 recognised, however, that the robotic technique is already being used by certain 19 centres in the UK. The committee would not want those centres with established 20 programmes to stop performing robotic surgery but in the absence of clinical and cost 21 effectiveness evidence in favour of robotic technique, the committee would only 22 recommend robotic surgery to be considered within these established programmes. It 23 was also considered important that audit data is collected within these programmes 24 to assess the effectiveness and safety of robotic technique in clinical practice. The 25 techniques and equipment of robotic surgery develop rapidly and more evidence on 26 its usefulness will be available in the future. 27 Similarly, TaTME is used in some of centres in the UK. It was agreed that TaTME 28 should be considered as a treatment option only within proctored programmes. 29 These structured and supervised programmes should also collect outcome data for 30 the national TaTME registry in order to enable assessment of the safety and 31 effectiveness of TaTME in clinical practice.
32 Cost effectiveness and resource use 33 Bespoke economic modelling for this review question suggested that a laparoscopic 34 approach to surgery would be both cost saving and health improving compared to an 35 open approach. These increases in QALYs and cost savings were largely driven by 36 survival parameters, which were clinically significant in the clinical evidence review 37 favouring the laparoscopic approach. The deterministic and probabilistic sensitivity 38 analysis results suggested that results were robust to alternative assumptions. The 39 committee were therefore confident that recommending laparoscopic surgery was 40 both cost effective and cost saving. 41 Whilst the bespoke economic analysis suggested that robotic surgery was not cost 42 effective, the committee highlighted that this was a fast moving and expending area 43 and as volumes increase (across all disease areas), costs of robotic surgery would 44 decrease and, potentially, outcomes will also improve. For these reasons the 45 committee thought that conclusions around cost effectiveness would become more 46 favourable to robotic surgery potentially within a short period of time and 47 recommending against it, based on current efficiency grounds, would be 48 inappropriate. Given the above the committee recommended robotic surgery should 49 only be considered in centres where there are already established programmes.
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DRAFT FOR CONSULTATION Optimal surgical technique for rectal cancer
1 A speculative analysis as part of the bespoke economic analysis suggested that 2 TaTME could be both cost saving and health improving compared to all other 3 potential approaches. The committee however acknowledge that this was a new 4 technique and that it was difficult to place a large amount of confidence in the results 5 given the evidence to inform the model. The committee therefore only recommended 6 its use in centres with structured and supervised programmes with appropriate 7 auditing allowing for evaluation of the technique in future. 8 The committee were of the opinion that all recommendations were cost effective and 9 all would potentially be cost saving within a short period of time compared to current 10 practice. This would be largely driven by reducing the number of more intensive, 11 expensive and potentially less effective procedures. 12
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DRAFT FOR CONSULTATION Optimal surgical technique for rectal cancer
1 References 2 ACOSOG Z6051 trial 3 Fleshman J, Branda M, Sargent DJ, et al. (2015) Effect of laparoscopic-assisted 4 resection vs open resection of stage II or III rectal cancer on pathologic outcomes the 5 ACOSOG Z6051 randomized clinical trial. Journal of the American Medical 6 Association 314(13): 1346-55 7 Fleshman J, Branda ME, Sargent DJ et al. (2019) Disease-free Survival and Local 8 Recurrence for Laparoscopic Resection Compared With Open Resection of Stage II 9 to III Rectal Cancer: Follow-up Results of the ACOSOG Z6051 Randomized 10 Controlled Trial. Annals of Surgery 269(4): 589-95 11 ALaCaRT trial 12 Stevenson ARL, Solomon MJ, Lumley JW et al. (2015) Effect of laparoscopic- 13 assisted resection vs open resection on pathological outcomes in rectal cancer: The 14 ALaCaRT randomized clinical trial. Journal of the American Medical Association 15 314(13): 1356-63 16 Stevenson ARL, Solomon MJ, Brown CSB et al. (2019) Disease-free Survival and 17 Local Recurrence After Laparoscopic-assisted Resection or Open Resection for 18 Rectal Cancer: The Australasian Laparoscopic Cancer of the Rectum Randomized 19 Clinical Trial. Annals of Surgery 269(4): 596-602 20 Arteaga Gonzalez 2006 21 Arteaga Gonzalez I, Diaz Luis H, Martin Malagon A et al. (2006) A comparative 22 clinical study of short-term results of laparoscopic surgery for rectal cancer during the 23 learning curve. International Journal of Colorectal Disease 21(6): 590-5 24 Bordeaux’ trial 25 Denost Q, Loughlin P, Chevalier R et al. (2018) Transanal versus abdominal low 26 rectal dissection for rectal cancer: long-term results of the Bordeaux' randomized 27 trial. Surgical Endoscopy 32(3): 486-94 28 Pontallier A, Denost Q, Van Geluwe B et al. (2016) Potential sexual function 29 improvement by using transanal mesorectal approach for laparoscopic low rectal 30 cancer excision. Surgical Endoscopy and Other Interventional Techniques 30(11): 31 4924-33 32 Braga 2007 33 Braga M, Frasson M, Vignali A et al. (2007) Laparoscopic resection in rectal cancer 34 patients: Outcome and cost-benefit analysis. Diseases of the Colon and Rectum 35 50(4): 464-71 36 Buonpane 2017 37 Buonpane C, Efiong E, Hunsinger M et al. (2017) Predictors of utilization and quality 38 assessment in robotic rectal cancer resection: A review of the national cancer 39 database. American Surgeon 83(8): 918-24
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1 CLASICC trial 2 Green B, Marshall H, Collinson F et al. (2013) Long-term follow-up of the Medical 3 Research Council CLASICC trial of conventional versus laparoscopically assisted 4 resection in colorectal cancer, British Journal of Surgery 100: 75-82 5 Guillou PJ, Quirke P, Thorpe H et al. (2005) Short-term endpoints of conventional 6 versus laparoscopic-assisted surgery in patients with colorectal cancer (MRC 7 CLASICC trial): multicentre, randomised controlled trial. Lancet 365(9472): 1718-26 8 Jayne DG, Brown JM, Thorpe H et al. (2005) Bladder and sexual function following 9 resection for rectal cancer in a randomized clinical trial of laparoscopic versus open 10 technique. British Journal of Surgery 92(9): 1124-32 11 Jayne DG, Thorpe HC, Copeland J et al. (2010) Five-year follow-up of the Medical 12 Research Council CLASICC trial of laparoscopically assisted versus open surgery for 13 colorectal cancer. British Journal of Surgery 97(11): 1638-45 14 Quah HM, Jayne DG, Eu KW et al. (2002) Bladder and sexual dysfunction following 15 laparoscopically assisted and conventional open mesorectal resection for cancer. 16 British Journal of Surgery 89(12): 1551-6 17 COLOR II trial 18 Andersson J, Abis G, Gellerstedt M et al. (2014) Patient-reported genitourinary 19 dysfunction after laparoscopic and open rectal cancer surgery in a randomized trial 20 (COLOR II). British Journal of Surgery 101(10): 1272-9 21 Andersson J, Angenete E, Gellerstedt M et al. (2013) Health-related quality of life 22 after laparoscopic and open surgery for rectal cancer in a randomized trial. British 23 Journal of Surgery 100(7): 941-9 24 Bonjer HJ, Deijen CL, Abis GA et al. (2015) A randomized trial of laparoscopic versus 25 open surgery for rectal cancer. New England Journal of Medicine 372, 1324-32 26 van der Pas MH, Haglind E, Cuesta MA et al. (2013) Laparoscopic versus open 27 surgery for rectal cancer (COLOR II): short-term outcomes of a randomised, phase 3 28 trial. Lancet Oncology 14(3): 210-8 29 Corbellini 2016 30 Corbellini C, Biffi R, Luca F et al. (2016) Open, laparoscopic, and robotic surgery for 31 rectal cancer: medium-term comparative outcomes from a multicenter study. Tumori 32 102(4): 414-21 33 COREAN trial 34 Jeong SY, Park JW, Nam BH et al. (2014) Open versus laparoscopic surgery for mid- 35 rectal or low-rectal cancer after neoadjuvant chemoradiotherapy (COREAN trial): 36 Survival outcomes of an open-label, non-inferiority, randomised controlled trial. 37 Lancet Oncology 15(7): 767-74 38 Kang SB, Park JW, Jeong SY et al. (2010) Open versus laparoscopic surgery for mid 39 or low rectal cancer after neoadjuvant chemoradiotherapy (COREAN trial): Short- 40 term outcomes of an open-label randomised controlled trial. Lancet Oncology 11(7): 41 637-45 42 Ielpo 2017
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DRAFT FOR CONSULTATION Optimal surgical technique for rectal cancer
1 Ielpo B, Duran H, Diaz E et al. (2017) Robotic versus laparoscopic surgery for rectal 2 cancer: a comparative study of clinical outcomes and costs. International Journal of 3 Colorectal Disease 32(10): 1423-9 4 Ishibe 2017 5 Ishibe A, Ota M, Fujii S et al. (2017) Midterm follow-up of a randomized trial of open 6 surgery versus laparoscopic surgery in elderly patients with colorectal cancer. 7 Surgical Endoscopy and Other Interventional Techniques 31(10): 3890-7 8 Kim 2016 9 Kim J, Yu C, Lim S, et al. (2016) Comparative analysis focusing on surgical and early 10 oncological outcomes of open, laparoscopy-assisted, and robot-assisted approaches 11 in rectal cancer patients. International Journal of Colorectal Disease 31(6): 1179-87 12 Kim 2017a 13 Kim M, Park S, Park J, et al. (2017a) Robot-assisted Versus Laparoscopic Surgery 14 for Rectal Cancer: A Phase II Open Label Prospective Randomized Controlled Trial. 15 Annals of Surgery 25 16 Kim 2017b 17 Kim J, Baek S, Kang D, et al. (2017b) Robotic Resection is a Good Prognostic Factor 18 in Rectal Cancer Compared with Laparoscopic Resection: Long-term Survival 19 Analysis Using Propensity Score Matching. Diseases of the Colon and Rectum 60(3): 20 266-73 21 Law 2017 22 Law W and Foo D (2017) Comparison of short-term and oncologic outcomes of 23 robotic and laparoscopic resection for mid- and distal rectal cancer. Surgical 24 Endoscopy and Other Interventional Techniques 31(7): 2798-807 25 Liang 2011 26 Liang X, Hou S, Liu H, et al. (2011) Effectiveness and safety of laparoscopic 27 resection versus open surgery in patients with rectal cancer: a randomized, 28 controlled trial from China. Journal of Laparoendoscopic Advanced Surgical 29 Techniques A 21(5): 381-5 30 Lujan 2011 31 Lujan J, Valero G, Hernandez Q et al. (2009) Randomized clinical trial comparing 32 laparoscopic and open surgery in patients with rectal cancer. British Journal of 33 Surgery 96(12): 982-9 34 Ng 2008 35 Ng S, Leung K, Lee J, et al. (2008) Laparoscopic-assisted versus open 36 abdominoperineal resection for low rectal cancer: A prospective randomized trial. 37 Annals of Surgical Oncology 15(9): 2418-25 38 Ng 2009 39 Ng S, Leung K, Lee J, et al. (2009) Long-term morbidity and oncologic outcomes of 40 laparoscopic-assisted anterior resection for upper rectal cancer: ten-year results of a 41 prospective, randomized trial. Diseases of the Colon and Rectum 52(4): 558-66
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1 Ng 2014 2 Ng S, Lee J, Yiu R, et al. (2014) Laparoscopic-assisted versus open total mesorectal 3 excision with anal sphincter preservation for mid and low rectal cancer: a 4 prospective, randomized trial. Surgical Endoscopy 28(1): 297-306 5 Park 2015 6 Park E, Cho M, Baek S, et al. (2015) Long-term oncologic outcomes of robotic low 7 anterior resection for rectal cancer. Annals of Surgery 261(1): 129-37 8 ROLARR trial 9 Jayne D, Pigazzi A, Marshall H, et al. (2017) Effect of robotic-assisted vs 10 conventional laparoscopic surgery on risk of conversion to open laparotomy among 11 patients undergoing resection for rectal cancer: the ROLARR randomized clinical 12 trial. Journal of the American Medical Association 318(16): 1569-1580 13 Rouanet 2018 14 Rouanet P, Bertrand M, Jarlier M, et al. (2018) Robotic Versus Laparoscopic Total 15 Mesorectal Excision for Sphincter-Saving Surgery: Results of a Single-Center Series 16 of 400 Consecutive Patients and Perspectives. Annals of Surgical Oncology 25(12): 17 3572-9. 18 Yoo 2015 19 Yoo B, Cho J, Shin J, et al. (2015) Robotic Versus Laparoscopic Intersphincteric 20 Resection for Low Rectal Cancer: Comparison of the Operative, Oncological, and 21 Functional Outcomes. Annals of Surgical Oncology 22(4): 1219-25 22 Zhou 2004 23 Zhou Z, Hu M, Li Y, et al. (2004) Laparoscopic versus open total mesorectal excision 24 with anal sphincter preservation for low rectal cancer. Surgical Endoscopy 18(8): 25 1211-5
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1 Appendices
2 Appendix A – Review protocol
3 Review protocol for review question: What is the optimal surgical 4 technique for rectal cancer? 5 Table 7: Review protocol for optimal surgical technique for rectal cancer Field (based on PRISMA-P) Content Review question What is the optimal surgical technique for rectal cancer? Type of review Intervention question Objective of the review To determine the optimal surgical technique for rectal cancer. Eligibility criteria – Adults with non-metastatic rectal cancer based on TNM population/disease/con classification system: dition/issue/domain • T1-2 N1-2 • T3 N any • T4 N any • M0.
Staging determined by ultrasound, MRI, computed tomography scan.
Rectal cancer defined as any tumour within 15 cm from anal verge excluding anal canal.
Exclusions: • bowel obstruction, metastatic cancer
Eligibility criteria – Surgical resection (for example abdominoperineal resection or intervention(s)/exposur low anterior resection) e(s)/prognostic • Open factor(s) • Laparoscopic • Robotic • Transanal total mesorectal excision (TaTME; only anterior resection) Eligibility criteria – Surgical techniques compared to each other comparator(s)/control or reference (gold) standard Outcomes and Critical outcomes: prioritisation • Overall survival (MID: statistical significance) • Quality of life measured using validated scales only (MID: from literature, see further down this document) o Overall o Sexual function o Bladder function • Resection margins (positive/negative; MID: statistical significance)
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Field (based on PRISMA-P) Content
Important outcomes: • Local recurrence (MID: statistical significance) • Length of hospital stay (MID: statistical significance) • 90-day mortality (MID: statistical significance) • Treatment-related complications (MID: statistical significance): o Anastomotic leak (only relevant in anterior resection) o Surgical site infection o Blood loss
Quality of life MIDs from the literature: • EORTC QLQ-C30: 5 points • EORTC QLQ-CR29: 5 points • EORTC QLQ-CR38: 5 points • EQ-5D: 0.09 to 0.10 using FACT-G quintiles • FACT-C: 5 points • FACT-G: 5 points • SF-12: >3.77 for the mental component summary and > 3.29 for the physical component summary of the Short Form SF-12 (SF- 12) • SF-36: >7.1 for the physical functioning scale, >4.9 for the bodily pain scale, and >7.2 for the physical component summary Eligibility criteria – • Systematic reviews of (RCTs study design • RCTs • If eligible RCTs are not available for critical outcomes: comparative observational studies Other inclusion Inclusion: exclusion criteria • English-language • Published full texts • All settings will be considered that consider medications and treatments available in the UK • Studies published since 2000
Studies published 2000 onwards will be considered for this review question, as the GC felt that surgical techniques have evolved and evidence prior to 2000 would not be relevant any longer. Proposed In case of high heterogeneity in meta-analysis, the sensitivity/sub-group following subgroups will be considered: analysis, or meta- • People who underwent abdominoperineal resection regression • People who underwent (low) anterior resection • People who received preoperative radiotherapy or chemoradiotherapy • People who did not receive preoperative radiotherapy or chemoradiotherapy Selection process – Sifting, data extraction, appraisal of methodological quality and duplicate GRADE assessment will be performed by the systematic screening/selection/an reviewer. Resolution of any disputes will be with the senior alysis systematic reviewer and the Topic Advisor. Quality control will be performed by the senior systematic reviewer.
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Field (based on PRISMA-P) Content Dual sifting will be undertaken for this question for a random 10% sample of the titles and abstracts identified by the search. Data management Pairwise meta-analyses will be performed using Cochrane (software) Review Manager (RevMan5).
‘GRADEpro’ will be used to assess the quality of evidence for each outcome.
NGA STAR software will be used for study sifting, data extraction, recording quality assessment using checklists and generating bibliographies/citations. Information sources – Potential sources to be searched: Medline, Medline In-Process, databases and dates CCTR, CDSR, DARE, HTA, Embase Limits (e.g. date, study design): • Apply standard animal/non-English language exclusion • Limit to RCTs and systematic reviews in first instance, but download all results • Dates: from 2000 Identify if an update Not an update Author contacts https://www.nice.org.uk/guidance/indevelopment/gid-ng10060 Developer: NGA Highlight if amendment For details please see section 4.5 of Developing NICE guidelines: to previous protocol the manual Search strategy – for For details please see appendix B. one database Data collection A standardised evidence table format will be used, and published process – as appendix D (clinical evidence tables) or H (economic evidence forms/duplicate tables). Data items – define all For details please see evidence tables in appendix D (clinical variables to be evidence tables) or H (economic evidence tables). collected Methods for assessing Standard study checklists were used to critically appraise bias at outcome/study individual studies. For details please see section 6.2 of level Developing NICE guidelines: the manual
Appraisal of methodological quality: The methodological quality of each study will be assessed using an appropriate checklist: • ROBIS for systematic reviews • Cochrane risk of bias tool for RCTs • ROBINS-I tool for non-randomised studies (if applicable) The quality of the evidence for an outcome (i.e. across studies) will be assessed using GRADE.
The risk of bias across all available evidence was evaluated for each outcome using an adaptation of the ‘Grading of Recommendations Assessment, Development and Evaluation (GRADE) toolbox’ developed by the international GRADE working group http://www.gradeworkinggroup.org/ Criteria for quantitative For details please see section 6.4 of Developing NICE guidelines: synthesis the manual
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Field (based on PRISMA-P) Content Methods for Synthesis of data: quantitative analysis – Pairwise meta-analysis of randomised trials will be conducted combining studies and where appropriate. exploring When meta-analysing continuous data, final and change scores (in)consistency will be pooled if baselines are comparable. If any studies reports both, the method used in the majority of studies will be analysed.
MIDs: The guideline committee identified statistically significant differences as appropriate indicators for clinical significance for all outcomes except quality of life for which published MIDs from literature will be used (see outcomes section for more information). Meta-bias assessment For details please see section 6.2 of Developing NICE guidelines: – publication bias, the manual. selective reporting bias If sufficient relevant RCT evidence is available, publication bias will be explored using RevMan software to examine funnel plots. Confidence in For details see sections 6.4 and 9.1 of Developing NICE cumulative evidence guidelines: the manual. Rationale/context – For details please see the introduction to the evidence review. what is known Describe contributions A multidisciplinary committee developed the guideline. The of authors and committee was convened by The National Guideline Alliance and guarantor chaired by Peter Hoskin in line with section 3 of Developing NICE guidelines: the manual. Staff from The National Guideline Alliance undertook systematic literature searches, appraised the evidence, conducted meta- analysis and cost-effectiveness analysis where appropriate, and drafted the guideline in collaboration with the committee. For details please see Supplement 1: methods. Sources of The National Guideline Alliance is funded by NICE and hosted by funding/support the Royal College of Obstetricians and Gynaecologists Name of sponsor The National Guideline Alliance is funded by NICE and hosted by the Royal College of Obstetricians and Gynaecologists Roles of sponsor NICE funds the National Guideline Alliance to develop guidelines for those working in the NHS, public health, and social care in England PROSPERO Not registered registration number 1 CCTR: Cochrane Central Register of Controlled Trials; CDSR: Cochrane Database of Systematic 2 Reviews; DARE: Database of Abstracts of Reviews of Effects; EQ-5D: EuroQol five dimensions 3 questionnaire; EORTC QLQ-C30: European Organisation for Research and Treatment of Cancer 4 Quality of Life Questionnaire Core 30 Items; EORTC QLQ-CR29: European Organisation for Research 5 and Treatment of Cancer Quality of Life Questionnaire colorectal cancer module (29 items); EORTC 6 QLQ-CR38: European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire 7 colorectal cancer module (38 items); FACT-C: Functional Assessment of Cancer Therapy questionnaire 8 (colorectal cancer); FACT-G: Functional Assessment of Cancer Therapy questionnaire (general); GC: 9 Guideline committee; GRADE: Grading of Recommendations Assessment, Development and 10 Evaluation; HTA: Health Technology Assessment; MID: minimal important difference; MRI: magnetic 11 resonance imaging; NGA: National Guideline Alliance; NHS: National Health Service; NICE: National 12 Institute for Health and Care Excellence; PRISMA-P: Preferred Reporting for Systematic review and 13 Meta-Analysis Protocols; PROSPERO: international prospective register of systematic reviews; RCT: 14 randomised controlled trial; ROBINS-I: a tool for assessing risk of bias in non-randomised studies of 15 interventions; ROBIS: a tool for assessing risk of bias in systematic reviews; SD: standard deviation; SF-
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1 12: 12-Item Short Form Survey; SF-36: 36-Item Short Form Survey; TaTME: transanal total mesorectal 2 excision; TNM: cancer classification, standing for tumour, nodal and metastasis stages
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1 Appendix B – Literature search strategies
2 Literature search strategies for review question: What is the optimal surgery for 3 rectal cancer? 4 A combined search was conducted for the following three review questions: 5 • What is the most effective treatment for early rectal cancer? 6 • What is the effectiveness of preoperative radiotherapy or chemoradiotherapy for rectal 7 cancer? 8 • What is the optimal surgical technique for rectal cancer?
9 Database: Embase/Medline 10 Last searched on: 12/02/2019 # Search 1 exp Rectal Neoplasms/ use prmz 2 *rectum cancer/ or *rectum tumor/ 3 2 use oemezd 4 exp Adenocarcinoma/ 5 (T1 or T2 or N0 or M0).ti,ab. 6 1 or 3 7 4 or 5 8 6 and 7 9 ((rectal or rectum) adj3 (cancer* or neoplas* or malignan* or tumo?r* or carcinom* or adeno*)).ti,ab. 10 early rect* cancer.ti,ab. 11 6 or 8 or 9 or 10 12 exp radiotherapy/ or exp radiation oncology/ or exp external beam radiotherapy/ or exp Brachytherapy/ or exp preoperative care/ or exp neoadjuvant therapy/ or exp multimodality cancer therapy/ or exp chemotherapy/ or exp antineoplastic agent/ or exp drug therapy/ or exp chemoradiotherapy/ or exp fluorouracil/ or exp folinic acid/ or exp capecitabine/ or exp oxaliplatin/ or exp bevacizumab/ or exp methotrexate/ or exp radiation dose fractionation/ or exp tumor recurrence/ 13 12 use oemezd 14 exp Radiotherapy/ or exp Radiation Oncology/ or exp Radiotherapy, Computer-Assisted/ or exp Brachytherapy/ or exp Preoperative Care/ or exp Neoadjuvant Therapy/ or exp Combined Modality Therapy/ or exp Chemoradiotherapy/ or exp Antineoplastic Combined Chemotherapy Protocols/ or exp Drug Therapy/ or exp Antineoplastic Agents/ or exp Fluorouracil/ or exp Leucovorin/ or exp Capecitabine/ or exp Bevacizumab/ or exp Methotrexate/ or exp Dose Fractionation/ 15 14 use prmz 16 ((radiotherap* or chemoradio* or radiation or brachytherapy* or chemotherapy*) adj (pre?op* or preop* or periop* or neoadjuvant)).ti,ab. 17 (5-fluorouracil or 5-FU or leucovorin or folinic acid or capecitabine or oxaliplatin or bevacizumab or methotrexate or dose* or fraction* or recurren*).ti,ab. 18 13 or 15 or 16 or 17 19 exp Laparoscopy/ or exp Transanal Endoscopic Microsurgery/ or exp Minimally Invasive Surgical Procedures/ or exp Endoscopy/ or exp Endoscopic Mucosal Resection/ or exp Surgical Procedures, Operative/ or exp Robotic Surgical Procedures/ or exp Surgery, Computer-Assisted/ or exp Dissection/ 20 19 use prmz 21 exp laparoscopy/ or exp endoscopic surgery/ or exp transanal endoscopic microsurgery/ or exp endoscopy/ or exp minimally invasive surgery/ or exp endoscopic mucosal resection/ or exp surgery/ or exp robotic surgical procedure/ or exp computer assisted surgery/ or exp dissection/ or exp total mesorectal excision/ or exp excision/ or exp rectum resection/ or exp endoscopic polypectomy/ or exp polypectomy/ or exp endoscopic submucosal dissection/ 22 21 use oemezd 23 (laparoscop* or endoscop* or transanal excision* or TAE or transanal endoscopic microsurger* or TEM or TEMS or transanal resection or TART or transanal minimally invasive surger* or TAMIS or total mesorectal excision* or TaTME or transanal total mesorectal excision* or TME or anterior resection* or abdominoperineal resection* or endoscopic resection* or polypectomy or endoscopic submucosal dissection* or ESD or endoscopic mucosal resection* or EMR or surger* or surgic* or operat*).ti,ab. 24 20 or 22 or 23 25 11 and 18 26 11 and 18 and 24 27 25 or 26 28 limit 27 to english language 29 limit 28 to yr="1997 -Current" 30 (conference abstract or letter).pt. or letter/ or editorial.pt. or note.pt. or case report/ or case study/ use oemezd 31 Letter/ or editorial/ or news/ or historical article/ or anecdotes as topic/ or comment/ or case report/ use prmz
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# Search 32 (letter or comment* or abstracts).ti. 33 or/30-32 34 randomized controlled trial/ use prmz 35 randomized controlled trial/ use oemezd 36 random*.ti,ab. 37 or/34-36 38 33 not 37 39 (animals/ not humans/) or exp animals, laboratory/ or exp animal experimentation/ or exp models, animal/ or exp rodentia/ use prmz 40 (animal/ not human/) or nonhuman/ or exp animal experiment/ or exp experimental animal/ or animal model/ or exp rodent/ use oemezd 41 (rat or rats or mouse or mice).ti. 42 38 or 39 or 40 or 41 43 29 not 42 44 clinical Trials as topic.sh. or (controlled clinical trial or pragmatic clinical trial or randomized controlled trial).pt. or (placebo or randomi#ed or randomly).ab. or trial.ti. 45 44 use prmz 46 crossover procedure/ or double blind procedure/ or randomized controlled trial/ or single blind procedure/ or (assign* or allocat* or crossover* or cross over* or ((doubl* or singl*) adj blind*) or factorial* or placebo* or random* or volunteer*).ti,ab. 47 46 use oemezd 48 or/45,47 49 43 and 48 50 epidemiologic studies/ or observational study/ or case control studies/ or retrospective studies/ or cohort studies/ or longitudinal studies/ or follow-up studies/ or prospective studies/ or cross-sectional studies/ 51 50 use prmz 52 exp observational study/ or exp case control study/ or exp retrospective study/ or exp cohort analysis/ or exp longitudinal study/ or exp follow up/ or exp prospective study/ or exp cross-sectional study/ 53 52 use oemezd 54 ((retrospective* or cohort* or longitudinal or follow?up or prospective or cross section*) adj3 (stud* or research or analys*)).ti. 55 51 or 53 or 54 56 43 and 55 57 49 or 56 58 57 not 56 59 56 or 58
1 Database: Cochrane Library 2 Last searched on: 12/02/2019 # Search 1 MeSH descriptor: [Rectal Neoplasms] explode all trees 2 MeSH descriptor: [Adenocarcinoma] explode all trees 3 T1 or T2 or N0 or M0 4 #2 or #3 5 #1 and #4 6 (rectal or rectum) near (cancer* or neoplas* or malignan* or tumo?r* or carcinom* or adeno*) 7 early rect* cancer 8 #1 or #5 or #6 or #7 9 MeSH descriptor: [Radiotherapy] explode all trees 10 MeSH descriptor: [Radiation Oncology] explode all trees 11 MeSH descriptor: [Radiotherapy, Computer-Assisted] explode all trees 12 MeSH descriptor: [Brachytherapy] explode all trees 13 MeSH descriptor: [Preoperative Care] explode all trees 14 MeSH descriptor: [Neoadjuvant Therapy] explode all trees 15 MeSH descriptor: [Combined Modality Therapy] explode all trees 16 MeSH descriptor: [Chemoradiotherapy] explode all trees 17 MeSH descriptor: [Antineoplastic Combined Chemotherapy Protocols] explode all trees 18 MeSH descriptor: [Drug Therapy] explode all trees 19 MeSH descriptor: [Antineoplastic Agents] explode all trees 20 MeSH descriptor: [Fluorouracil] explode all trees 21 MeSH descriptor: [Capecitabine] explode all trees 22 MeSH descriptor: [Bevacizumab] explode all trees 23 MeSH descriptor: [Methotrexate] explode all trees 24 MeSH descriptor: [Dose Fractionation] explode all trees 25 (radiotherap* or chemoradio* or radiation or brachytherapy* or chemotherapy*) near (pre?op* or preop* or periop* or neoadjuvant) 26 5-fluorouracil or 5-FU or leucovorin or folinic acid or capecitabine or oxaliplatin or bevacizumab or methotrexate or dose* or fraction* or recurren*
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# Search 27 #9 or #10 or #11 or #12 or #13 or #14 or #15 or #16 or #17 or #18 or #19 or #20 or #21 or #22 or #23 or #24 or #25 or #26 28 MeSH descriptor: [Laparoscopy] explode all trees 29 MeSH descriptor: [Transanal Endoscopic Microsurgery] explode all trees 30 MeSH descriptor: [Minimally Invasive Surgical Procedures] explode all trees 31 MeSH descriptor: [Endoscopy] explode all trees 32 MeSH descriptor: [Endoscopic Mucosal Resection] explode all trees 33 MeSH descriptor: [Surgical Procedures, Operative] explode all trees 34 MeSH descriptor: [Robotic Surgical Procedures] explode all trees 35 MeSH descriptor: [Surgery, Computer-Assisted] explode all trees 36 MeSH descriptor: [Dissection] explode all trees 37 laparoscop* or endoscop* or transanal excision* or TAE or transanal endoscopic microsurger* or TEM or TEMS or transanal resection or TART or transanal minimally invasive surger* or TAMIS or total mesorectal excision* or TME or anterior resection* or abdominoperineal resection* or endoscopic resection* or polypectomy or endoscopic submucosal dissection* or ESD or endoscopic mucosal resection* or EMR or surger* or surgic* or operat* 38 #28 or #29 or #30 or #31 or #32 or #33 or #34 or #35 or #36 or #37 39 #8 and #27 40 #8 and #27 and #38 41 #39 or #40 Publication Year from 1997 to 2017 1
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1 Appendix C – Clinical evidence study selection
2 Clinical study selection for review question: What is the optimal surgery for rectal 3 cancer?
4 Figure 1: Study selection flow chart 5
Titles and abstracts identified, N=8,151*
Full copies retrieved Excluded, N=7,865 and assessed for (not relevant population, eligibility, N=286 design, intervention, comparison, outcomes, unable to retrieve)
Publications included Publications excluded in review, N=37 from review, N=249 (refer to excluded studies list)
6 7 *The literature search was done for 3 review questions at once including the current review and review questions: 8 ‘What is the most effective treatment for early rectal cancer?’ and ‘What is the effectiveness of preoperative 9 radiotherapy and chemoradiotherapy for rectal cancer?’. The number of titles and abstracts identified applies for 10 all three reviews but all the other numbers are applicable to this specific review only. In addition, possibly relevant 11 studies were added from systematic reviews.
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1 Appendix D – Clinical evidence tables
2 Clinical evidence tables for review question: What is the optimal surgery for rectal cancer? 3 Table 8: Clinical evidence tables Outcomes and Study details Participants Interventions Methods Results Comments Full citation Sample size Interventions Details Results Limitations Andersson, J., See Bonjer 2015 Abis, G., (COLOR II trial). Other information Gellerstedt, M., Angenete, E., Characteristics Angeras, U.,
Cuesta, M. A., Jess, P., Inclusion criteria Rosenberg, J., Bonjer, H. J., Exclusion criteria Haglind, E., Patient-reported genitourinary dysfunction after laparoscopic and open rectal cancer surgery in a randomized trial (COLOR II), Br J Surg, 103, 1746, 2016 Ref Id 810630 Country/ies where the study was carried out Study type
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Outcomes and Study details Participants Interventions Methods Results Comments
Aim of the study
Study dates
Source of funding Full citation Sample size Interventions Details Results Limitations Andersson, J., See Bonjer 2015 Angenete, E., (COLOR II trial). Other information Gellerstedt, M., Angeras, U., Jess, Characteristics P., Rosenberg, J.,
Furst, A., Bonjer, J., Haglind, E., Inclusion criteria Health-related quality of life after Exclusion criteria laparoscopic and open surgery for rectal cancer in a randomized trial, Br J Surg, 100, 941-9, 2013
Ref Id 810631
Country/ies where the study was carried out
Study type
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Outcomes and Study details Participants Interventions Methods Results Comments Aim of the study
Study dates
Source of funding Full citation Sample size Interventions Details Results Limitations Arteaga N=40 randomised; Laparoscopic surgery Randomisation and Outcome: Radial Cochrane risk of bias tool Gonzalez, I., Diaz n=20 laparoscopic versus open surgery allocation concealment margin >2 mm Selection bias Luis, H., Martin surgery; n=20 open No details provided. Laparoscopic 20/20 Random sequence Malagon, A., surgery Type of surgery, n/n: Open 16/20 generation: unclear risk Lopez-Tomassetti Haartmann Blinding (Details not reported.) Fernandez, E. M., Characteristics Allocation Arranz Duran, J., Laparoscopic 5/20 No blinding. Outcome: Tumour- concealment: unclear risk Carrillo Pallares, Age in years, mean±SD: Open 6/20 free distal margin (Details not reported.) A., A comparative Laparoscopic 66.6±12.6 Lower anterior resection Follow-up/outcomes Laparoscopic 20/20
clinical study of Open 70.7±9.2 Laparoscopic 9/20 Clinical Open 20/20 Performance bias short-term results Open 10/20 and anatomopathological of laparoscopic Blinding of participants and Male sex, n/n: Abdominoperineal data were prospectively Outcome: Length of surgery for rectal personnel: high risk (No Laparoscopic 11/20 resection collected into a database. hospital stay in days, cancer during the mean±SD blinding.) learning curve, Open 8/20 Laparoscopic 6/20 Statistical analysis Laparoscopic 9.1±5.7 International Open 4/20 (n=20) Detection bias Journal of BMI, mean±SD Continuous variables compared using Student's t- Open Blinding of outcome Colorectal Laparoscopic 26.0±2.9 Total mesorectal test and categorical 15.6±6.1 (n=20) assessment: high risk (No Disease, 21, 590- excision (TME) was Open 27.9±5.1 variables compared using blinding.) 595, 2006 performed on all Chi-squared or Fisher's tumours located in the Outcome: Tumour distance to anal exact test. Ref Id middle or lower thirds of Anastomotic leak Attrition bias verge, n/n: Incomplete outcome 745480 the rectum. Laparoscopic 0/20 0-5 cm data: low risk (It is not clear Open 2/20 Laparoscopic 9/20 if the Sample size reported Laparoscopic surgery Country/ies is the original sample Open 7/20 was performed with 4-6 where the study Outcome: Wound randomised. However, this 6-11 cm ports. was carried out infection paper only reports short-
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Outcomes and Study details Participants Interventions Methods Results Comments Spain Laparoscopic 6/20 Laparoscopic 3/20 term outcomes and no one Study type Open 7/20 Patients with Open 6/20 was lost to follow-up.) RCT 11-15 cm preoperatively staged T3 Laparoscopic 5/20 or T4 middle and Outcome: Blood loss Reporting bias lower third tumours or Aim of the study Open 6/20 in ml, mean±SD Selective reporting: low risk mesorectal adenopathy Laparoscopic To assess without distant 243.4±129.6 (n=20) reliability and TNM staging, n/n: metastases received a Other bias efficiency of I regimen of preoperative Open 405.0±151.2 Other sources of bias: - laparoscopy in the (n=20) Laparoscopic 4/20 radiotherapy curative treatment (45 Gy in 4 weeks). Other information of rectal Open 7/20
carcinoma. II None Laparoscopic 7/20 Study dates Open 5/20 Enrolment III between January Laparoscopic 7/20 2003 to April Open 3/20 2004. IV Laparoscopic 2/20 Source of Open 5/20 funding
None reported.
Inclusion criteria Carcinomas located less than 15 cm from the anal verge (determined with a flexible endoscope).
Exclusion criteria Tumours with obstruction or perforation symptoms; preoperatively diagnosed T4 staging; tumours
Colorectal cancer (update): evidence reviews for the optimal surgical technique for rectal cancer DRAFT (July 2019) 48 DRAFT FOR CONSULTATION Optimal surgical technique for rectal cancer
Outcomes and Study details Participants Interventions Methods Results Comments larger than 7 cm; candidates for local surgery. Full citation Sample size Interventions Details Results Limitations Bonjer, H. J., N=1,103 randomised; Laparoscopic surgery Randomisation and Outcome: Overall Cochrane risk of bias tool Deijen, C. L., n=739 allocated to versus open surgery allocation concealment survival at 3 years Selection bias Abis, G. A., laparoscopic surgery of The participants were Laparoscopic 86.7% Random sequence Cuesta, M. A., which 40 were excluded, All procedures had to registered on the trial's Open 83.6% generation: low risk Van Der Pas, M. n=699 included in comply with the website by the local (No statistical Allocation concealment: low H. G. M., De analysis ; n=364 principles of TME or investigator to ensure difference between risk Lange-De Klerk, allocated to open partial mesorectal allocation concealment. groups, narratively E. S. M., Lacy, A. surgery of which 19 were excision (PME). Randomisation was done in reported. No number M., Bemelman, Performance bias excluded, n=345 a 2:1 ratio in accordance of events, no HR, no W. A., Andersson, included in analysis with a list of randomisation Blinding of participants and Resection with PME, n p-values reported.) J., Angenete, E., numbers and treatment personnel: high risk (No (main reasons for (%) Rosenberg, J., exclusion were that the allocation. This list was blinding.) Laparoscopic 72 (10) Outcome: Global Fuerst, A., participant had distant computer generated by the quality of life (QLQ- Haglind, E., A metastasis, did not have Open 35 (10) trial statistician. The Detection bias C30; scale 0 to 100, randomized trial carcinoma, had T4 Resection with TME, n randomisation was stratified higher score Blinding of outcome of laparoscopic tumour, withdrew (%) by centre, tumour location, indicating better assessment: low/high risk versus open consent) Laparoscopic 418 (60) and preoperative surgery for rectal quality of life)* (No blinding. High risk of Open 230 (67) radiotherapy. It was bias for subjective cancer, New implemented by use of an Baseline score Characteristics Abdominoperineal outcomes.) England Journal internet application to allow Laparoscopic 72.8±2 resection of Medicine, 372, Age in years, mean±SD central randomisation. 0.18 (n=243) Laparoscopic 200 (29) Attrition bias 1324-1332, 2015 Laparoscopic 66.8±10.5 Open 68.6±20.81 Open 65.8±10.9 Open 80 (23) Blinding (n=109) Incomplete outcome data: low risk (Around 5% of the Ref Id Hartmann procedure Mean difference at 4 No blinding. randomised were excluded 745799 Male sex, (%) Laparoscopic 36 (5) weeks adjusted for from analysis because of Open 25 (7) baseline† Laparoscopic 448 (64) Follow-up/outcomes distant metastasis, the Laparoscopic Country/ies Open 211 (61) Minimal required follow-up patient had no carcinoma, (n=230) - open where the study Preoperative included annual clinical withdrawal of consent etc.) (n=108) was carried out BMI, mean±SD radiotherapy, n (%) examinations for 5 years Laparoscopic 26.1±4.5 Laparoscopic 412 (59) after surgery. Three years Reporting bias
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Outcomes and Study details Participants Interventions Methods Results Comments Belgium, Canada, Open 26.5±4.7 Open 199 (58) after the index surgery, CT 0.3 (95% CI -4.7 to Selective reporting: low risk Denmark, or MRI of the pelvis 5.3) Germany, the Tumour distance from Preoperative combined with imaging of Mean difference at 6 Other bias Netherlands, the liver and the chest were the anal verge, n (%) chemotherapy, n (%) months adjusted for Other sources of bias: - Poland, South performed. baseline† <5 cm Laparoscopic 196/609 Korea, Spain, The primary outcome was Laparoscopic Laparoscopic 203 (29) (32) Other information Sweden the proportion of patients (n=221) - Open Open 93 (27) Open 99/295 (34) with local recurrence at 3 (n=106) None 5-<10 cm Study type years. -2.2 (95% CI -6.8 to RCT (COLOR II Laparoscopic 273 (39) For health-related quality of 2.4) trial) Open 136 (39) life, validated Swedish, Mean difference at Dutch, Danish, English and 10-15 cm 12 months adjusted German translations of the Laparoscopic 223 (32) for baseline† Aim of the study following instruments were To compare 3- Open 116 (34) used: EQ-5D, EORTC Laparoscopic year rates of QLQ-C30 and EORTC (n=208) - Open cancer recurrence Clinical stage, n (%) QLQ-CR38. (Information on (n=97) in the pelvic or I quality of life scales is -1.8 (95% CI -6.1 to perineal area 2.4) Laparoscopic 201 (29) extracted from Andersson (locoregional 2013.) Open 96 (28) recurrence) and The EQ-5D is a Outcome: Global II survival after standardised non-disease- health status (EQ- laparoscopic and Laparoscopic 209 (30) specific (generic) instrument VAS; scale 0 to 100, open resection of Open 107 (31) for assessing self-reported higher score rectal cancer. III health status. It comprises a indicating better Laparoscopic 257 (37) description of the patient’s health status)* Study dates Open 126 (37) health in five dimensions Baseline score (mobility, self-care, daily January 2004 to Missing Laparoscopic 77.3±1 May 2010 activity, pain/discomfort and Laparoscopic 32 (5) 6.6 (n=245) anxiety/depression). Open 16 (5) Open 74.9±16.6 (n=1 Source of The EORTC QLQ-C30 is 07) a 30-item questionnaire funding Mean difference at 4 developed to assess the Ethicon Endo- Pathological stage, n (%) weeks quality of life of patients Surgery I with cancer. There are five Europe; Swedish Laparoscopic 231 (33)
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Outcomes and Study details Participants Interventions Methods Results Comments Cancer Open 107 (31) functional scales (physical, Laparoscopic Society; the II role, emotional, cognitive (n=232) - Open Health Laparoscopic 180 (26) and social functioning), (n=104) and Medical Care three symptom scales Open 91 (26) 1.6 (95% CI -3.3 to Committee of the (fatigue, nausea/vomiting 6.5) Regional III and pain), six single-item Mean difference at 6 Executive Board, Laparoscopic 180 (26) questions (about dyspnoea, months Region Västra Open 125 (36) insomnia, loss of appetite, Laparoscopic Götaland, and an IV constipation, diarrhoea and agreement financial difficulties) and a (n=219) - Open Laparoscopic 4 (1) concerning global health/quality-of-life (n=102) research Open 0 index. The latter assesses 1.7 (95% CI -2.4 to and education of Missing overall health and overall 5.9) doctors, Laparoscopic 18 (3) quality of life on a 7-point Mean difference at Sahlgrenska Open 3 (1) scale (1 indicating very poor 12 months University and 7 indicating Laparoscopic Hospital, excellent). All other (n=206) - Open Gothenburg, questions have four (n=91)
Sweden; the possible answers: ‘not at 0.6 (95% CI -3.4 to
Departments of all’, ‘a little’, ‘quite a bit’ and 4.7) Surgery and ‘very much’. The time frame
Biostatistics, Inclusion criteria was ‘during the past week’. Outcome: Sexual Erasmus The EORTC QLQ-CR38 A single rectal cancer functioning (QLQ- University Medical questionnaire is a 38-item within 15 cm from the CR38; scale 0 to 100, Center, questionnaire used to anal verge (confirmed at higher score Rotterdam, measure more specific colonoscopy, rigid indicating better the Netherlands; information about quality of rectoscopy, or barium functioning)** the Department of life in patients with enema); no evidence of Baseline score Surgery, distant colorectal cancer. Dalhousie metastases; candidate The questions cover 4 Laparoscopic University, for elective surgery functional scales/single 19.9±22.4 (n=224) Halifax, NS, items (body image, sexual Open 24.3±24.7 Canada; and the functioning, sexual (n=102) Exclusion criteria Department of enjoyment, future Mean difference at 4 Surgery, T4 tumours or T3 perspective) and eight weeks adjusted for VU University tumours within 2 mm of symptom scales/items baseline†
Colorectal cancer (update): evidence reviews for the optimal surgical technique for rectal cancer DRAFT (July 2019) 51 DRAFT FOR CONSULTATION Optimal surgical technique for rectal cancer
Outcomes and Study details Participants Interventions Methods Results Comments Medical Center, the endopelvic fascia (as (micturition problems, Laparoscopic Amsterdam determined on CT scan chemotherapy side-effects, (n=207) - Open or MRI); T1 tumour gastrointestinal symptoms, (n=98) treated with local male sexual problems, 2.5 (95% CI -0.3 to transanal excision; rectal female sexual problems, 6.3) cancer other than defaecation problems, Mean difference at 6 adenocarcinoma; history stoma-related problems and months adjusted for of other malignancy weight loss). For this baseline† except basocellular review, sexual functioning, carcinoma of the skin or sexual enjoyment, Laparoscopic in-situ carcinoma of the micturition problems, male (n=206) - Open cervix uteri; signs of sexual problems and (n=96) acute intestinal female sexual problems -0.8 (95% CI -5.5 to obstruction; need for were considered. All 3.9) synchronous colorectal questions have four Mean difference at surgery; familial possible responses: ‘not at 12 months adjusted adenomatous polyposis all’, ‘a little’, ‘quite a bit’ and for baseline† coli; hereditary non- ‘very much’. The time frame Laparoscopic polyposis colorectal was previous 4 weeks. (n=197) - Open cancer; active Crohn’s For both QLQ-30 and QLQ- (n=89) disease or active CR38, the individual scores 3.1 (95% CI -1.7 to ulcerative colitis; were converted to a score 7.9) absolute ranging from 0 to 100. A Mean difference at contraindications to high score for the 24 months adjusted general anaesthesia or symptom/item scales for baseline† prolonged represents a high level of Laparoscopic pneumoperitoneum; ASA symptoms/problems, (n=141) - Open category >III; pregnancy. whereas a high score for (n=64) the functional scales and the global health/general 4.6 (95% CI -1.7 to quality-of-life index 10.9) represents a high level of functioning, overall health Outcome: and quality of life. Sexual enjoyment (QLQ-CR38; scale 0 to 100, higher score
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Outcomes and Study details Participants Interventions Methods Results Comments Statistical analysis indicating better Kaplan–Meier method to enjoyment)** estimate the difference in Baseline score recurrence rates and Laparoscopic survival between the study 49.1±33.0 (n=97) groups. Open 61.3±32.5 (n=50) Mean difference at 6 months adjusted for baseline Laparoscopic (n=72) - Open (n=37) 0.7 (95% CI -13.6 to 15.0) Mean difference at 12 months adjusted for baseline Laparoscopic (n=87) - Open (n=38) 8.0 (95% CI -5.0 to 21.0) Mean difference at 24 months adjusted for baseline Laparoscopic (n=41) - Open (n=21) -2.1 (95% CI -17.2 to 13.0)
Outcome: Female sexual problems (QLQ-
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Outcomes and Study details Participants Interventions Methods Results Comments CR38; scale 0 to 100, higher score indicating worse problems)** Baseline score Laparoscopic 10.9±15.6 (n=23) Open 12.2±19.4 (n=15) Mean difference at 6 months adjusted for baseline† Laparoscopic (n=19) - Open (n=10) 5.1 (95% CI -16.5 to 26.8) Mean difference at 12 months adjusted for baseline† Laparoscopic (n=19) - Open (n=14) 0.9 (95% CI -20.8 to 22.7) Mean difference at 24 months adjusted for baseline† Laparoscopic (n=7) - Open (n=5) 11.8 (95% CI -18.9 to 42.5)
Outcome: Male sexual problems (QLQ-CR38; scale 0
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Outcomes and Study details Participants Interventions Methods Results Comments to 100, higher score indicating worse problems)** Baseline score Laparoscopic 36.2±35.2 (n=124) Open 27.8±29.5 (n=54) Mean difference at 4 weeks adjusted for baseline† Laparoscopic (n=91) - Open (n=41) -6.5 (95% CI -19.9 to 6.8) Mean difference at 6 months adjusted for baseline† Laparoscopic (n=116) - Open (n=47) -6.9 (95% CI -20.5 to 6.7) Mean difference at 12 months adjusted for baseline† Laparoscopic (n=117) - Open (n=50) -9.8 (95% CI -22.3 to 2.6) Mean difference at 24
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Outcomes and Study details Participants Interventions Methods Results Comments months adjusted for baseline† Laparoscopic (n=78) - Open (n=37) 1.1 (95% CI -12.2 to 14.4)
Outcome: Micturition al symptoms (QLQ- CR38; scale 0 to 100, higher score indicating worse symptoms)** Baseline score Laparoscopic 24.0±18.1 (n=240) Open 23.3±17.7 (n=110) Mean difference at 4 weeks adjusted for baseline† Laparoscopic (n=219) - Open (n=103) 0.9 (95% CI -4.4 to 6.2) Mean difference at 6 months adjusted for baseline† Laparoscopic (n=219) - Open (n=101) -1.0 (95% CI -5.0 to 3.0)
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Outcomes and Study details Participants Interventions Methods Results Comments Mean difference at 12 months adjusted for baseline† Laparoscopic (n=209) - Open (n=95) 2.2 (95% CI -2.0 to 6.4) Mean difference at 24 months adjusted for baseline† Laparoscopic (n=170) - Open (n=79) 2.4 (95% CI -2.4 to 7.2)
Outcome: Positive CRM (<2 mm) Laparoscopic 56/588 Open 30/300 (denominator is the number without complete remission)
Outcome: Locoregional recurrence at 3 years Laparoscopic 5.0% Open 5.0%
Colorectal cancer (update): evidence reviews for the optimal surgical technique for rectal cancer DRAFT (July 2019) 57 DRAFT FOR CONSULTATION Optimal surgical technique for rectal cancer
Outcomes and Study details Participants Interventions Methods Results Comments No statistical difference between groups, narratively reported.
Outcome: Length of hospital stay, mean±SD; median (IQR)*** Laparoscopic 11.9±1 1.8; 8.0 (6.0-13.0) Open 12.1±10.6; 9.0 (7.0-14.0)
Outcome: 28-day mortality*** Laparoscopic 8/699 Open 6/345
Outcome: Anastomotic leak*** Laparoscopic 58/461 Open 25/240
Outcome: Blood loss in ml, median (IQR)*** Laparoscopic 200 (100-400) Open 400 (200-700) p<0.0001
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Outcomes and Study details Participants Interventions Methods Results Comments Outcome: Wound infection*** Laparoscopic 28/697 Open 17/345
*Data extracted from Andersson 2013. **Data extracted from Andersson 2014. ***Data extracted from van der Pas 2013. †The analysis of mean difference between groups at a specific time point was adjusted for differing baseline scores and/or Characteristics, however, it is not clear from the paper what was actually done and why the baseline scores were different even though the groups were randomly assigned. Full citation Sample size Interventions Details Results Limitations Braga, M., N=168 randomised; Laparoscopic surgery Randomisation and Outcome: Quality of Cochrane risk of bias tool Frasson, M., n=83 allocated to versus open surgery allocation concealment life - General health Selection bias Vignali, A., laparoscopic surgery; Randomization list was score at 12 months Random sequence Zuliani, W., n=85 allocated to open Type of surgery, n/n generated by a computer (modified SF-36; generation: low risk Capretti, G., Di surgery Low anterior resection program. Assignments were
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Outcomes and Study details Participants Interventions Methods Results Comments Carlo, V., Laparoscopic 76/83 made by means of sealed scale 0-100, higher Allocation concealment: low Laparoscopic Characteristics Open 74/85 sequenced masked indicating better) risk resection in rectal Age in years, mean±SD Abdominoperineal envelopes, which were Laparoscopic 74 cancer patients: opened before the induction (n=83) Laparoscopic 62.8±12.6 resection Performance bias Outcome and of anaesthesia by a nurse Open 65 (n=85) cost-benefit Open 65.3±10.3 Laparoscopic 7/83 unaware of the trial design. Blinding of participants and p=0.0001 personnel: high risk (No analysis, Open 11/85 blinding.) Diseases of the Male sex, n/n Blinding Colon and Outcome: Quality of Laparoscopic 55/83 In both laparoscopy and No blinding. Rectum, 50, 464- open groups TME was life - General health Detection bias Open 64/85 471, 2007 performed when cancer score at 24 months Blinding of outcome
was located in the Follow-up/outcomes (modified SF-36; assessment: high risk (No Obesity, n/n scale 0-100, higher Ref Id middle or low portion of Follow-up for infectious and blinding.) Laparoscopic 9/83 noninfectious complications indicating better) 745870 the rectum. Open 5/85 was performed for 30 days Laparoscopic Attrition bias after hospital discharge by 72 (n=83) Patients with a Incomplete outcome Country/ies weekly office visits. Long- Open 68 (n=85) where the study Dukes stage, n/n preoperative diagnosis data: low risk (Intention-to- term follow-up was (p-value not reported was carried out I of T3 stage cancer treat analysis was done. No performed every six months but not significant Laparoscopic 25/83 received preoperative losses to follow-up.) Italy by office visits. difference between chemoradiotherapy: Open 24/85 continuous infusion of 5- Quality of life was assessed groups) Reporting bias Study type II fluorouracil 20 mg/m² by a modified version of the Medical Outcomes Study Selective reporting: low risk RCT Laparoscopic 16/83 daily for 45 days plus Outcome: Positive Short Form 36 (SF-36) Open 19/85 4,500 Gy distributed in distal margin questionnaire. Aim of the study III 19 days (from day 14) Laparoscopic 0/83 Other bias plus oxaliplatin 100 To evaluate the Laparoscopic 31/83 Open 0/85 Other sources of bias: - mg/m² on days 1, 14, Statistical analysis impact of Open 29/85 and 28. Intention-to-treat analysis laparoscopic IV Other information was done. Survival curves Outcome: Positive rectal resection on Laparoscopic 11/83 circumferential None short-term were constructed with the Open 13/85 resection margin postoperative Kaplan-Meier method and Laparoscopic 1/83 morbidity and were compared with the costs. Tumour distance from log-rank test. Open 2/85 the anal verge in cm, mean
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Outcomes and Study details Participants Interventions Methods Results Comments Study dates Laparoscopic 9.1 Outcome: Local Not reported. Open 8.6 recurrence 3 years after surgery Source of Tumour distance 10-15 Laparoscopic 3/83 funding cm from the anal verge, Open 4/85 n/n None reported. Laparoscopic 30/83 Outcome: Length of Open 24/85 hospital stay in days, mean±SD Laparoscopic 10±4.9 (n=83)
Open 13.6±10 (n=85) Inclusion criteria
Adenocarcinoma of the rectum; age 18 years or Outcome: Operative older; suitability to mortality elective surgery. Laparoscopic 1/83 Open 1/85 Exclusion criteria Cancer infiltrating Outcome: adjacent organs Anastomotic leak assessed by CT scan or Laparoscopic 8/83 MRI; cardiovascular Open 9/85 dysfunction (New York Heart Association Class Outcome: Wound > 3); respiratory infection dysfunction (arterial pO2 < 70 mmHg); hepatic Laparoscopic 6/83 dysfunction (Child-Pugh Open 13/85 Class C); ongoing infection; plasma Outcome: Blood loss neutrophil level < in ml, mean±SD 2x10(9)/L. Laparoscopic 213±236 (n=83)
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Outcomes and Study details Participants Interventions Methods Results Comments Open 396±367 (n=85) Full citation Sample size Interventions Details Results Limitations Buonpane, C., N=1,937 robotic surgery; Robotic surgery versus Randomisation and Outcome: Positive ROBINS-I checklist for non- Efiong, E., N=7,185 laparoscopic open surgery allocation concealment surgical margin randomised studies of Hunsinger, M., surgery (not considered Not a randomised study. Robotic 106/1,937 Interventions Fluck, M., for this review because The data for this study was Pre-intervention Neoadjuvant Open 1,256/14,735 Shabahang, M., RCT data exists on radiotherapy, n (%) received from a national Bias due to Wild, J., Halm, K., critical outcomes); Robotic 66.2 oncology database that confounding: Serious risk of Long, K., Buzas, N=14,735 open surgery captures more than 70% of Open 58.0 bias (This is a retrospective C., Blansfield, J., all newly diagnosed non-randomised
Predictors of Characteristics malignancies in the observational study. No utilization and Neoadjuvant Age, % US. Records of all surgically matching of groups was quality chemotherapy, n (%) resected rectal cancers 18-29 years done. The study did assessment in Robotic 64.5 were obtained. not control for potential Robotic Not reported robotic rectal Open 57.4 confounding in the cancer resection: (NR) Blinding analysis.) A review of the Open 0.7 Bias in selection of national cancer Not applicable. 30-39 participants into the study: database, Robotic NR Low risk of bias American Follow-up/outcomes Open 3.5 Surgeon, 83, 918- Data from a database was 40-49 924, 2017 used. At intervention Robotic 15.2 Bias in classification of Open 13.1 Interventions: Low risk of Ref Id Statistical analysis 50-59 bias 745976 Analysis of outcomes of
Robotic 30.7 interest for this review were Post-intervention Country/ies Open 27.1 not adjusted for potential where the study 60-69 confounders or case-mix. Bias due to deviations from was carried out Robotic 28.7 intended Interventions: Low risk of bias US Open 27.8 Bias due to missing data: 70-79 Low risk of bias Study type Robotic 14.6 Open 18.6
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Outcomes and Study details Participants Interventions Methods Results Comments Retrospective 80+ Bias in measurement of cohort study Robotic 6.3 outcomes: Low risk of bias Open 9.2 Bias in selection of the Aim of the study reported result: Low risk of bias To evaluate Male sex, %
the use of robotic Robotic 62.7 surgery in rectal Other information Open 60.2 cancer None resection compar ed with open and T stage, % laparoscopic In situ techniques and to Robotic NR assess the quality Open 1.4 of resection. x
Robotic 15.3 Study dates Open 21.3 2010 to 2012 T0
Robotic NR Source of Open 0.3 funding T1 None reported. Robotic 9.3 Open 9.4 T2 Robotic 12.6 Open 12.2 T3 Robotic 57.8 Open 48.9 T4 Robotic 3.8 Open 6.5
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Outcomes and Study details Participants Interventions Methods Results Comments N stage, n (%) x Robotic 7.7 Laparoscopic 7.7 Open 9.7 N0 Robotic 56.4 Open 57.7 N1 Robotic 29.6 Open 26.7 N2 Robotic 6.3 Open 5.9
Metastatic disease, % Robotic 5.8 Open 9.7
Inclusion criteria Surgically resected rectal cancers diagnosed from 2010 through 2012.
Exclusion criteria If surgical approach for the resection of the primary tumour was not reported or if data required for analysis was missing.
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Outcomes and Study details Participants Interventions Methods Results Comments Full citation Sample size Interventions Details Results Limitations Corbellini, C, Biffi, N=65 patients received Robotic versus Randomisation and Outcome: Overall ROBINS-I checklist for non- R, Luca, F, robotic surgery; N=40 laparoscopic versus allocation concealment survival at 3 years randomised studies of Chiappa, A, patients received open surgery This study was not a Robotic 88.2% Interventions Costa, S, Bertani, laparoscopic surgery randomised study. Data Laparoscopic 96.4% Pre-intervention E, Bona, S, (only considered for Type of surgery, n (%) was prospectively collected Open 93.9% Bias due to Lombardi, D, overall survival because but the choice of surgical Anterior resection p=0.522 confounding: Serious risk of Tamayo, D, for other critical technique was done bias (This is a non- Robotic 58 (89) Botteri, E, outcomes there is RCT according to preference of randomised study, the Laparoscopic 38 (95) Andreoni, B, data); N=55 patients the surgeon and the Outcome: R1 groups were not matched Open, received open surgery Open 43 (78) patient. Robotic 0/65 by any characteristic. The laparoscopic, and Abdominoperinal Open 2/55 study did not control for robotic surgery for Characteristics resection Blinding potential confounding or rectal cancer: Age in years, median Robotic 7 (11) case-mix in the analysis.) medium-term No blinding. Outcome: Distal (range) Laparoscopic 1 (2.5) Bias in selection of comparative surgical margin <2 participants into the study: outcomes from a Robotic 64 (39-78) Open 11 (20) Follow-up/outcomes cm (Abdominoperineal Low risk of bias multicenter study, Laparoscopic 64 (36-80) Hartmann Follow-up visits were 3 resection excluded) Tumori, 102, 414- Open 62 (40-80) Robotic 0 (0) months after surgery and 421, 2016 Laparoscopic 1 (2.5) every 6 months for the first Robotic 22/58 At intervention Male sex, n (%) Open 1 (2) 3 years, including a Open 10/44 Bias in classification of Interventions: Low risk of Ref Id Robotic 35 (54) physical examination and tumour marker testing. bias 746335 Laparoscopic 23 (58) Choice of surgical Colonoscopy was done 1 technique was carried Open 36 (66) and 3 years after surgery. according to the Post-intervention Country/ies Chest and abdominopelvic surgeon's and the Bias due to deviations from where the study computer tomography was was carried out patient's preferences. intended Interventions: Low BMI, n (%) done once a year and risk of bias Italy TME with nerve abdominal ultrasound <25 Bias due to missing data: preservation was examination was Robotic 36 (55) performed in low and Low risk of bias Study type done every 6 months. Laparoscopic 17 (43) muddle rectal cancers Bias in measurement of A prospective, Open 33 (60) and partial mesorectal outcomes: Low risk of bias multi-centre excision was performed Statistical analysis
cohort study. in upper rectal cancers. Differences in survival were 25-30 analysed using the log-rank
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Outcomes and Study details Participants Interventions Methods Results Comments Aim of the study Robotic 23 (35) All robotic-assisted test. No multivariate Bias in selection of the To analyse and Laparoscopic 14 (35) laparoscopic anterior analysis was done. reported result: Low risk of resolve Open 13 (24) resection surgeries were bias performed by hybrid advantages of robotic surgery technique. >30 Other information with respect to Robotic 6 (9) None open surgery and Preoperative laparoscopic Laparoscopic 9 (23) chemoradiotherapy and surgery in the Open 9 (16) postoperative management of chemotherapy were rectal cancer. Tumour distance from recommended for anal margin, n (%) patients with locally Study dates <6 cm advanced rectal cancer. April 2009 to Robotic 21 (34) August 2011 Laparoscopic 9 (23) Open 20 (37) Source of funding 6-9.9 cm No financial Robotic 18 (29) support. Laparoscopic 13 (33) Open 16 (30)
>=10 cm Robotic 23 (37) Laparoscopic 18 (45) Open 18 (33)
Pathologic staging, n (%) I Robotic 17 (26) Laparoscopic 15 (38)
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Outcomes and Study details Participants Interventions Methods Results Comments Open 11 (20)
II Robotic 17 (26) Laparoscopic 13 (33) Open 15 (27)
III Robotic 31 (48) Laparoscopic 12 (30) Open 29 (53)
Inclusion criteria A single rectal cancer within 12 cm from the anal verge; without evidence of distant metastases; candidates for elective, good-chance surgery.
Exclusion criteria Tumours treated with local transanal excision; rectal cancers other than adenocarcinoma; recent history of other malignancies; familial adenomatous polyposis coli; hereditary nonpolyposis colorectal cancer; Chrohn disease or ulcerative colitis;
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Outcomes and Study details Participants Interventions Methods Results Comments preoperative clinical stage IV. Full citation Sample size Interventions Details Results Limitations Denost, Q., N=100 randomised; TaTME versus Randomisation and Outcome: Overall Cochrane risk of bias tool Loughlin, P., n=50 allocated to laparoscopic TME allocation concealment survival, median 60.2 Selection bias Chevalier, R., transanal TME (TaTME); The randomization of months of follow-up Random sequence Celerier, B., n=50 allocated to Surgery was performed patients was performed by TaTME n=50, 7 generation: unclear risk Didailler, R., laparoscopic surgery 6 weeks after the end of the assistant researcher the events* (Limited details reported.) Rullier, E., radiotherapy. day before surgery, when Laparoscopic n=50, Allocation concealment: Transanal versus Characteristics the investigator has 13 events* unclear risk (Details not abdominal low obtained the patient’s Age in years, median Preoperative p=0.135 reported.) rectal dissection written informed consent. (range) radiotherapy, n/n for rectal cancer: Randomization was blind long-term results TaTME 64 (39-82) TaTME 40/50 for the patient and was Outcome: Urinary Performance bias of the Bordeaux' Laparoscopic 63 (31-90) Laparoscopic 44/50 stratified by surgeon. No function median Blinding of participants and randomized trial, other details reported. score (range) (IPSS, personnel: high risk (No scale 0 to 35, higher Surgical Male sex, n/n Preoperative blinding.) Endoscopy and indicating worse TaTME 37/50 chemotherapy, n/n Blinding Other urinary function)** TaTME 39/50 Detection bias Interventional Laparoscopic 32/50 No blinding. TaTME 5.5 (0- Blinding of outcome Techniques, 1-9, Laparoscopic 42/50 23) (n=38) assessment: low/high risk 2017 BMI, median (range) Follow-up/outcomes Laparoscopic 3.5 (0- (No blinding. High risk of
TaTME 25.1 (17.3–33.2) Follow-up visits were at 1 27) (n=34) bias for subjective Ref Id Laparoscopic 25.6 month, then every 4 months p=0.821 outcomes.) up to 2 years and 6 months 746561 (18.3–38.3) subsequently. Outcome: Urinary Postoperative surveillance Attrition bias Tumour location from the function quality of life Country/ies included clinical Incomplete outcome data: anal verge in cm, median median score (range) where the study examination, CEA low/high risk (For (range) (IPSS, scale 0 to 6, was carried out level assessment recurrence, survival and lower indicating France TaTME 4 (2-6) and computer tomography perioperative outcomes better quality of life)** Laparoscopic 4 (2-6) scan. Colonoscopy was intention-to-treat analysis TaTME 1 (0- Study type performed 1 year following was done. However, for 6) (n=38) sexual and urinary function RCT (Bordeaux' Tumour stage, n/n surgery, then every 5 years. only 72/100 participants trial) T1-2
Colorectal cancer (update): evidence reviews for the optimal surgical technique for rectal cancer DRAFT (July 2019) 68 DRAFT FOR CONSULTATION Optimal surgical technique for rectal cancer
Outcomes and Study details Participants Interventions Methods Results Comments TaTME 10/50 Local recurrence was Laparoscopic 1 (0- were included in the Aim of the study Laparoscopic 9/50 defined as any recurrence 5) (n=34) analysis.) To compare T3-4 diagnosed or suspected in p=0.967 the pelvis. Recurrences outcomes TaTME 40/50 Reporting bias were confirmed with between transanal Outcome: Sexual Selective reporting: low risk Laparoscopic 41/50 radiological or histological and laparoscopic activity maintained examination. Overall rectal dissection after treatment (in N1-2, n/n survival was measured from Other bias in laparoscopic previously sexually the date of surgery to Other sources of bias: - sphincter TaTME 30/50 active participants)** death. preservation for Laparoscopic 33/50 TaTME 20/28 low rectal cancer. Assessment of urinary and Other information sexual function was Laparoscopic 9/23 The definition of local performed at least 12 p=0.02 Study dates recurrence is unclear. The Inclusion criteria months after stoma closure. June 2008 to paper reports that local Low rectal cancer (<6 (All data relating to urinary Outcome: Sexual February 2012 recurrence was defined as cm from the anal verge); and sexual function dysfunction at diagnosed or suspected suitable for laparoscopic extracted from Pontallier median 3.2 years recurrence in the pelvis, Source of sphincter-saving 2016.) after treatment (FSFI however, it also reports that funding resection. Urinary function was score ≤19) in all recurrences were None reported. assessed by the previously sexually confirmed by radiological or Exclusion criteria International Prostate active female histological examination. Exclusion criteria for Symptom score (IPSS). The participants functional outcome IPSS questionnaire is TaTME 2/5 assessments were: based on 7 items Laparoscopic 2/3 (incomplete bladder death; local or recurrent p=1.00 disease; presence of a emptying, frequency, intermittency, urgency, Outcome: Erectile stoma. weak stream, straining and function median nocturia). Each item value score (range) in is ranged from 0 to 5 (0=not sexually active men at all; 1=less than one time; (IIEF, scale 5-25, 2=less than half the time; higher indicating 3=about half the time; better erectile 4=more than half the time; function)** and 5=almost always). Total TaTME 17.5 (5-25) IPSS was calculated by (N not reported)
Colorectal cancer (update): evidence reviews for the optimal surgical technique for rectal cancer DRAFT (July 2019) 69 DRAFT FOR CONSULTATION Optimal surgical technique for rectal cancer
Outcomes and Study details Participants Interventions Methods Results Comments adding the score for each Laparoscopic 7 (5- item and ranges from 0 (no 21) (N not reported) urinary disorder) to 35 p=0.119 (major urinary disorder). The quality of urinary function was graded Outcome: Erectile in three subgroups dysfunction (IIEF according to their IPSS: score <=21) after normal function (IPSS 0–7 treatment** points), moderate TaTME 67% (N not dysfunction (IPSS 8–19 reported) points) and severe Laparoscopic 93% (N dysfunction (IPSS 20–35 not reported) points). The quality of life p=0.108 included in the IPSS questionnaire ranged from Outcome: Normal 0 (best) to 6 (worst). ejaculatory function Male sexual function was after treatment assessed by the 5-item among sexually version of the International active men before Index of Erectile Function surgery (IIEF)** questionnaire (IIEF-5; items TaTME 14/21 (67%) included erection (denominator calculat confidence, maintenance ed from percentage ability, maintenance reported) frequency, erection firmness, and sexual Laparossopic 7/16 satisfaction). Each item (44%) (denominator value is ranged from 0 to 5 calculated from (0=did not attempt percentage reported) intercourse; 1=almost never p=0.224 or never; 2=less than half the time; 3=about half the Outcome: Positive time; 4=more than half the distal margin (not time; and 5=almost always). defined) The IIEF-5 score was
Colorectal cancer (update): evidence reviews for the optimal surgical technique for rectal cancer DRAFT (July 2019) 70 DRAFT FOR CONSULTATION Optimal surgical technique for rectal cancer
Outcomes and Study details Participants Interventions Methods Results Comments calculated by adding the TaTME 1/50 score for each item and Laparoscopic 4/50 ranges from 5 to 25. A total score at or below 21 was considered Outcome: "R1 ‘‘abnormal.’’ Erectile resection (positive function in patients with CRM)" (not defined) sexual inactivity (score from TaTME 2/50 0 to 4) was not analysed. Laparoscopic 9/50 Female sexual function was assessed by the 6-item Outcome: Local version of the Female recurrence at 5 years Sexual Function Index TaTME 2.6% (95% (FSFI-6; items CI 2.3% to 7.5%) included sexual desire, Laparoscopic 4.8% sexual activity, lubrication, (95% CI 1.7 to dyspareunia, sexual arousal 11.3%) and satisfaction). Each item value is ranged from 0 to 5 p = 0.300 (0=did not attempt intercourse; 1=almost never Outcome: Length of or never; 2=less than half hospital stay in days, the time; 3=about median (range) half the time; 4=more than TaTME 7 (3-54) half the time; 5=almost (n=50) always). The FSFI-6 score Laparoscopic 8 (2- was calculated by adding 29) (n=50) the score for each item and p=0.281 ranges from 0 to 30. A total score at or below 19 was considered ‘‘abnormal.’’ Outcome: Sexual activity in both male Postoperative and female was assessed mortality before and after treatment. TaTME 0/50 In case of a loss of sexual Laparoscopic 1/50 activity after surgery,
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Outcomes and Study details Participants Interventions Methods Results Comments patients should report whether this postoperative Outcome: impairment was due or not Anastomotic leak to the surgical procedure. and/or abscess TaTME 1/50 Statistical analysis Laparoscopic 5/50 Recurrence and survival were evaluated by the *Number of events Kaplan–Meier method and calculated from the compared with the log-rank Kaplan-Meier curve. test. **Data extracted from
Pontallier 2016.
Full citation Sample size Interventions Details Limitations Denost Q, Loughlin P, (See Denost 2017 (See Denost 2017 (See Denost 2017 (See Denost 2017 Chevalier R et al. BORDEAUX trial) BORDEAUX trial) BORDEAUX trial) BORDEAUX trial) Transanal versus abdominal low Other information rectal dissection for rectal cancer: None long-term results of the Bordeaux’ randomized trial. Surg Endosc. 2018 Mar;32(3):1486- 1494.
Ref Id 982355
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Outcomes and Study details Participants Interventions Methods Results Comments Country/ies where the study was carried out France
Study type RCT (Bordeaux' trial)
Aim of the study To compare outcomes between transanal and laparoscopic rectal dissection in laparoscopic sphincter preservation for low rectal cancer.
Study dates June 2008 to February 2012
Source of funding None reported.
Full citation Sample size Interventions Details Results Limitations Fleshman, J., N=486 randomised; Laparoscopic surgery Randomisation and Outcome: Negative Cochrane risk of bias tool Branda, M., n=243 allocated to versus open surgery allocation concealment distal margin (>=1 Selection bias Sargent, D. J., laparoscopic surgery but Randomization was mm) Random sequence Boller, A. M., 3 did not receive performed centrally. generation: low risk
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Outcomes and Study details Participants Interventions Methods Results Comments George, V., intervention as Previous therapy Stratification by surgeon, Laparoscopic Allocation concealment: Abbas, M., randomised, n=240 received, n (%) site of primary tumor (high, 234/240 unclear risk (Details not Peters, W. R., analysed; n=243 Chemotherapy + middle, or low rectum Open 218/222 reported.) Maun, D., Chang, allocated to open radiotherapy according to the G., Herline, A., surgery but 21 not subclassification of the 12 Laparoscopic 227 (95.0) Performance bias Fichera, A., included in analysis cm of rectum into equal Outcome: CRM > Mutch, M., because did not undergo Open 217 (91.2) thirds), and planned 1mm or distance = Blinding of participants and Wexner, S., intervention as Radiotherapy alone operative procedure not applicable personnel: high risk (No Whiteford, M., randomised or problem Laparoscopic 8 (3.3) (lowanterior resectionwith Laparoscopic blinding.) Marks, J., with consent, n=222 Open 13 (5.5) anastomosis or 211/240 Birnbaum, E., analysed. Chemotherapy alone abdominoperineal resection Open 205/222 Detection bias Margolin, D., with colostomy). Laparoscopic 4 (1.7) Blinding of outcome Larson, D., Characteristics Outcome: Distance to assessment: low/high risk Marcello, P., Open 8 (3.4) Age in years, mean±SD Blinding radial margin (No blinding. High risk of Posner, M., Read, Unknown bias on subjective Laparoscopic 57.7±11.5 No blinding was done. <=1 mm T., Monson, J., Laparoscopic 3 outcomes.) Laparoscopic 29/240 Wren, S. M., Open 57.2±12.1 Open 1 Pisters, P. W. T., Follow-up/outcomes Open 17/222 Attrition bias Nelson, H., Effect Patients were assessed for >1 mm Male sex, n (%) Planned surgical of laparoscopic- complications at discharge Incomplete outcome Laparoscopic 156 (64.5) approach, n (%) Laparoscopic assisted resection from the hospital and at 4 to data: unclear risk (Modified Open 158 (66.1) 211/240 vs open resection Abdominoperineal 6 weeks postoperatively. intention-to-treat analysis resection Open 205/222 done. 3 in one group and of stage II or III BMI, mean±SD Laparoscopic 55 (22.7) 22 in one group of the rectal cancer on Statistical analysis pathologic Laparoscopic 26.4±4.0 Open 57 (23.8) Outcome: Local and originally randomised not Modified intention-to-treat. regional recurrence* analysed.) outcomes the Open 26.8±4.2 Low anterior resection Patients who did not was 4.6% from ACOSOG Z6051 Laparoscopic 187 (77.3) randomized receive the randomised laparoscopic Reporting bias Open 182 (76.2) clinical trial, JAMA Location of tumour in the intervention were not resection and 4.5% included in the analysis but Selective reporting: low risk - Journal of the rectum, n (%) for open resection. patients who had a American Medical High Surgical approach used, conversion to open surgery Other bias Association, 314, Laparoscopic 33 (13.6) n (%) Outcome: Length of were included in the Other sources of bias: - 1346-1355, 2015 Open 28 (11.7) Abdominoperineal hospital stay in days, analysis as originally resection mean±SD Middle allocated. Other information Ref Id Laparoscopic 85 (35.1) Laparoscopic 58 (24.2) Laparoscopic 7.3 (5.4)
Colorectal cancer (update): evidence reviews for the optimal surgical technique for rectal cancer DRAFT (July 2019) 74 DRAFT FOR CONSULTATION Optimal surgical technique for rectal cancer
Outcomes and Study details Participants Interventions Methods Results Comments 746895 Open 95 (39.7) Open 47 (21.2) Open 7.0 (3.4) Note that "laparoscopic Low Low anterior resection surgery" includes robotic Country/ies Laparoscopic 124 (51.2) Laparoscopic 69 (28.8) Outcome: 30-day (14%), hand-assisted laparoscopic (17%) and where the study Open 116 (48.5) Open 73 (32.9) mortality conventional laparoscopic was carried out Low anterior resection + Laparoscopic 2/240 (69%) surgery. US Preoperative clinical coloanal anastomosis Open 2/222 stage, n (%) Laparoscopic 110 (45.8) Study type I Open 96 (43.2) Outcome: RCT (ACOSOG Laparoscopic 2 (0.8) Low Hartmann Anastomotic leak Z6051 trial) Open 3 (1.3) Laparoscopic 1 (0.4) during postoperative period IIA Open 0 Laparoscopic 5/240 Aim of the study Laparoscopic 99 (40.9) Total proctocolectomy Open 5/222 To determine Open 92 (38.5) Laparoscopic 2 (0.8) whether IIIA Open 6 (2.7) laparoscopic Outcome: Blood loss Laparoscopic 11 (4.5) resection is in ml, mean±SD noninferior to Open 11 (4.6) Surgical technique in the (median, IQR) laparoscopic arm, n (%) open resection. IIIB Laparoscopic 256.1± Laparoscopic 114 (47.1) Laparoscopic 165 (68.8) 305.8 (150, 100-300) Study dates Open 114 (47.7) Hand-assisted 41 (17.1) Open 318.4±331.7 October 2008 to IIIC Robotic assisted 34 (200±100-400) September 2013 Laparoscopic 16 (6.6) (14.2) Open 19 (7.9) *Data extracted from Source of Fleshman 2019. funding The National Cancer
Institute; The American Society Inclusion criteria of Colon and Aged 18 years or Rectal older; BMI of 34 or less,; Surgeons; The Eastern Cooperative Society of Oncology Group
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Outcomes and Study details Participants Interventions Methods Results Comments American performance score less Gastrointestinal than 3; histologically and proven adenocarcinoma Endoscopic of the rectum at or below Surgeons 12 cm above the anal verge (by rigid proctoscopy); clinical stage II, IIIA, IIIB (T3N0M0, TanyN1 or 2, M0, and no T4) determined by rectal cancer protocol magnetic resonance imaging or transrectal ultrasonography
Exclusion criteria History of invasive pelvic malignancy within 5 years; psychiatric or addictive disorders that affected compliance to the protocol; severe incapacitating disease (ASA classification IV or V); systemic disease that would preclude use of a laparoscopic approach (for example cardiovascular, renal, hepatic); conditions that would limit the success of laparoscopic resection (multiple previous
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Outcomes and Study details Participants Interventions Methods Results Comments laparotomies or severe adhesions). Full citation Sample size Interventions Details Results Limitations Fleshman J, See Fleshman 2015 Branda ME, Sargent DJ, et al. Disease-free Survival and Local Recurrence for Laparoscopic Resection Compared With Open Resection of Stage II to III Rectal Cancer: Follow-up Results of the ACOSOG Z6051 Randomized Controlled Trial. Ann Surg. 2019 Apr;269(4):589- 595.
Ref Id 982405
Country/ies where the study was carried out US
Study type
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Outcomes and Study details Participants Interventions Methods Results Comments RCT (ACOSOG Z6051 trial)
Aim of the study To determine whether laparoscopic resection is noninferior to open resection.
Study dates October 2008 to September 2013
Source of funding The National Cancer Institute; The American Society of Colon and Rectal Surgeons; The Society of American Gastrointestinal and Endoscopic Surgeons
Full citation Sample size Interventions Details Results Limitations Green B, Marshall See Jayne 2010 H, Collinson F et (CLASICC trial).
Colorectal cancer (update): evidence reviews for the optimal surgical technique for rectal cancer DRAFT (July 2019) 78 DRAFT FOR CONSULTATION Optimal surgical technique for rectal cancer
Outcomes and Study details Participants Interventions Methods Results Comments al. (2013) Long- Other information term follow-up of Characteristics the Medical Research Council CLASICC trial of Inclusion criteria conventional versus Exclusion criteria laparoscopically assisted resection in colorectal cancer, British Journal of Surgery 100: 75-82 Ref Id 747298
Country/ies where the study was carried out
Study type
Aim of the study
Study dates
Source of funding
Full citation Sample size Interventions Details Results Limitations Guillou, P. J., See Jayne 2010 Quirke, P., (CLASICC trial). Other information Thorpe, H.,
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Outcomes and Study details Participants Interventions Methods Results Comments Walker, J., Jayne, Characteristics D. G., Smith, A. M., Heath, R. M., Inclusion criteria Brown, J. M., Mrc Clasicc trial group, Short-term Exclusion criteria endpoints of conventional versus laparoscopic- assisted surgery in patients with colorectal cancer (MRC CLASICC trial): multicentre, randomised controlled trial, Lancet, 365, 1718-26, 2005
Ref Id 809742
Country/ies where the study was carried out
Study type
Aim of the study
Study dates
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Outcomes and Study details Participants Interventions Methods Results Comments Source of funding Full citation Sample size Interventions Details Results Limitations Ielpo, B., Duran, N=86 robotic surgery; Robotic versus Randomisation and Outcome: Overall ROBINS-I checklist for non- H., Diaz, E., N=112 laparoscopic laparoscopic surgery allocation concealment survival at 3 years randomised studies of Fabra, I., Caruso, surgery Operative procedure, n This study was not a Robotic 91% Interventions R., Malave, L., (%) randomised study. The data Laparoscopic 94% Pre-intervention Ferri, V., Nunez, Characteristics Lower anterior resection was obtained from a p=0.7 Bias due to J., Ruiz-Ocana, Age in years, mean±SD Robotic 62 (72) prospectively collected confounding: Serious risk of A., Jorge, E., database of rectal surgeries Robotic 63.9±9.5 Laparoscopic 73 (65) bias (This is a non- Lazzaro, S., in the study institution. No randomised study. No Laparoscopic 61.6±11.9 Abdominoperineal Kalivaci, D., matching of the groups was matching of groups was resection Quijano, Y., done. done. The study did Vicente, E., Male sex, n/n Robotic 20 (23) not control for potential Robotic versus Robotic 48/86 Laparoscopic 32 (29) Blinding confounding in the laparoscopic Laparoscopic 67/112 Colo-anal analysis.) surgery for rectal No blinding. Bias in selection of cancer: a Robotic 4 (5) participants into the study: comparative study BMI, mean±SD Laparoscopic 7 (6) Follow-up/outcomes Low risk of bias of clinical Robotic 26.1±4.1 Outcome data was obtained
outcomes and Laparoscopic 25.7±3.4 Robotic surgery was retrospectively from a At intervention costs, performed with da Vinci prospectively-collected International Robotic Surgical System Bias in classification of Tumour location from the database. Journal of model Si and Xi. Interventions: Low risk of anal verge, n (%) Follow-up assessments Colorectal bias <5 cm were performed at 15 Disease, 32, Patients with T3 or N+ postoperative days, at 1, 3 Robotic 25/86 1423-1429, 2017 cancer received and 6 months, and every 6 Post-intervention Laparoscopic 32/112 neoadjuvant months up to 5 years post- Bias due to deviations from Ref Id 5-9 cm chemoradiation followed operation. A colonoscopy intended Interventions: 747778 Robotic 30/86 by surgery within 8 was performed at the year 1 Low risk of bias Laparoscopic 39/112 weeks. and 3. A chestabdominal- Bias due to missing data: pelvic CT-scan was used Country/ies 10-15 cm Neoadjuvant therapy, n Low risk of bias for the detection of where the study (%) Bias in measurement of Robotic 31/86 locoregional or systemic was carried out Robotic 65 (76) outcomes: Low risk of bias Laparoscopic 41/112 recurrence at 2 and 6
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Outcomes and Study details Participants Interventions Methods Results Comments Spain Laparoscopic 87 (78) months after surgery, and Bias in selection of the Inclusion criteria every 6 months thereafter, reported result: Low risk of Study type Patients with diagnosed or whenever suspected. bias
Retrospective rectal cancer who cohort study underwent laparoscopic Statistical analysis Other information or robotic surgery. No adjustments for potential None confounding or case-mix Aim of the study was done. To compare the Exclusion criteria clinical outcomes T4 rectal cancers and cost differences of robotic versus laparoscopic surgery in the treatment of rectal cancer.
Study dates October 2010 to March 2017
Source of funding This study has not been funded in whole or in part by any organisation. Full citation Sample size Interventions Details Results Limitations Ishibe, A., Ota, N=200 randomised in Laparoscopic versus Randomisation and Outcome: Overall Cochrane risk of bias tool M., Fujii, S., total of which 58 were open surgery allocation concealment survival at 3 years Selection bias Suwa, Y., Suzuki, rectal cancer patients; Details not reported. (rectal cancer) Random sequence S., Suwa, H., n=29 rectal cancer Medial-to-lateral Laparoscopic 85.7% generation: unclear risk Momiyama, M., patients allocated to approach in the Blinding Open 83.1% (Details not reported.)
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Outcomes and Study details Participants Interventions Methods Results Comments Watanabe, J., laparoscopic surgery; laparoscopic surgery No blinding. p = 0.557 Allocation Watanabe, K., n=29 rectal cancer was performed in all concealment: unclear risk Taguri, M., patients allocated to patients in the Follow-up/outcomes Outcome: Local (Details not reported.) Kunisaki, C., open surgery laparoscopic group. recurrence (median Endo, I., Midterm The follow-up schedule was 42.5 months of Performance bias follow-up of a specific to the disease Characteristics High anterior resection follow-up) randomized trial stage. Stage 0 or I: Blinding of participants and Characteristics in the of rectum, n/n of open surgery outpatient examinations Laparoscopic 0/29 personnel: high risk (No total cohorts (both colon Laparoscopic 5/29 versus once a year for 5 years, Open 4/29 blinding.) and rectal cancers): laparoscopic Open 7/29 including tumour marker measurements and surgery in elderly Low anterior resection of Detection bias computed tomography of patients with Age >=80 years, n (%) rectum Blinding of outcome the chest, abdomen, and colorectal cancer, Laparoscopic 44 (45) Laparoscopic 19/29 assessment: high risk (No pelvis. Stage II or Surgical blinding, high risk of bias Open 39 (42) Open 19/29 IIIA: Computed tomography Endoscopy and Abdominoperineal for subjective outcomes.) Other and tumour marker Male sex, n (%) resection Interventional measurements every 6 Laparoscopic 4/29 Attrition bias Techniques, 31, Laparoscopic 49 (50) months for the first 2 years, 3890-3897, 2017 Open 55 (60) Open 2/29 once a year from years 3 to Incomplete outcome 5. Stage IIIB or IIIC: data: low risk Intersphincteric resection Computed tomography and Ref Id BMI >=25, n (%) tumour marker Laparoscopic 1/29 Reporting bias 747811 Laparoscopic 33 (34) measurements every 4 Open 0/29 Selective reporting: low risk Open 34 (37) months for the first 2 years,
Country/ies and every 6 months from where the study Tumour site, n (%) years 3 to 5. Other bias Other sources of bias: - was carried out Colon Adjuvant chemotherapy, n (%) (for the total Japan Laparoscopic 69 (70) Statistical analysis population, including Other information Open 63 (69) Survival was analysed colon and rectal using the Kaplan–Meier Study type Rectum None cancers) method, difference between RCT Laparoscopic 29 (30) Laparoscopic 16 (16) the groups was determined
Open 29 (32) Open 10 (11) by log-rank test. Aim of the study To compare open pStage, n (%) surgery with
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Outcomes and Study details Participants Interventions Methods Results Comments laparoscopic 0 surgery in elderly Laparoscopic 5 (5) patients with Open 2 (2) colorectal cancer. I
Laparoscopic 27 (28) Study dates Open 24 (26) August 2008 to August 2012 II Laparoscopic 36 (37) Source of Open 33 (36) funding III Laparoscopic 30 (31) None. Open 33 (36)
Inclusion criteria Age of 75 years or older; a histologically confirmed diagnosis of colorectal adenocarcinoma; a clinical stage of up to T4a tumours; any N stage; no evidence of metastasis (M0); elective surgery.
Exclusion criteria Synchronous or metachronous (within 5 years) malignancy in another organ except carcinoma-in situ; multiple colorectal cancer needing
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Outcomes and Study details Participants Interventions Methods Results Comments reconstruction two or more times; acute intestinal obstruction or perforation due to colorectal cancer; bulky tumour >8 cm in diameter; lower rectal cancer that required pelvic side wall lymphadenectomy; history of laparotomy for colorectal resection except appendectomy; pregnancy or breastfeeding; inability to tolerate pneumoperitoneum on the basis of general condition. Full citation Sample size Interventions Details Results Limitations Jayne, D. G., See Jayne 2010 Brown, J. M., (CLASICC trial). Other information Thorpe, H., Walker, J., Characteristics Quirke, P.,
Guillou, P. J., Bladder and Inclusion criteria sexual function following Exclusion criteria resection for rectal cancer in a randomized clinical trial of laparoscopic versus open
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Outcomes and Study details Participants Interventions Methods Results Comments technique, Br J Surg, 92, 1124- 32, 2005
Ref Id 809743
Country/ies where the study was carried out
Study type
Aim of the study
Study dates
Source of funding Full citation Sample size Interventions Details Results Limitations Jayne, Dg, N=794 randomised (both Laparoscopic versus Randomisation and Outcome: Overall Cochrane risk of bias tool Thorpe, Hc, colon and rectal cancers) open surgery allocation concealment survival at 5 years Selection bias Copeland, J, of which N=381 were Randomisation was done (rectal cancer) Random sequence Quirke, P, Brown, rectal cancer patients; Anterior resection (rectal by telephone by the trial Laparoscopic 62.8% generation: unclear risk Jm, Guillou, Pj, n=253 rectal cancer cancer), n (%) coordinator. Randomisation Open 52.9% (Limited details reported.) Five-year follow- patients allocated to Laparoscopic 167 (66) was stratified by surgeon, p=0.247 Allocation up of the Medical laparoscopic surgery; proposed site of operation, concealment: unclear risk Research Council Open 79 (62) n=128 rectal cancer presence of liver (Limited details reported.) CLASICC trial of patients allocated to Abdominoperineal metastases, and Outcome: Quality of
laparoscopically open surgery resection, n (%) preoperative radiotherapy life - Overall sexual dysfunction at Performance bias assisted versus Laparoscopic 63 (25) administration. open surgery for median 3 years after Characteristics Open 34 (27) colorectal cancer, surgery among Blinding
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Outcomes and Study details Participants Interventions Methods Results Comments British Journal of Characteristics of the Surgery with curative No blinding. previously sexually Blinding of participants and Surgery, 97, total population (both intent (rectal cancer), n active men (IIEF; personnel: high risk (No 1638-1645, 2010 colon and rectal (%) Follow-up/outcomes rectal cancer only)* blinding.) cancers): Laparoscopic 7/15 Laparoscopic 233 (92) Follow-up visits were at 1 Ref Id Open 99 (77) and 3 months after Open 1/22 Detection bias 747887 Age in years, mean±SD Palliative surgery (rectal surgery, then every 3 Blinding of outcome Laparoscopic 69±11 cancer), n (%) months for the first year, Outcome: Quality of assessment: high risk (No Country/ies Open 69±12 Laparoscopic 11 (4) every 4 months for the life - A severe blinding. High risk of bias where the study Open 22 (17) second year, and every 6 change in overall for subjective outcomes months afterwards. level of sexual such as quality of life.) was carried out Female sex, n (%) Overall survival was function perceived in UK Laparoscopic 230 (44) calculated from the date of men (IIEF; rectal Attrition bias Open 123 (46) randomisation to the date of cancer only)** Incomplete outcome Study type death from any cause. Laparoscopic 23/56 data: low risk RCT (CLASICC BMI, mean±SD The International Prostate Open 6/26 trial) Laparoscopic 25±4 Symptom Score (I- Reporting bias Open 26±4 PSS), International Index of Outcome: Quality of Aim of the study Erectile Function (IIEF) Selective reporting: unclear life - Overall level of risk (Because this trial To evaluate the and Female Sexual sexual function Tumour site, n (%) Function Index (FSFI) were included patients with both technical and decreased ‘quite a Colon used as symptom-specific colon and rectal cancers, oncological safety lot’ or ‘severely’ as a Laparoscopic 273 (52) tools to assess bladder and not all outcomes were and efficacy of result of surgery in sexual function. A global reported by the site of the laparoscopically Open 140 (52) women (FSFI; rectal question tumour.) assisted surgery Rectum cancer only)** in comparison was added to each Laparoscopic 253 (48) Laparoscopic 8/29 with conventional questionnaire to investigate Other bias Open 128 (48) Open 3/17 open surgery for the effect of surgery on Other sources of bias: -
the treatment of sexual and bladder function pT stage, n (%) from the patient’s Outcome: Quality of colorectal cancer. Other information pT1 perspective. Quality of life life - Bladder function was measured with the None Study dates Laparoscopic 26 (6) (I-PSS; rectal cancer European Organization for Open 12 (5) only)** July 1996 to July Research and Treatment of 2002 pT2 "No differences in Cancer (EORTC) colorectal bladder function, Laparoscopic 68 (15) module QLQ-CR38 either in overall score
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Outcomes and Study details Participants Interventions Methods Results Comments Source of Open 35 (15) questionnaire, including 10 or in individual funding items relating to sexual and symptom scores, UK Medical pT3 bladder function, with were detected information being collected between the Research Council Laparoscopic 261 (56) prospectively before laparoscopic and Open 136 (56) operation, and 2 weeks open rectal resection (bladder function only), 3, 6 groups." pT4 and 18 months after Laparoscopic 70 (15) surgery. Outcome: Quality of Open 33 (14) life - Bladder function Missing Statistical analysis (QLQ-CR38; rectal cancer only)** Laparoscopic 33 (7) Differences in survival and recurrences between "No differences in Open 24 (10) groups were compared bladder function were using Kaplan–Meier curves detected at any time pN stage, n (%) and tested with log-rank point between the pN0 test. laparoscopic and Laparoscopic 244 (53) open rectal groups." Open 129 (54) Outcome: Local pN1 recurrence at 5 years (anterior resection for Laparoscopic 107 (23) rectal cancer only) Open 52 (22) Laparoscopic 9.4%
Open 7.6% pN2 p=0.740 Laparoscopic 72 (16)
Open 38 (16) Outcome: Length of Not investigated hospital stay in days Laparoscopic 4 (1) (rectal cancer), Open - median (IQR)*** Missing Laparoscopic 11 (9- Laparoscopic 35 (8) 15) Open 22 (9) Open 13 (9-18)
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Outcomes and Study details Participants Interventions Methods Results Comments
pM stage, n (%) Outcome: in-hospital pM0 mortality*** Laparoscopic 167 (36) Laparoscopic 17/585 Open 91 (38) Open: 27/823
pM1 Outcome: Wound infection (rectal Laparoscopic 12 (3) cancer)*** Open 7 (3) Laparoscopic 33/253
Open 15/125 Not investigated
Laparoscopic 229 (50) *Data extracted from Open 112 (46) Quah 2002. ** Data extracted Missing from Jayne 2005. Laparoscopic 54 (12) ***Data extracted Open 31 (13) from Guillou 2005.
Inclusion criteria Patients with cancer of the colon or rectum suitable for right hemicolectomy, left hemicolectomy, sigmoid colectomy, anterior resection, or abdominoperineal resection.
Exclusion criteria Adenocarcinoma of the transverse colon;
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Outcomes and Study details Participants Interventions Methods Results Comments contraindications to pneumoperitoneum (chronic cardiac or pulmonary disease); acute intestinal obstruction; malignant disease in the past 5 years; synchronous adenocarcinomas; pregnancy; associated gastrointestinal disease needing surgical intervention. Full citation Sample size Interventions Details Results Limitations Jayne D, Pigazzi N=471 randomised; Robotic versus Randomisation and Outcome: Female A, Marshall H, n=237 allocated to laparoscopic surgery allocation concealment sexual function at 6 Cochrane risk of bias tool Croft J, Corrigan robotic surgery; n=234 Type of resection, n (%) Randomisation was done months (FSFI) Selection bias N, Copeland J, allocated to laparoscopic Adjusted* difference High anterior resection with stratification for treating Random sequence Quirke P, West N, surgery in score Robotic 35 (15) surgeon, sex, preoperative generation: unclear Rautio T, Laparoscopic (n=29) Laparoscopic 34 (15) radiotherapy or risk (Details not reported.) Thomassen N, Characteristics Low anterior resection chemoradiotherapy, minus robotic (n=25) Tilney H, 1.23 (95% CI -3.54 to Allocation concealment: Age in years, mean±SD Robotic 159 (67) intended procedure, and Gudgeon M, 6.00), p=0.60 unclear risk (Details not Robotic 64.4±11 Laparoscopic 158 (68) BMI. No other details Bianchi PP, Edlin reported.) Laparoscopic 65.5±12 Abdominoperineal reported. Outcome: Male R, Hulme C, resection sexual function at 6 Male sex, n (%) Brown J. Effect of Robotic 43 (18) months (IIEF) Performance bias Robotic 161 (68) Blinding Robotic-Assisted Laparoscopic 42 (18) Adjusted* difference Blinding of participants and Laparoscopic 159 (68) No blinding. vs Conventional Preoperative in score personnel: high risk (No BMI ≥30, n (%) Laparoscopic radiotherapy or Laparoscopic (n=84) blinding.) Robotic 54 (23) Surgery on Risk chemoradiotherapy Follow-up/outcomes minus robotic (n=97) of Conversion to Laparoscopic 55 (24) Robotic 111 (47) Primary endpoint of the trial 0.80 (95% CI -4.10 to Detection bias Open Laparotomy Pathological T stage, n was conversion to open 5.70), p=0.75 Laparoscopic 108 (46) Blinding of outcome Among Patients (%) resection. Secondary Outcome: Bladder assessment: high risk (No Undergoing pT0 endpoints included for function at 6 months blinding.) Resection for Robotic 22 (9) example: CRM+ (defined as (IPSS)
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Outcomes and Study details Participants Interventions Methods Results Comments Rectal Cancer: Laparoscopic 24 (10) tumour ≤1 mm), Adjusted* difference The ROLARR pT1 intraoperative and in score Attrition bias Randomized Robotic 24 (10) postoperative Laparoscopic Incomplete outcome data: Clinical Trial. Laparoscopic 20 (9) complications, (n=176) minus low risk JAMA 318(16), pT2 postoperative 30-day robotic (n=175) 0.743 1569-1580, 2017 Robotic 64 (27) mortality, and patient- (95% CI -0.59 to Laparoscopic 61 (27) reported sexual and bladder 2.07), p=0.27 Reporting bias Ref Id pT3 function at baseline and at Outcome: Positive Selective reporting: low risk Robotic 117 (50) 6 months. Female sexual 839317 CRM Laparoscopic 114 (50) function was self-assessed Robotic 12/235 Other bias pT4 by the patients using Laparoscopic 14/224 Country/ies Other sources of bias: - Robotic 5 (2) Female Sexual Function Outcome: Positive where the study Laparoscopic 8 (4) Index (FSFI), with scores proximal resection was carried out Other information Tx or missing ranging from 2 to 36 and margin UK, Italy, Robotic 4 (2) higher score indicating Robotic 0/235 None Denmark, US, Laparoscopic 3 (1) better functioning. Male Laparoscopic 0/224 Finland, South sexual function was self- Pathological N stage, n Outcome: Positive Korea, Germany, assessed by the patients (%) distal resection France, Australia using International Index of pN0 margin and Singapore Erectile Function (IIEF), Robotic 146 (62) Robotic 0/235 with scores ranging from 5 Study type Laparoscopic 150 (65) Laparoscopic 1/224 pN1 to 75 and higher scores RCT (ROLARR Outcome: Length of Robotic 63 (27) meaning better functioning. trial) hospital stay Laparoscopic 58 (25) Bladder function was self- (mean±SD days) pN2 assessed by the patients Robotic 8.0±5.85 Aim of the study Robotic 25 (11) using International Prostate (n=237) To compare Laparoscopic 21 (9) Symptom Score (IPSS), Laparoscopic robotic-assisted Missing with scores ranging from 0 8.2±6.03 (n=234) versus Robotic 2 (1) to 35, higher score conventional Laparoscopic 1 (0.4) indicating worse symptoms. Outcome: 30-day laparoscopic operative mortality
surgery for risk of Robotic 2/236 Statistical analysis conversion to Inclusion criteria Laparoscopic 2/230 Intention-to-treat analysis open laparotomy Age ≥18 years; able to Outcome: was done. among patients provide written informed Anastomotic leak undergoing consent; diagnosis of (within 6 months)
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Outcomes and Study details Participants Interventions Methods Results Comments resection for rectal cancer amenable Robotic 22/180 rectal cancer. to curative surgery either Laparoscopic 18/181 by low anterior resection, Outcome: Surgical Study dates high anterior resection, site infection (within or abdominoperineal January 7th 2011 30 days) resection i.e. staged T1- to September Robotic 21/236 3, N0-2, M0 by imaging 30th 2014 Laparoscopic 19/230 as per local practice; Outcome: Surgical rectal cancer suitable for site infection Source of resection by either (between 30 days funding standard or robotic- and 6 months) Efficacy and assisted laparoscopic Robotic 4/236 Mechanism procedure; fit for robotic- Laparoscopic 8/230 Evaluation assisted or standard *Adjusted for Programme, a laparoscopic rectal baseline scores and partnership resection; ASA physical stratification factors between Medical status classification less (surgeon, sex, Research Council than or equal to 3; preoperative therapy, and National capable of completing intended procedure Institute for Health required questionnaires and BMI) Research with at time of consent.
contributions from
the Chief Scientist Exclusion criteria Office in Scotland, Benign lesions of the the National rectum; benign or Institute of Social malignant diseases of Care and Health the anal canal; locally Research in advanced cancers not Wales, and the amenable to curative Health and Social surgery; locally Care Research advanced cancers and Development requiring en bloc multi- Division, Public visceral resection; Health Agency in synchronous colorectal Northern Ireland; tumours requiring multi- National Institute
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Outcomes and Study details Participants Interventions Methods Results Comments for Health segment surgical Research; resection; co-existent Yorkshire Cancer inflammatory bowel Research; the disease; clinical or Medical Research radiological evidence of Council metastatic spread; Bioinformation concurrent or previous Initiative. diagnosis of invasive cancer within 5 years that could confuse diagnosis; history of psychiatric or addictive disorder or other medical condition that, in the opinion of the investigator, would preclude the patient from meeting the trial requirements; pregnancy; participation in another rectal cancer clinical trial relating to surgical technique Full citation Sample size Interventions Details Results Limitations Jeong, S. Y., N=340 randomised; Laparoscopic surgery Randomisation and Outcome: Overall Cochrane risk of bias tool Park, J. W., Nam, n=170 allocated versus open surgery allocation concealment survival (median 4 Selection bias B. H., Kim, S., to laparoscopic surgery; Computer-generated years of follow-up; Random sequence Kang, S. B., Lim, n=170 allocated to open Type of surgery, n (%) randomisation list was event is death from generation: low risk S. B., Choi, H. S., any cause) surgery Abdominoperineal generated through Centre Allocation concealment: low Kim, D. W., resection for Clinical Trials with a Laparoscopic N=170, risk Chang, H. J., Kim, random permuted block 20 events Characteristics Laparoscopic 19 (11) D. Y., Jung, K. H., design, 1:1 ratio, Open N=170, 25 Age in years, mean±SD Open 24 (14) Performance bias Kim, T. Y., Kang, randomisation stratified by events G. H., Chie, E. K., Laparoscopic 57.8 (11.1) Low anterior resection Blinding of participants and sex and preoperative HR 0.8 95% CI 0.44 Kim, S. Y., Sohn, Open 59.1 (9.9) personnel: high risk Laparoscopic 151 (89) chemotherapy regimen. to 1.45*
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Outcomes and Study details Participants Interventions Methods Results Comments D. K., Kim, D. H., Open 146 (86) Randomisation was done at (Patients and clinicians not Kim, J. S., Lee, H. Male sex, n (%) the coordinating centre via Outcome: Positive blinded.) S., Kim, J. H., Oh, Laparoscopic 110 (65) Laparoscopic surgery telephone. CRM (<1 mm) J. H., Open was done with 5 ports. Laparoscopic 5/170 Detection bias versus Open 110 (65) Blinding Blinding of outcome laparoscopic Open 7/170 Patients and clinicians not assessment: low/high risk surgery for mid- BMI >25, n (%) Surgeries were done 6– blinded. During follow-up, (Patients and clinicians not rectal or low-rectal 8 weeks after Outcome: Local Laparoscopic 63 (37) radiologists and blinded but at follow- cancer after completion of recurrence (median 4 Open 64 (38) pathologists were blinded. up radiologists and neoadjuvant preoperative years of follow-up; pathologists were blinded. chemoradiotherap chemoradiotherapy. event is local High risk on subjective y (COREAN trial): Tumour distance from Radiotherapy was Follow-up/outcomes recurrence) outcomes if no blinding Survival outcomes anal verge, n (%) delivered to the whole Patients were followed- Laparoscopic N=170, done.) of an open-label, 0-3 cm pelvis at a dose of 45 Gy up every 3 months for the 2 events
non-inferiority, Laparoscopic 35 (21) in 25 fractions, followed first 2 years, every 6 Open N=170, 4 Attrition bias randomised Open 46 (27) by a boost to the primary months for the next 3 years, events controlled trial, tumour of 5.4 Gy in and every 6 months or Incomplete outcome data: 3-6 cm HR 0.40 95% CI 0.13 The Lancet three fractions during yearly thereafter. For the low risk (Intention-to-treat Laparoscopic 66 (39) to 1.30* Oncology, 15, 5.5 weeks. postoperative follow-up, analysis done.) Open 59 (35) 767-774, 2014 a physical examination, 6-9 cm Outcome: Length of Type of preoperative complete blood-cell count, Reporting bias Laparoscopic 69 (41) liver function tests, hospital stay in days, Ref Id chemotherapy, n (%) Selective reporting: low risk Open 65 (38) serum CEA tests, and chest median (IQR)** 747902 Fluoropyrimidines alone radiography were done Laparoscopic 8 (7- Laparoscopic 156 (92) every 3 months or 12) Other bias Clinical classification, n Country/ies Open 156 (92) 6 months; abdominal and Open 9 (8-12) Other sources of bias: - where the study (%) Capecitabine and pelvic computer p=0.056 was carried out cN0 irinotecan tomography were done Other information South Korea Laparoscopic 59 (35) Laparoscopic 3 (2) every 6 months. Outcome: 90-day None Open 52 (31) Open 1 (1) Colonoscopic examinations were done 1 year mortality** Study type cN+ Capecitabine, irinotecan, postoperatively and once Laparoscopic 0/170 RCT (COREAN Laparoscopic 111 (65) and cetuximab every 2 years thereafter. Open 0/170 trial) Open 118 (69) Laparoscopic 11 (6) The primary outcome was Open 13 (8) disease-free survival (not of Outcome: Aim of the study interest to this Anastomotic leak**
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Outcomes and Study details Participants Interventions Methods Results Comments To compare Inclusion criteria Postoperative adjuvant review). Secondary Laparoscopic 2/170 survival outcomes Mid-rectal or low-rectal chemotherapy was outcomes were overall Open 0/170 of laparoscopic cancer; cT3N0- recommended for all survival, local recurrence, surgery with open patients, irrespective of and quality of life. 2M0; previous Outcome: Blood loss surgery for the surgical pathology Local recurrence was preoperative in ml, median (IQR)** patients with mid- chemoradiotherapy; 18– results. defined as any recurrence Laparoscopic 200.0 rectal low-rectal 80 years of age within the pelvic cavity or (100.0-300.0) cancer. the perineum. Overall survival was defined as Open 217.5 (150.0- Exclusion criteria 400.0) Study dates time from surgery to death Synchronous distant from any cause. p=0.006 April 4 2006 to metastases, another A validated Korean version August 26 2009 primary malignancy, of the European cardiopulmonary *The HR reported in Organization for Research the paper was Source of dysfunction, active and Treatment of Cancer inverted in order to funding uncontrolled infection, Quality-of-Life have open surgery as National Cancer active uncontrolled psychosis, and intestinal Questionnaire (EORTC the reference. Center, (South QLQ)–C30 questionnaire perforation or **Data extracted from Korea) (version 3.0) and the obstruction. Kang 2010. colorectal cancer module QLQ–CR38 to assess quality of life preoperatively and at months 3, 12, 24, and 36 after surgery.
Statistical methods All analysis based on intention-to-treat population. Kaplan-Meier method with log-rank test to assess difference between groups. Full citation Sample size Interventions Details Results Limitations Kang, S. B., Park, See Jeong 2014 J. W., Jeong, S. (COREAN trial). Other information Y., Nam, B. H.,
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Outcomes and Study details Participants Interventions Methods Results Comments Choi, H. S., Kim, D. W., Lim, S. B., Characteristics Lee, T. G., Kim, D. Y., Kim, J. S., Chang, H. J., Lee, Inclusion criteria H. S., Kim, S. Y., Jung, K. H., Hong, Exclusion criteria Y. S., Kim, J. H., Sohn, D. K., Kim, D. H., Oh, J. H., Open versus laparoscopic surgery for mid or low rectal cancer after neoadjuvant chemoradiotherap y (COREAN trial): Short-term outcomes of an open-label randomised controlled trial, The Lancet Oncology, 11, 637-645, 2010 Ref Id 748017 Country/ies where the study was carried out Study type
Aim of the study
Study dates
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Outcomes and Study details Participants Interventions Methods Results Comments
Source of funding Full citation Sample size Interventions Details Results Limitations Kim, J., Baek, S. N=224 robotic TME; Robotic versus Randomisation and Outcome: Overall ROBINS-I checklist for non- J., Kang, D. W., N=224 laparoscopic laparoscopic TME allocation concealment survival at 5 years randomised studies of Roh, Y. E., Lee, J. TME (groups matched This was not a randomised Stages I-III Interventions W., Kwak, H. D., by sex, age, BMI, All robotic TME study but a retrospective Robotic 90.5% Pre-intervention Kwak, J. M., Kim, comorbidity, ASA score, procedures were observational study. Laparoscopic 78.0% Bias due to confounding: S. H., Robotic tumour height from the Matching of groups were performed by a single p=0.323 Moderate risk of bias (This Resection is a anal verge, tumour docking totally robotic done based on: is a Stage II Good Prognostic location, preoperative technique using the da retrospective observational Factor in Rectal chemoradiotherapy, and Robotic 91.2% Vinci Surgical System. Blinding study. Groups were Cancer Compared TNM stage) Laparoscopic 87.0% matched.) with Laparoscopic Not applicable. p=0.896 Bias in selection of Resection: Long- Type of resection, n (%) Characteristics Stage III participants into the study: term Survival Anterior resection Follow-up/outcomes Matched group Robotic 83.1% Low risk of bias Analysis Using Robotic 2 (1) For those who underwent Characteristics: Propensity Score Laparoscopic 7 (3) chemotherapy, laboratory Laparoscopic 64.2% At intervention Matching, Lower anterior resection tests including CEA and p=0.526 Diseases of the Age in years, mean±SD Bias in classification of Robotic 169 (75) abdominopelvic computer Colon & Rectum, Robotic 60.7±11.7 tomography scan were Interventions: Low risk of Laparoscopic 168 (75) 60, 266-273, 2017 Laparoscopic 61.0±11.0 performed at 3- to 4-cycle bias Intersphincteric intervals during resection Ref Id Male sex, n (%) chemotherapy. Other Post-intervention Robotic 41 (18) examinations such as chest 748152 Robotic 145 (65) Bias due to deviations from Laparoscopic 35 (16) CT, sigmoidoscopy or total Laparoscopic 141 (63) intended Interventions: Low Abdominoperineal colonoscopy, and positron risk of bias Country/ies emission tomography and resection Bias due to missing data: where the study BMI, mean±SD CT were added when was carried out Robotic 12 (5) Low risk of bias Robotic 23.3±3.0 necessary. After South Korea Laparoscopic 14 (6) Bias in measurement of Laparoscopic 23.4 (3.3) chemotherapy, follow-up examinations were outcomes: Low risk of bias
Study type Preoperative concurrent performed at 3-month chemoradiotherapy was intervals in the first 2 years,
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Outcomes and Study details Participants Interventions Methods Results Comments Retrospective coh Tumour location from the given selectively based at 6-month intervals until 5 Bias in selection of the ort study anal verge, n (%) on the following years, and annually reported result: Low risk of Lower indications: T4; CRM thereafter, unless there was bias Aim of the study Robotic 128 (57) positive or threatened; evidence of recurrence. or suggestive metastasis To evaluate long Laparoscopic 136 (61) Other information of lateral pelvic lymph Statistical analysis term oncologic Middle node, defined as a None Propensity score matching outcomes of Robotic 88 (39) lymph node beyond the was conducted to reduce robotic TME TME plane such as the Laparoscopic 78 (35) the bias due to non- compared with iliac and obturator lymph Upper randomization of patients, laparoscopic nodes, on preoperative Robotic 8 (4) based on: sex, age, BMI, TME. staging. Laparoscopic 10 (5) comorbidity, ASA score,
Study dates tumour height, tumour Preoperative location, preoperative Pathologic TNM stage, n April 2007 to chemoradiotherapy, n concurrent (%) March 2014 (%) chemoradiotherapy, and I Robotic 50 (22) TNM stage. Source of Robotic 62 (28) Laparoscopic 50 (22) Survival was analysed funding Laparoscopic 63 (28) using the Kaplan-Meier National II The indications for method, and comparison of Research Robotic 59 (26) postoperative the survival between the Foundation of Laparoscopic 54 (24) radiotherapy were: T4; groups was performed by Korea; the the paired Prentice- III CRM or distal resection Ministry of Wilcoxon test. Robotic 75 (34) margin positive (CRM <2 Science, ICT, and mm, distal resection Laparoscopic 75 (34) Future Planning margin <5 mm); or (Republic of IV lateral pelvic lymph Korea) Robotic 28 (13) nodes suspicious on Laparoscopic 32 (14) preoperative diagnostic images but not receiving Inclusion criteria preoperative radiotherapy. Primary rectal cancer with pathologically proven adenocarcinoma
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Outcomes and Study details Participants Interventions Methods Results Comments within 15 cm of the anal verge; underwent minimally invasive surgery for rectal cancer.
Exclusion criteria Patients with pathological stage IV cancer excluded from survival analysis. Full citation Sample size Interventions Details Results Limitations Kim, J. C., Yu, C. N=2,114 consecutive Robotic versus open Randomisation and Outcome: Overall ROBINS-I checklist for non- S., Lim, S. B., rectal cancer patients; surgery allocation concealment survival at 3 years randomised studies of Park, I. J., Kim, C. n=533 patients This was not a randomised Robotic 94.6% Interventions W., Yoon, Y. S., underwent robotic All procedures included study. Consecutive rectal Open 91.9% Pre-intervention Comparative surgery; n=1,095 open TME with at least cancer patients were p=0.352 Bias due to analysis focusing surgery (n=486 provided with full unilateral pelvic confounding: Serious risk of on surgical and laparoscopic surgery, not autonomic nerve information on the three bias (This is a non- Outcome: Sexual early oncological considered for this preservation. procedures (open, randomised study. dysfunction in men outcomes of review because almost laparoscopic, and robotic The outcomes of interest <=65 years of age open, half of the population in approaches) and chose were not controlled for Type of surgery, n (%) (total; VAS; scale 0- laparoscopy- this intervention group one. potential confounding and Anterior resection 5; 2-3 indicating assisted, and with stage 0 or I cancer) case-mix in the analysis.) robot-assisted Robotic 4 (1) moderate Blinding Bias in selection of approaches in dysfunction; 4-5 Characteristics Open 33 (3) participants into the study: rectal cancer No blinding. indicating severe Age in years, mean±SD Lower anterior resection Low risk of bias patients, dysfunction) Robotic 503 (94) International Robotic 55±9 Follow-up/outcomes Robotic 27/141 Open 942 (86) Journal of Open 59±9 Follow-up examinations Open 108/332 At intervention Abdominoperineal Colorectal were done every 6 months Bias in classification of Disease, 31, resection Interventions: Low risk of Male sex, n (%) for the first 3 years and Outcome: Severe 1179-1187, 2016 Robotic 26 (5) bias Robotic 333 (63) annually thereafter until five sexual dysfunction in Ref Id Open 700 (64) Open 120 (11) postoperative men <=65 years of years. Recurrence was 748163 age (VAS 4-5) Post-intervention confirmed either by imaging
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Outcomes and Study details Participants Interventions Methods Results Comments Country/ies BMI, mean±SD Preoperative studies or histologic Robotic 13/141 Bias due to deviations from where the study Robotic 24.1±3 chemoradiotherapy was examinations. Male sexual Open 37/332 intended Interventions: Low was carried out Open 23.8±3 principally indicated for dysfunction was assessed risk of bias patients with clinical at two postoperative years South Korea Outcome: Moderate Bias due to missing data: stage III or T4 cancers in ≤65 years old men by Study type sexual dysfunction in Low risk of bias Tumour distance from but was ultimately evaluating Prospective men <=65 years of Bias in measurement of the anal verge, n (%) determined by the both erectile firmness and cohort study age (VAS 2-3) outcomes: Moderate risk of Lower surgeon. Postoperative ejaculatory frequency using Robotic 14/141 bias (The clinicians were Robotic 258 (49) chemoradiotherapy was a visual analogue scale not blinded to the Aim of the study (VAS): 0-1 indicating none– Open 71/332 Open 429 (39) administered in intervention, therefore, mild dysfunction, 2-3 To compare open, Middle pathologic stage III subjective outcomes might laparoscopic, and patients without indicating moderate Robotic 229 (43) Outcome: Positive be biased.) robotic TME for preoperative dysfunction, and 4-5 CRM (<=1 mm) Bias in selection of the rectal cancer in Open 554 (51) chemoradiotherapy. Pati indicating severe Robotic 8/533 reported result: Low risk of terms of Upper ents with preoperative or dysfunction. Open 26/1,095 bias sphincter-saving Robotic 45 (9) postoperative
operation Open 112 (10) chemoradiotherapy Statistical analysis received a total of 45– Outcome: Positive Other information achievement, Survival outcomes and 50.4 Gy with fluorouracil distal resection surgical recurrences were compared None cStage (AJCC) + leucovorin or margin (<=5 mm) complications, using the Kaplan-Meier 0 capecitabine. and early method with the log-rank Robotic 5/533 Robotic 10 (2) oncological test. Multivariate analysis Open 13/1,095 outcomes. Open 112 (10) Preoperative was not done for the
I chemoradiotherapy, n outcomes of interest. Study dates Robotic 137 (26) (%) July 2010 to Open 164 (15) Robotic 172 (32) February 2015 II Laparoscopic 61 (13) Robotic 101 (19) Open 553 (51) Source of Open 197 (18) funding III Korea Research Robotic 285 (54) Foundation; Minist ry of Science, Open 721 (66) ICT, and Future Planning; the Inclusion criteria
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Outcomes and Study details Participants Interventions Methods Results Comments Korea Health 21 Curatively resected R&D adenocarcinoma of the Project; Ministry rectum (≤stage III); an of Health,Welfare, Eastern Cooperative and Family Affairs Oncology Group (Republic of performance status of 0– Korea). 3; age ≤75 years.
Exclusion criteria Previous history of any cancer; hereditary colorectal cancer; inflammatory bowel disease. Full citation Sample size Interventions Details Results Limitations Kim, M. J., Park, N=163 randomised; Robot-assisted surgery Randomisation and Outcome: Quality of Cochrane risk of bias tool S. C., Park, J. W., n=82 allocated to robot- versus laparoscopic allocation concealment life global health Selection bias Chang, H. J., Kim, assisted surgery but surgery Randomisation was status score at Random sequence D. Y., Nam, B. H., n=16 dropped before computer-generated, and baseline, at 3 weeks, generation: low risk Sohn, D. K., Oh, 3 months and 12 allocated surgery, in the Robotic surgery was allocation was Allocation concealment: low J. H., Robot- months after surgery end n=66 included in performed with the da communicated via risk assisted Versus analysis; Vinci Surgical System. telephone by the trial (QLQ-C30) Laparoscopic n=81 allocated to coordinator at the Clinical No difference Surgery for Rectal Trials Research office at the between the two Performance bias laparoscopic surgery but All study participants Cancer: A Phase National Cancer Center. groups. (Reported Blinding of participants and 8 dropped before underwent TME and II Open Label Randomisation was narratively and in a personnel: high risk (No allocated surgery, in the pelvic autonomic nerve Prospective stratified according to sex figure, no mean blinding.) end n=73 included in preservation, and the Randomized analysis and preoperative scores presented.) Controlled Trial, operative extent was the chemoradiotherapy adminis Detection bias Annals of same for both groups. tration using a block Outcome: Quality of Blinding of outcome Surgery., 25, Characteristics permutation approach. life - sexual function assessment: low/high risk 2017 Age in years, mean±SD Surgical approach, n (%) subscale mean score (Pathologist was blinded Robotic 60.4 (9.7) Low anterior resection Blinding at 12 months after but participants were not. Ref Id Laparoscopic 59.7 (11.7) with double stapling surgery (QLQ-CR38) anastomosis
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Outcomes and Study details Participants Interventions Methods Results Comments 748185 Robotic 40 (61) No blinding of patients. (scale 0 to 100, High risk of bias for Male sex, n (%) Laparoscopic 48 (66) Pathologists examining the higher indicating subjective outcomes.) Country/ies Robotic 51 (77) Low anterior resection macroscopic quality of the better) TME were blinded to Robotic 35.2 (95% CI where the study Laparoscopic 52 (71) with hand-sewn Attrition bias allocation. 26.9 to 43.5) SD 33.8 was carried out anastomosis Incomplete outcome South Korea Robotic 25 (38) (n=66) data: unclear risk (Per BMI, mean±SD Laparoscopic 23.0 Laparoscopic 22 (30) Follow-up/outcomes protocol analysis done. Robotic 24.1 (3.3) (95% CI 15.7 to 30.2) Study type Abdominoperineal The primary outcome of the 16/82 and 8/81 not included Laparoscopic 23.6 (3.0) trial was completeness of SD 31.1 (n=73) in analysis for robotic and RCT resection TME. Secondary outcomes laparoscopic groups, Robotic 1 (1.5) Tumour location from the included for example Outcome: Positive respectively. Reasons for Aim of the study anal verge, n (%) Laparoscopic 2 (2.7) resection margins, morbidity CRM (<=1 mm) these were reported (main To compare the <=5 cm Hartmann operation and quality of life. Robotic 4/66 reasons: participants refused the allocated outcomes of Robotic 33 (50) Robotic 0 (0) Quality of life was evaluated Laparoscopic 4/73 robotic surgery Laparoscopic 1 (1.4) before surgery and 3 surgery, or distant Laparoscopic 35 (48) metastasis was detected). with those of weeks, 3 months, and 12 laparoscopic >5 cm Outcome: Length of Preoperative months after surgery using surgery in patients Robotic 33 (50) hospital stay in days, chemoradiotherapy the validated Korean Reporting bias with rectal cancer. Laparoscopic 38 (52) mean±SD received, n (%) version of the EORTC QLQ- Selective reporting: low risk C30 questionnaire (version Robotic 10.3±3.4 Robotic 51 (77) (n=66) Study dates 3.0) and the colorectal Laparoscopic 58 (80) cancer module QLQ-CR38. Laparoscopic Other bias February 21 2012 Scale was 0 to 100, higher 10.8±7.4 (n=73) Other sources of bias: - to March 11 2015 Inclusion criteria score indication better People with mid- or low- quality of life for global Outcome: Other information Source of lying (within 9 cm from health status and Anastomotic leak None funding the anal verge) functioning scores. Robotic 8/66 National Cancer rectal adenocarcinoma w ithout distant Laparoscopic 5/73 Center (Republic Statistical analysis of Korea) metastasis. Per protocol analysis was Outcome: Blood loss done. Exclusion criteria in ml, median (range) Cancer invading Robotic 100 (0- adjacent organs (T4), 1,000) (n=66) distant metastasis (M1),
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Outcomes and Study details Participants Interventions Methods Results Comments severe concomitant Laparoscopic 50 (0- disease that might limit 300) (n=73) compliance or completion of the protocol, any other malignancy, pregnant or breastfeeding females, hereditary colorectal cancer, and emergency operation. Full citation Sample size Interventions Details Results Limitations Law, W. L., Foo, N=220 robotic surgery; Robotic versus Randomisation and Outcome: Overall ROBINS-I checklist for non- D. C. C., N=171 laparoscopic laparoscopic surgery allocation concealment survival at 5 years randomised studies of Comparison of surgery For robotic surgeries, This was not a randomised Robotic 71.8% Interventions short-term and the Da Vinci surgical study. The groups were not Laparoscopic 74.3% Pre-intervention oncologic Characteristics robotic system was matched. p=0.423 Bias due to outcomes of Age in years, median used. The majority of confounding: Serious risk of robotic and (range) robotic surgeries were Blinding bias (This is a non- laparoscopic performed with the Robotic 65 (34-90) No blinding. randomised, resection for mid- hybrid technique with left observational study, the Laparoscopic 67 (23-96) and distal rectal colon mobilisation and groups were not matched cancer, Surgical division of the inferior Follow-up/outcomes by any characteristic. The Endoscopy and Male sex, n/n mesenteric vessels The patients were followed study did not control for Other Robotic 148/220 using the conventional up at intervals of 2–3 potential confounding or Interventional Laparoscopic 97/171 laparoscopic technique. months during the first 2 case-mix in the analysis.) Techniques, 31, years and every 4–6 Bias in selection of 2798-2807, 2017 Type of surgery, n (%) months from 3 to 5 years participants into the study: BMI, mean and annually thereafter. Lower anterior resection Low risk of bias Robotic 24.9 The visits included: history, Ref Id Laparoscopic 24.6 Robotic 206 (94) physical examination, blood 748501 At intervention Laparoscopic 152 (88) tests and serum CEA level. Bias in classification of Tumour distance from Abdominoperineal A digital rectal examination Country/ies Interventions: Low risk of the anal verge in cm, resection was performed at each visit where the study bias median (range) Robotic 11 (5) to detect any anastomotic was carried out stricture or local recurrence. Robotic 7.0 (0-12) Laparoscopic 14 (8)
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Outcomes and Study details Participants Interventions Methods Results Comments Hong Kong Laparoscopic 8.0 (0-12) Hartmann Colonoscopy was Post-intervention Robotic 3 (1.4) performed regularly for the Bias due to deviations from Study type Laparoscopic 5 (3) detection of metachronous intended Interventions: Low lesions. If recurrences were risk of bias Retrospective suspected, endoscopic Bias due to missing data: cohort study Inclusion criteria Neoadjuvant examination, CT scan or Low risk of bias People with rectal cancer chemoradiation was other imaging studies Aim of the study within 12 cm from the offered to patients when were performed to Bias in measurement of outcomes: Low risk of bias To compare the anal verge and the mesorectal margin determine whether salvage short-term underwent elective was at risk (<1 mm by surgery could be Bias in selection of the operative as well radical resection. MRI) and to those with performed. reported result: Low risk of as oncologic findings of poor Data, including survival bias prognosis with distal outcomes of Exclusion criteria data, were prospectively laparoscopic and cancer destined for collected in a database for Other information People who underwent abdominoperineal robotic rectal open resection. rectal cancer. None resection. resection or low anterior resection with hand-
sewn coloanal Statistical analysis Study dates anastomosis. Survival was analysed January 2008 to using the Kaplan–Meier June 2015 method, and the groups Preoperative were compared with the radiotherapy, n (%) log-rank test. No matching Source of Robotic 91 (41) funding or adjusting was done. Laparoscopic 50 (29) None reported.
An enhanced recovery care program was adopted for patients following surgery for rectal cancer during the study period. Full citation Sample size Interventions Details Results Limitations Liang, X., Hou, S., N=343 randomised; Laparoscopic surgery Randomisation and Outcome: Overall Cochrane risk of bias tool Liu, H., Li, Y., versus open surgery allocation concealment survival at 3 years Selection bias Jiang, B., Bai, W.,
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Outcomes and Study details Participants Interventions Methods Results Comments Li, G., Wang, W., n=169 allocated to Randomisation was done Laparoscopic 76.0% Random sequence Feng, Y., Guo, J., laparoscopic surgery, 2 Surgical approach, n/n on the day before surgery Open 82.8% generation: unclear risk (No Effectiveness and people lost to follow-up Abdominoperineal through sealed opaque p=0.462 sufficient detail provided.) safety of and n=167 included in envelopes. resection Allocation concealment: low laparoscopic analysis; n=174 risk resection versus Laparoscopic 83/169 Outcome: 30-day allocated to open Blinding open surgery in surgery, 2 people lost to Open 70/174 mortality Short-term complications Performance bias patients with follow-up and n=172 Lower anterior resection Laparoscopic 0/169 were reviewed by a single rectal cancer: a included in analysis. Laparoscopic 86/169 Open 0/174 Blinding of participants and person blinded to treatment personnel: high risk (No randomized, Open 104/174 controlled trial allocation. Otherwise no blinding.) Characteristics Outcome: from China, J blinding. Age in years, mean±SD No one received Anastomotic leak Laparoendosc Detection bias Adv Surg Tech A, Laparoscopic 57.3±14.1 preoperative Follow-up/outcomes Laparoscopic 4/169 (chemo)radiotherapy (in Blinding of outcome 21, 381-5, 2011 Open 57.4±13.1 Patients were assessed for Open 6/174 fact that was an assessment: high risk (No complications at the time of exclusion reason). blinding.) Ref Id Male sex, n/n hospital discharge by a Outcome: Wound single reviewer blinded to infection 809748 Laparoscopic 104/169 Attrition bias the treatment assignments. Laparoscopic 9/169 Open 92/174 Incomplete outcome Follow-up visits were at 1 Open 8/174 Country/ies and 3 months after surgery, data: low risk (2 patients in
where the study BMI, mean (assumed to every 3 months for the first each group lost to follow-up was carried out be mean, not reported) 2 years and every 6 months Outcome: Blood and not included in survival China Laparoscopic 21.45 thereafter. The visits transfusion analysis.) Open 22.31 included physical Laparoscopic 4/169 Study type examination, abdominal Open 8/174 Reporting bias and pelvic part RCT TNM stage, n/n Selective reporting: low risk ultrasonography, chest T1-2N0M0 radiography, examination of Aim of the study Laparoscopic 9/169 alimentary tract tumour Other bias To assess Open 7/174 markers and Other sources of bias: - efficacy and T3-4N0M0 colonofiberscope safety of Laparoscopic 72/169 examination. Recurrence Other information laparoscopic was confirmed by imaging None surgery for Open 84/174 or pathological examination. TxN1-2M0
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Outcomes and Study details Participants Interventions Methods Results Comments treatment of rectal Laparoscopic 88/169 Statistical analysis cancer. Open 83/174 For survival, Kaplan-Meier method was used and log- Study dates rank test was used to compare the interventions. May 2005 to April 2008 Inclusion criteria Rectal cancer Source of diagnosed by pathologic funding examination; written None reported. informed consent.
Exclusion criteria Liver or lung metastases assessed by computer tomography, magnetic resonance imaging or ultrasonography; BMI of >30 kg/m²; acute intestinal obstruction; serious infection; previous abdominal surgery; patients who had received neoadjuvant therapy.
Full citation Sample size Interventions Details Results Limitations Lujan, J., Valero, N=204 randomised; Laparoscopic versus Randomisation and Outcome: Overall Cochrane risk of bias tool G., Hernandez, n=101 allocated to open surgery allocation concealment survival at 5 years Selection bias Q., Sanchez, A., laparoscopic surgery but Randomisation was Laparoscopic 72.1% Random sequence Frutos, M. D., n=97 included in All patients underwent computer-generated with (95% CI 54.1% to generation: low risk Parrilla, P., analysis (2 excluded due TME with preservation the surgical approach 90.1% Allocation concealment: low Randomized to postoperative deaths of the hypogastric concealed in a sealed Open 75.3% (95% CI risk clinical trial and 2 excluded because nerves. 63.3% to 87.3%) comparing
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Outcomes and Study details Participants Interventions Methods Results Comments laparoscopic and of tumour persistence); envelope until the day of p=0.980 Performance bias open surgery in n=103 allocated to open The laparoscopic operation. Blinding of participants and patients with surgery but n=96 surgery was performed Outcome: CRM personnel: high risk (No rectal cancer, included in analysis (3 with 4 or sometimes 5 Blinding involved (not defined) blinding.) British Journal of excluded due to ports. No blinding. Surgery, 96, 982- postoperative deaths Laparoscopic 4/101
989, 2009 and 4 excluded because Open 3/103 Detection bias Surgical approach, n (%) of tumour persistence) Follow-up/outcomes Blinding of outcome Anterior resection assessment: low/high risk Ref Id Postoperative complications Outcome: Distal Laparoscopic 77 (76) were regarded as those (No blinding. High risk of 748829 Characteristics margin involved (not Open 81 (79) occurring during admission defined) bias for subjective Age in years, mean±SD outcomes.) Abdominoperineal or up to 30 days after Laparoscopic 0/101 Country/ies Laparoscopic 67.8 (12.9) surgery. All patients were resection Open 0/103 where the study Open 66.0 (9.9) followed up as outpatients Attrition bias was carried out Laparoscopic 24 (24) every 3 months for the first Incomplete outcome data: Open 22 (21) Outcome: Local Spain Male sex, n/n 2 years and every 6 months low risk (Intention-to-treat recurrence at 5 years Laparoscopic 64/103 thereafter. On each visit the analysis done for most Neoadjuvant therapy, n participants had a physical Laparoscopic 4.8% Study type Open 62/101 outcomes, for survival (%) examination, general blood (95% CI 0% to outcomes per-protocol RCT Laparoscopic 73 (72) tests and determination of 11.5%) analysis done.) Tumour location from the Open 77 (75) the CEA level. Every 6 Open 5.3% (0% to Aim of the study anal verge in cm, months they alternated 11.2%) Reporting bias To compare mean±SD between thoracic and p=0.781 surgical outcomes Laparoscopic 5.49 (3.04) abdominal computer Selective reporting: low risk
after laparoscopic tomography or abdominal Open 6.24 (2.91) Outcome: Length of and open ultrasonography and chest Other bias approaches for radiography. A complete hospital stay in days, Preoperative stage, n Other sources of bias: - mid and low rectal colonoscopy was performed mean±SD (%) cancers. yearly. Laparoscopic 8.2±7.3 I Other information The primary endpoints were Open 9.9±6.8 Laparoscopic 11 (11) None Study dates number of lymph nodes Open 15 (15) January 2002 to isolated, circumferential Outcome: February 2007 II margin involvement, rate of Postoperative complications and length of Laparoscopic 35 (35) mortality (up to 30 Open 39 (38) hospital stay. Secondary days after surgery) endpoints were local
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Outcomes and Study details Participants Interventions Methods Results Comments Source of III recurrence, disease-free Laparoscopic 2/101 funding Laparoscopic 45 (45) and overall survival. (Only Open 3/103 outcomes relevant for this None reported. Open 44 (43) review are reported here.) IV Outcome: Local recurrence was Anastomotic leak (in Laparoscopic 10 (10) defined as reappearance of anterior resection Open 5 (5) tumour in the surgical field only) and it was confirmed by Laparoscopic 5/77 Inclusion criteria histological examination. Open 10/81 Patients with mid and low rectal Statistical analysis adenocarcinoma. Kaplan–Meier estimation Outcome: Surgical method and survival curves wound infection Exclusion criteria were compared with the log Laparoscopic 0/101 Locally advanced rank test. Open 2/103 disease (T4); familial adenomatous polyposis; Outcome: Blood loss those who underwent in ml, mean±SD emergency surgery. Total Laparoscopic 127.8±113.3 Open 234.2±174.3 t-test p=<0.001 Anterior resection Laparoscopic 109.6±117.3 Open 199.5±153.3 t-test p=0.001 Abdominoperineal resection Laparoscopic 187.5±74.9 Open 346.9±195.3
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Outcomes and Study details Participants Interventions Methods Results Comments t-test p=0.006
Full citation Sample size Interventions Details Results Limitations Ng, S. S. M., N=99 randomised; Laparoscopic-assisted Randomisation and Outcome: Overall Cochrane risk of bias tool Leung, K. L., Lee, n=51 allocated to abdominoperineal allocation concealment survival after curative Selection bias J. F. Y., Yiu, R. Y. laparoscopic surgery; resection versus open Randomisation was resection (stages I- Random sequence C., Li, J. C. M., n=48 allocated to open abdominoperineal performed on the day III) (median 87 or 90 generation: low risk Teoh, A. Y. B., resection months of follow-up) surgery before surgery according to Allocation Leung, W. W., a computer-generated Laparoscopic n=40, concealment: unclear risk Laparoscopic- Laparoscopic surgery random sequence kept 12 events (No sufficient detail assisted versus Characteristics was performed with 3 concealed by an Open n=36, 17 provided.) open Age in years, mean±SD independent operating ports. events abdominoperineal Laparoscopic 63.7±11.8 theatre coordinator. p=0.20 Performance bias resection for low Open 63.5±12.6 rectal cancer: A No one received Blinding of participants and Blinding prospective preoperative Outcome: CRM personnel: high risk (No Male sex, n/n randomized trial, (chemo)radiotherapy. No blinding. involvement (not blinding.) Laparoscopic 31/51 Annals of Surgical defined) Open 30/48 Oncology, 15, Follow-up/outcomes Laparoscopic 3/40 Detection bias 2418-2425, 2008 All patients were followed Open 2/36 Blinding of outcome AJCC staging, n/n up regularly at 3-month assessment: high risk (No Ref Id I intervals in the first 2 years Outcome: blinding.) and then every 6 months 749447 Laparoscopic 10/51 Local/peritoneal thereafter for clinical Open 8/48 recurrence after Attrition bias examination and CEA curative resection Country/ies II Incomplete outcome data: testing. The survival status (stages I-III) (median where the study Laparoscopic 13/51 unclear risk (Not clear how was cross-checked with the 87 or 90 months of was carried out many were lost to follow- Open 8/48 networked computer follow-up) Hong Kong database of local hospital up. Survival analysis not III Laparoscopic 2/40 authority. done on intention-to-treat Laparoscopic 17/51 Open 4/36 Study type population although the Open 20/48 paper claims so.) RCT Statistical analysis IV
Laparoscopic 11/51 Reporting bias
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Outcomes and Study details Participants Interventions Methods Results Comments Aim of the study Open 12/48 Survival and disease-free Outcome: Length of Selective reporting: low risk To compare interval were calculated by hospital stay in days, laparoscopic- the Kaplan-Meier method, mean (range) Other bias and differences between assisted versus Inclusion criteria Laparoscopic 10.8 Other sources of bias: - open groups were compared with (5-27) Patients diagnosed low abdominoperineal the log-rank test. The paper rectal cancer within 5 cm Open 11.5 (5-38) resection in claims to have done Other information from the anal verge. p=0.55 patients with low intention-to-treat analysis None
rectal cancer. but survival analysis was Outcome: Exclusion criteria not done on all randomised patients. Postoperative death Study dates Tumour >6 cm; tumour infiltration to the adjacent (timeframe not September 1994 organs on provided) to February 2005 ultrasonography and/or Laparoscopic 1/51 computed tomography; Open 1/48 Source of recurrent disease; did funding not consent to Outcome: Perineal None reported. randomisation; intestinal wound infection obstruction or Laparoscopic 10/51 perforation. Open 6/48
Abdominal wound infection Laparoscopic - (not applicable) Open 4/48
Outcome: Blood loss in ml, mean (range)* Laparoscopic 321.7 (0–3000) Open 555.6 (0–4720) p=0.093
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Outcomes and Study details Participants Interventions Methods Results Comments Full citation Sample size Interventions Details Results Limitations Ng, S. S., Leung, N=153 randomised; Laparoscopic anterior Randomisation and Outcome: Overall Cochrane risk of bias tool K. L., Lee, J. F., n=76 allocated to resection versus open allocation concealment survival after curative Selection bias Yiu, R. Y., Li, J. laparoscopic anterior anterior resection resection Random sequence C., Hon, S. S., resection; n=77 allocated Blinding (median 109 and generation: low risk Long-term 112.5 months of to open anterior No blinding. Allocation morbidity and follow-up) resection concealment: unclear risk oncologic Laparoscopic n=59, (No sufficient detail outcomes of Follow-up/outcomes Characteristics 22 events provided.) laparoscopic- After surgery, the patients Age in years, mean±SD Open n=67, 26 assisted anterior were followed up regularly events resection for Laparoscopic 66.5±11.9 at 3-month intervals in the Performance bias p=0.303 upper rectal Open 65.7±12.0 first 2 years and then every Blinding of participants and
cancer: ten-year 6 months until year 5. personnel: high risk (No Outcome: CRM results of a Male sex, n/n Thereafter, patients were blinding.) prospective, seen annually. Clinical involvement Laparoscopic 37/76 randomized trial, examination, rigid Laparoscopic 2/76 Detection bias Dis Colon Open 48/77 sigmoidoscopy, and serum Open 1/77 Blinding of outcome Rectum, 52, 558- CEA testing were done at assessment: high risk (No 66, 2009 AJCC stage, n/n each visit. Colonoscopy Outcome: blinding.) was performed at one year I Locoregional after surgery, and thereafter Ref Id Laparoscopic 11/76 recurrence at 10 every 3 years. If recurrence Attrition bias 809749 Open 13/77 years was suspected, computed Incomplete outcome II tomography or positron Laparoscopic 7.1% data: low risk (No losses to Country/ies Laparoscopic 29/76 emission tomography would Open 4.9% follow-up. Survival analysis where the study Open 29/77 be performed. Data p=0.677 not done on intention-to- was carried out III regarding long-term treat population although Hong Kong Laparoscopic 20/76 morbidity, mortality, Outcome: Length of the paper claims so.) recurrence, and survival Open 28/77 hospital stay in days, Study type were prospectively mean (range) Reporting bias IV recorded. The survival RCT Laparoscopic 8.4 (2- Selective reporting: low risk Laparoscopic 16/76 status was cross-checked 32) (n=76) Open 7/77 with the networked Aim of the study Open 10.0 (3-39) computer database of the Other bias local hospital authority. (n=77)
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Outcomes and Study details Participants Interventions Methods Results Comments To compare Inclusion criteria Locoregional recurrence p=0.013 Other sources of bias: - laparoscopic and Patients with upper was defined as the open resection in rectal cancer (defined as presence of radiologically Outcome: Operative Other information patients with confirmed or histologically adenocarcinoma in the mortality None upper rectal proven tumour restricted to rectum of which the Laparoscopic 2/76 cancer. lowest margin of the the anastomosis or in the Open 4/77 tumour was located pelvis within the region of
Study dates between 12 and 15 cm the primary surgery. Outcome: September 1993 from the anal verge as Anastomotic leak to October 2002 determined by rigid Statistical analysis sigmoidoscopy). (The Laparoscopic 1/76 Data were analysed by the trial originally included intention-to-treat principle. Open 4/77 Source of rectosigmoid cancers funding Survival and recurrence and upper rectal cancers were calculated by the None reported. Outcome: Wound but this publication only Kaplan-Meier method, and reports outcomes for the infection differences between the Laparoscopic 5/76 subpopulation of people groups were compared by Open 9/77 with upper rectal the log-rank test. cancers.)
Outcome: Blood loss Exclusion criteria in ml, mean (range) Distal tumour needing Laparoscopic 280.0 anastomosis within 5 cm (0-3000) (n=76) of the dentate line; Open 337.3 (0-2542) tumour >6 cm; tumour (n=77) infiltration to adjacent p=0.338 organs on sonography with or without computer tomography scan; previous abdominal operations near the region of the colorectal operation; individuals who did not consent to randomisation; those
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Outcomes and Study details Participants Interventions Methods Results Comments with intestinal obstruction or perforation. Full citation Sample size Interventions Details Results Limitations Ng, Ss, Lee, Jf, N=80 randomised; Laparoscopic-assisted Randomisation and Outcome: Overall Cochrane risk of bias tool Yiu, Ry, Li, Jc, n=40 allocated to TME versus open TME allocation concealment survival after curative Selection bias Hon, Ss, Mak, Tw, laparoscopic TME; n=40 Randomisation was resection (stages I- Random sequence Ngo, Dk, Leung, allocated to open TME All surgeries were done performed on the day III) (median 75.7 generation: low risk Ww, Leung, Kl, months of follow-up) with anal sphincter before surgery according to Allocation Laparoscopic- Characteristics preservation. a computer-generated Laparoscopic concealment: unclear risk assisted versus random sequence kept n=36, 6 events* Age in years, mean±SD (No sufficient detail open total concealed by an Preoperative therapy Open n=36, 7 provided.) mesorectal Laparoscopic 60.2±11.3 independent operating was not given. (From events* excision with anal Open 62.1±12.6 theatre coordinator. September 2006 long- p=0.912 Performance bias sphincter preservation for course preoperative Blinding of participants and Male sex, n/n Blinding mid and low rectal chemoradiotherapy was Outcome: CRM personnel: high risk (No Laparoscopic 24/40 cancer: a offered to selected No blinding. involvement (not blinding.) Open 22/40 patients with radiologic prospective, defined) randomized trial, T3 or T4 and/or N+ Follow-up/outcomes Laparoscopic 3/40 disease but those Detection bias Surgical BMI mean±SD The patients were followed Open 2/40 patients were excluded Blinding of outcome Endoscopy, 28, Laparoscopic 23.1±3.4 up regularly at 3-month 297-306, 2014 from this study.) assessment: high risk (No Open 22.4±3.2 intervals in the first 2 years Outcome: blinding.) and then every 6 months Locoregional Ref Id until year 5. Thereafter, Tumour location from the recurrence after Attrition bias 749442 patients were seen curative resection anal verge in cm, Incomplete outcome annually. Clinical (stages I-III) (median mean±SD data: low risk (No losses to examination, rigid 75.7 months of Country/ies Laparoscopic 6.9±1.7 follow-up. Survival analysis sigmoidoscopy, and serum follow-up) where the study Open 7.1±2 CEA testing were done at not done on intention-to- Laparoscopic 1/36 was carried out each visit. Colonoscopy treat population although Open 4/36 Hong Kong AJCC staging, n/n was performed at one year the paper claims so.) after surgery, and thereafter I every three years. Data Outcome: Length of Study type Laparoscopic 5/40 Reporting bias RCT regarding perioperative hospital stay in says, Selective reporting: low risk Open 6/40 outcome, long-term mean (range)
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Outcomes and Study details Participants Interventions Methods Results Comments Aim of the study II morbidity, recurrence, and Laparoscopic 10.5 Other bias To Laparoscopic 15/40 survival were prospectively (5-35) Other sources of bias: - compare laparosc Open 11/40 recorded. The survival Open 15 (6-167) status was cross-checked opic-assisted and III p=0.071 Other information open TME with with the networked Laparoscopic 16/40 None anal sphincter computer database of the Outcome: Operative preservation in Open 19/40 local hospital authority. If death patients with mid IV recurrence was and low rectal Laparoscopic 4/40 suspected, computed Laparoscopic 0/40 tomography or positron cancer. Open 4/40 Open 0/40 emission tomography would
be performed. Study dates Inclusion criteria Primary endpoints Outcome: August 2001 to Patients diagnosed with were short-term clinical Anastomotic leak August 2007 mid and low rectal outcome, including cancer (lowest margin of postoperative recovery and Laparoscopic 1/40 Source of the tumour was located short-term morbidity. Open 0/40 funding between 5 and 12 cm Secondary endpoints were This study was from the anal verge as long-term morbidity and Outcome: Wound supported by any determined by rigid survival. infection sigmoidoscopy). grant. Laparoscopic 1/40
Statistical analysis Open 7/40 Exclusion criteria Data were analysed by Tumour larger than 6 intention-to-treat principle. Outcome: Blood loss cm; tumour infiltration to Recurrence and survival in ml, mean (range) the adjacent organs on were calculated by the Laparoscopic 142 (0- computed tomography; Kaplan-Meier method, and 2,000) recurrent disease; differences between the synchronous colorectal groups were compared with Open 361 (5-2,500) tumours; intestinal log-rank test. p<0.001 obstruction or perforation; patients who *Number of events required neoadjuvant calculated from the therapy; patients who did Kaplan-Meier curve
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Outcomes and Study details Participants Interventions Methods Results Comments not consent to randomisation. Full citation Sample size Interventions Details Results Limitations Park, E. J., Cho, N=133 robotic lower Robotic versus Randomisation and Outcome: Overall ROBINS-I checklist for non- M. S., Baek, S. J., anterior resection; N=84 laparoscopic lower allocation concealment survival at 5 years randomised studies of Hur, H., Min, B. laparoscopic lower anterior resection This was not a randomised Stages I-III Interventions S., Baik, S. H., anterior resection study. The groups were not Robotic 92.8% Pre-intervention Lee, K. Y., Kim, For robotic surgery, the matched. Laparoscopic 93.5% Bias due to confounding: N. K., Long-term Characteristics da Vinci surgical system Moderate risk of bias (This oncologic p=0.829 Age in years, mean±SD was used. All robotic- Blinding is a non-randomised study, outcomes of Stage II Robotic 59.2±11.4 assisted lower anterior No blinding. the groups were not robotic low resections were Robotic 94.2% matched by any Laparoscopic 63.5±11.2 anterior resection performed by the hybrid Laparoscopic 100% characteristic but the study for rectal cancer, technique. Follow-up/outcomes p=0.221 controlled for potential Annals of Male sex, n (%) Data were collected from Stage III confounding or case-mix in Surgery, 261, the Yonsei Colorectal Robotic 86 (65) Chemoradiotherapy was Robotic 86.8% the analysis.) 129-137, 2015 Cancer Database. Laparoscopic 60 (71) given for stage T3-4N0 Bias in selection of Laparoscopic 87.8% or N+ M0 low- and mid- The follow-up visits were at participants into the study: Ref Id 1 month, 3 months, and p=0.916 BMI, mean±SD rectal cancers. Majority Low risk of bias 749686 of the patients every 3 months for the first Robotic 23.±2.9 3 years and then 6 months underwent postoperative At intervention Laparoscopic 22.9±2.8 until 5 years after surgery. Country/ies chemoradiotherapy due Regular laboratory tests Bias in classification of where the study to the institute's Interventions: Low risk of Tumour location from the with CEA and a physical was carried out treatment protocol at the bias anal verge, n (%) time of the study. The examination were South Korea 0-5 cm regimen was based on performed. Colonoscopy was done 1 year after Post-intervention Robotic 33 (25) 5-FU and leucovorin. Study type surgery and at 5 years. Preoperative Bias due to deviations from Laparoscopic 16 (19) Chest and abdominopelvic Prospective chemoradiotherapy, n intended Interventions: Low 5.1-10 cm computed cohort study (%) risk of bias Robotic 60 (45) tomography scans were Bias due to missing data: Robotic 15 (11) obtained every 6 months to Aim of the study Laparoscopic 37 (44) Low risk of bias Laparoscopic 10 (12) detect local recurrence or 10.1-15 cm Bias in measurement of To evaluate the systemic metastasis during outcomes: Low risk of bias long-term Robotic 40 (30) the follow-up period.
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Outcomes and Study details Participants Interventions Methods Results Comments oncologic Laparoscopic 31 (37) Bias in selection of the outcomes of Statistical analysis reported result: Low risk of robotic surgery for Postoperative pathologic Survival was analysed bias rectal cancer TNM stage, n (%) using the Kaplan-Meier compared with method and the groups Other information conventional I were compared with the laparoscopic Robotic 49 (37) None log-rank test. Univariate surgery. Laparoscopic 22 (26) analysis of II clinicopathological factors Study dates Robotic 36 (27) upon overall survival was April 2006 to Laparoscopic 28 (33) performed using the log- August 2011 III rank test Robotic 48 (36) to determine the prognostic value of the surgical Source of Laparoscopic 34 (41) methods, all statistically funding significant factors None reported. Inclusion criteria determined by univariate People diagnosed with analysis were conducted for rectal adenocarcinoma; multivariate analysis by the underwent low anterior Cox proportional hazards resection by robotic or regression model with a conventional forward selection of laparoscopic approach. variables.
Exclusion criteria Open surgery; stage IV disease; patients lost to follow-up. Full citation Sample size Interventions Details Results Limitations van der Pas, M. See Bonjer 2015 H., Haglind, E., (COLOR II trial). Other information Cuesta, M. A., Furst, A., Lacy, A. Characteristics
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Outcomes and Study details Participants Interventions Methods Results Comments M., Hop, W. C., Bonjer, H. J., C. Inclusion criteria Olorectal cancer Laparoscopic or Open Resection II Exclusion criteria Study Group, Laparoscopic versus open surgery for rectal cancer (COLOR II): short-term outcomes of a randomised, phase 3 trial, Lancet Oncology, 14, 210-8, 2013 Ref Id 751236 Country/ies where the study was carried out Study type
Aim of the study
Study dates
Source of funding Full citation Sample size Interventions Results Limitations Pontallier, A., See Denost 2017 Denost, Q., Van (Bordeaux' trial). Other information Geluwe, B., Adam, J. P.,
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Outcomes and Study details Participants Interventions Methods Results Comments Celerier, B., Characteristics Rullier, E., Potential sexual Inclusion criteria function improvement by using transanal Exclusion criteria mesorectal approach for laparoscopic low rectal cancer excision, Surgical Endoscopy and Other Interventional Techniques, 30, 4924-4933, 2016
Ref Id 749925
Country/ies where the study was carried out
Study type
Aim of the study
Study dates
Source of funding Full citation Sample size Interventions Details Results Limitations
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Outcomes and Study details Participants Interventions Methods Results Comments Quah, H. M., See Jayne 2010 Jayne, D. G., Eu, (CLASICC trial). Other information K. W., Seow- Choen, F., Characteristics Bladder and
sexual dysfunction Inclusion criteria following laparoscopically Exclusion criteria assisted and conventional open mesorectal resection for cancer, Br J Surg, 89, 1551-6, 2002
Ref Id 809751
Country/ies where the study was carried out
Study type
Aim of the study
Study dates
Source of funding Full citation Sample size Interventions Details Results Limitations N=400 N=400
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Outcomes and Study details Participants Interventions Methods Results Comments Rouanet P, R-TME (n=200) Prospectively collected Overall survival: ROBINS-I checklist for non- Bertrand MM, Characteristics L-TME (n=200) records of 400 patients with Follow-up 4.1 years randomised studies of Jarlier M et al. Male, n (%) 131 65.5% mild or low rectal cancer (R-TME 3.1 years Interventions Robotic Versus (R-TME); 136 (68.0%) who underwent curative [95% CI 2.9, 3.4 Pre-intervention Laparoscopic conservative surgery years]; L-TME 5.7
Total Mesorectal years [95% CI 5.3, Bias due to confounding: Excision for Median age years 6.0 years]) Follow-up: NR Moderate risk of bias (This Sphincter-Saving (range) 64 (25, 85 (R- is a non-randomised study, Surgery: Results TME); 63.5 (35, 86) (L- the groups were not of a Single-Center TME) Statistical analysis: 3 year survival rate matched by any Series of 400 Patient Characteristics, and was 84.1% (95% characteristic.) Consecutive Tumour location, n (%) surgical and pathology CI 77.3, 88.9%) (R- Patients and results were described TME) vs 88.4% using frequency and Bias in selection of Perspectives. Ann Upper >/= 11 cm 27 percentage for categorical (95% participants into the study: Surg Oncol. 2018 (13.6); middle 6-10 cm variables and median and CI 82.9, 92.2%) (L- Low risk of bias Nov;25(12):3572- 83 (41.9); low (/= 11 cm 39 At intervention compared using the Ref Id (20.2); middle 6-10 cm Quality of life: Sexual Bias in classification of Pearson Chi square test or 75 (38.9); low (
robotic TME), with no were conducted to estimate with BMI >/= 28 Aim of the study previous or concurrent the odds ratios (ORs) for kg/m2 and low rectal Bias in measurement of outcomes: Low risk of bias To compare malignancy and no conversion to laparotomy tumour. A trend for robotic total evidence of distant and CRM involvement better symptom mesorectal between the groups. ORs scores was reported
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Outcomes and Study details Participants Interventions Methods Results Comments excision (R-TME) metastasis at time of and their 95% confidence for the R-TME group Bias in selection of the with laparoscopic surgery. intervals (95% CI) were in the high-risk reported result: Low risk of TME (L-TME) in a estimated using a univariate patients although it bias series of Exclusion criteria logistic regression model. was not significant consecutive rectal Overall survival was Not reported Other information cancer patients estimated using the None Kaplan–Meier method, and
Study dates survival curves were compared with the log-rank 2008 to 2012 and test. No imputation method 2012 to 2015 was used in Laparoscopic Versus Robotic Source of Proctectomy 3573 case of funding missing data. All tests were Financial support two-sided, and p value B was provided by 0.05 was considered Intuitive Surgical, statistically significant. Aubonne, Statistical analyses were Switzerland performed using STATA 13.0 (StataCorp, College Station, TX, USA). Full citation Sample size Interventions Details Results Limitations Stevenson, A. R. N=475 randomised; Laparoscopic surgery Randomisation and Outcome: Negative C Cochrane risk of bias tool L., Solomon, M. n=238 allocated to versus open surgery allocation concealment RM (>=1 mm) Selection bias J., Lumley, J. W., laparoscopic surgery; The open surgery was Randomisation was Laparoscopic Random sequence Hewett, P., n=237 allocated to open a hybrid operation in conducted at the National 222/238 generation: unclear risk Clouston, A. D., surgery which the abdominal Health and Medical Open 228/235 (Limited details reported.) Gebski, V. J., component (splenic Research Council Clinical Allocation concealment: Davies, L., flexure mobilization and Trials Centre via the Characteristics Outcome: Negative unclear risk (Details not Wilson, K., vessel division) could be Internet using the method of distal resection reported.) Hague, W., Age in years, median performed minimization and stratified margin (>=1 mm) Simes, J., Effect (IQR) laparoscopically; by the location of the of laparoscopic- Laparoscopic 65 (56-74) however, the rectal tumour from the anal verge, Laparoscopic Performance bias assisted resection Open 65 (56-73) mobilization had to be the registering surgeon, the 236/238 vs open resection performed as an open planned operative Open 234/235
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Outcomes and Study details Participants Interventions Methods Results Comments on pathological Male sex, n (%) procedure under direct procedure, body mass Blinding of participants and outcomes in rectal Laparoscopic 160 (67) vision via a laparotomy. index, preoperative Outcome: Length of personnel: high risk (No cancer: The Open 151 (64) Laparoscopic-assisted radiotherapy (yes or no), hospital stay in days, blinding.) ALaCaRT procedures could and distant metastasis (yes median (IQR) randomized include the use of a or no). No other details Laparoscopic 8 (6- Detection bias clinical trial, JAMA Tumour location from the hand port, but robotic were provided. 12) - Journal of the anal verge, n/n surgery was excluded. Blinding of outcome Open 8 (6-12) assessment: low/high risk American Medical <5 cm Blinding Association, 314, p=0.21 (Pathologist was blinded. Laparoscopic 82 (35) Planned surgical No blinding of participants. 1356-1363, 2015 Surgical team or patient Open 83 (35) approach, n (%) Pathologist blinded to was not blinded.) Ref Id 5-10 cm Low anterior resection allocation. Outcome: Blood loss in ml, median (IQR) 750805 Laparoscopic 103 (43) Laparoscopic 220 (92) Laparoscopic 100 Attrition bias Country/ies Open 102 (44) Open 218 (93) Follow-up/outcomes where the study (50-200) Incomplete outcome data: 10-15 cm Abdominoperineal A pathologist blinded to was carried out Open 150 (55-300) low risk Laparoscopic 53 (22) resection treatment allocation Australia examined the surgical p=0.02 Open 50 (21) Laparoscopic 18 (8) Reporting bias Study type specimen. The specimens Open 17 (7) RCT (ALaCaRT were photographed fresh Selective reporting: low risk
trial) Tumour stage, n/n and unopened to show the Surgical approach T1 mesorectal dissection Other bias performed, n (%) Aim of the study Laparoscopic 18 (8) anteriorly and posteriorly Other sources of bias: - Low anterior resection before inking. The To determine Open 11 (5) Laparoscopic 143 (60) pathologist assessed the whether T2 Other information distal margin in the fresh laparoscopic Laparoscopic 68 (29) Open 153 (65) and unstretched specimen. None resection is Open 68 (29) Low anterior resection and coloanal Other details not reported. noninferior to T3 open rectal anastomosis Laparoscopic 151 (63) cancer resection Laparoscopic 69 (29) Statistical analysis Open 155 (66) for adequacy of Open 58 (25) Wilcoxon rank sum test
cancer clearance. Abdominoperineal used to compare Nodal status, n/n resection continuous data between groups. Study dates N0 Laparoscopic 25 (11) Laparoscopic 107 (45) Open 23 (10) Open 123 (53)
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Outcomes and Study details Participants Interventions Methods Results Comments March 2010 N1 to November Laparoscopic 92 (39) Preoperative 2014 Open 80 (34) radiotherapy, n (%) N2 Laparoscopic 119 (50) Source of Laparoscopic 37 (16) Open 116 (49) funding Open 30 (13) The Colorectal
Surgical Society of Australia and Distant metastases New Zealand Laparoscopic 10 (4) Foundation and Open 10 (4) the National Health and Inclusion criteria Medical Research Aged 18 years or older; Council. histological diagnosis of adenocarcinoma of the rectum within 15 cm of the anal verge; life expectancy of at least 12 weeks; adequate performance status (Eastern Cooperative Oncology Group Scale score of ≤2); no comorbidity or condition that would preclude the use of either form of surgery.
Exclusion criteria T4 tumours or an involved CRM (determined by pretreatment pelvic MRI,
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Outcomes and Study details Participants Interventions Methods Results Comments or endorectal ultrasound if MRI was contraindicated); concurr ent or previous invasive pelvic malignant tumours (cervical, uterine, or rectal; excluding the prostate) within 5 years before study enrolment. (Distant metastases was not an exclusion criterion.) Full citation Sample size Interventions Details Results Limitations Stevenson ARL, Solomon MJ, (See Stevenson, 2015 Median follow-up was Brown CSB et al. (ALaCaRT study)) 3.2 years (range: 0.1- Other information Disease-free 5.4 yrs). Survival and Local Recurrence After Outcome OS 28 Laparoscopic- deaths within 2 years assisted and a 2-year survival Resection or estimate 94% for Open Resection LAP and 93% for for Rectal Cancer: OPEN (difference, The Australasian 0.9%, 95% CI, -3.6% Laparoscopic to -5.4%). HR 1.08 Cancer of the (95% CI 0.63, 1.86) Rectum Randomized Outcome: LRR Clinical Trial. Ann cumulative incidence Surg. 2019 at 2 years: LAP Apr;269(4):596- 5.4%; OPEN 3.1% 602. [difference, 2.3%; 95% confidence
interval (CI), -1.5% to Ref Id 6.1%; hazard ratio
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Outcomes and Study details Participants Interventions Methods Results Comments 983031 (HR) 1.7; 95% CI, 0.74-3.9, p=0.21. Country/ies where the study was carried out Australia Study type RCT (ALaCaRT trial)
Aim of the study To determine whether laparoscopic resection is noninferior to open rectal cancer resection for adequacy of cancer clearance.
Study dates March 2010 to November 2014
Source of funding The Colorectal Surgical Society of Australia and New Zealand Foundation and
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Outcomes and Study details Participants Interventions Methods Results Comments the National Health and Medical Research Council.
Full citation Sample size Interventions Details Results Limitations Yoo, B. E., Cho, N=44 robotic Robotic versus Randomisation and Outcome: Overall ROBINS-I checklist for non- J. S., Shin, J. W., intersphincteric laparoscopic allocation concealment survival at 3 years randomised studies of Lee, D. W., Kwak, resection; N=26 intersphincteric This was not a randomised Robotic 95.2% Interventions J. M., Kim, J., laparoscopic resection study. The groups were not Laparoscopic 88.5% Pre-intervention Kim, S. H., intersphincteric resection matched. Bias due to p=0.174 Robotic Versus Robotic surgery was confounding: Serious risk of Laparoscopic Characteristics performed with the da Blinding bias (This is a non- Intersphincteric Age in years, mean±SD Vinci Surgical System by No blinding. randomised study, the Resection for Low a single surgeon. groups were not matched Rectal Cancer: Robotic 59.8±12,3 by any characteristic. The Comparison of the Laparoscopic 60.5±10.8 Follow-up/outcomes Preoperative study did not control for Operative, Data was retrospectively chemoradiotherapy potential confounding or Oncological, and Male sex, n (%) obtained from a (5,080 cGy in 28 case-mix in the analysis.) Functional prospectively-collected Robotic 35 (80) fractions and 5- Bias in selection of Outcomes, Annals database. No details about Laparoscopic 19 (73) fluorouracil) was given s participants into the study: of Surgical follow-up visits reported. electively to locally Low risk of bias Oncology, 22, 1219-1225, 2015 BMI, mean±SD advanced cancers if the CRM was Statistical analysis Ref Id Robotic 24.13.3 At intervention suspicious/threatened/p Survival was analysed 751717 Laparoscopic 21.4±3.1 Bias in classification of ositive or if lymph nodes using the Kaplan-Meier Interventions: Low risk of Country/ies that escaped the TME method, the differences bias where the study Tumour distance from plane were detected between the groups were
was carried out the anal verge in cm, using MRI or CT scan. compared by log-rank test. South Korea mean Surgeries were The groups were not Post-intervention Study type Robotic 3.2±0.8 performed 8 weeks after matched and the analysis Bias due to deviations from intended Interventions: Retrospective Laparoscopic 3.7±0.9 preoperative did not control for potential Low risk of bias cohort study chemoradiotherapy. confounding or case-mix.
Clinical T stage, n (%)
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Outcomes and Study details Participants Interventions Methods Results Comments Aim of the study T1 Preoperative Bias due to missing data: To compare the Robotic 2 (5) chemoradiotherapy, n Low risk of bias operative, Laparoscopic 3 (12) (%) Bias in measurement of oncological, and T2 Robotic 24 (54) outcomes: Low risk of bias functional Robotic 15 (34) Laparoscopic 7 (27) Bias in selection of the outcomes of low reported result: Low risk of Laparoscopic 4 (15) rectal cancer bias T3 patients who underwent robotic Robotic 22 (50) Other information or laparoscopic Laparoscopic 18 (69) None intersphincteric T4 resection. Robotic 5 (11)
Laparoscopic 1 (4) Study dates
September 2006 Clinical N stage, n (%) to August 2011 N0
Source of Robotic 17 (39) funding Laparoscopic 14 (54) N1 None reported. Robotic 16 (36) Laparoscopic 2 (8) N2 Robotic 11 (25) Laparoscopic 10 (39)
Clinical M stage, n (%) M0 Robotic 39 (89) Laparoscopic 24 (92) M1 Robotic 5 (11) Laparoscopic 2 (8)
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Outcomes and Study details Participants Interventions Methods Results Comments
Inclusion criteria Patients with low rectal cancer (<5 cm from the anal verge) treated via laparoscopic or robotic intersphincteric resection.
Exclusion criteria Patients with synchronous tumours or clinical T4 stage tumours that did not respond to neoadjuvant treatment.
Full citation Sample size Interventions Details Results Limitations Zhou, Z. G., Hu, n=82 underwent Laparoscopic surgery Randomisation and Outcome: Positive Cochrane risk of bias tool M., Li, Y., Lei, W. laparoscopic surgery; versus open surgery allocation concealment resection margin Selection bias Z., Yu, Y. Y., n=89 underwent open No details reported. ("cancer cell found in Random sequence Cheng, Z., Li, L., surgery. How many were Open resection with the cut margins") generation: unclear Shu, Y., Wang, T. originally randomised TME. Blinding Laparoscopic 0/82 risk (Details not reported.) C., Laparoscopic and allocated to each Laparoscopic resection Open 0/89 Allocation concealment: versus open total group is not reported. No blinding. with TME and anal unclear risk (Details not mesorectal sphincter preservation. Outcome: Length of reported.) excision with anal Characteristics Follow-up/outcomes sphincter hospital stay in days, Age in years, mean Clinical data collected. preservation for mean±SD Performance bias (range) low rectal cancer, Laparoscopic 8.1±3.1 Blinding of participants and Statistical analysis Surg Endosc, 18, Laparoscopic 44 (26-85) (n=82) personnel: high risk (No 1211-5, 2004 Open 45 (30-81) Chi-square test and Open 13.3±3.4 blinding.) Student’s t-test was (n=89) performed to determine Ref Id Male sex, n/n p=0.001 Detection bias
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Outcomes and Study details Participants Interventions Methods Results Comments 809754 Laparoscopic 46/82 difference between the Blinding of outcome Open 43/89 laparoscopic and open Outcome: Operative assessment: high risk (No Country/ies groups. mortality (timeframe blinding.) where the study Dukes stage, n/n not reported) was carried out A Laparoscopic 0/82 Attrition bias China Laparoscopic 5/82 Open 0/89 Incomplete outcome data: unclear risk (The original Open 6/89 Study type Outcome: number randomised not B reported. Only outcomes RCT Anastomotic leak Laparoscopic 10/82 immediate to surgery Laparoscopic 1/82 Open 8/89 reported, therefore, no Open 3/89 Aim of the study C1 losses to follow-up.)
To compare open Laparoscopic 33/82 versus Outcome: Open 35/89 Reporting bias laparoscopic low Postoperative Selective reporting: unclear and ultralow C2 infection risk (Not clear which anterior Laparoscopic 30/82 Laparoscopic 2/82 outcomes should be resections, to Open 33/89 Open 3/89 reported.) assess the D
feasibility and Laparoscopic 4/82 efficacy of the Outcome: Blood loss Other bias Open 7/89 laparoscopic in ml, mean (range) Other sources of bias: - approach of TME Laparoscopic 20 (5- 120) (n=82) with anal Other information sphincter Open 92 (50-200) None preservation and Inclusion criteria (n=89) to analyse the Patients diagnosed with p=0.025 short-term results rectal adenocarcinoma, of patients with with the lowest margin of low rectal cancer. tumour located under the peritoneal reflection and Study dates 1.5 cm above the June 2001 to dentate line. September 2002
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Outcomes and Study details Participants Interventions Methods Results Comments Source of Exclusion criteria funding Low rectal cancer of National other pathological type Outstanding (for example lymphoma); Youth Foundation lowest margin of tumour of China within 1.5 cm above the dentate line; those in emergency situations (for example acute obstruction during enema, haemorrhage, and perforation); Dukes stage D with local infiltration affecting adjacent organs; those unwilling to take part in the study. 1 5-FU: 5-fluorouracil; AJCC: American Joint Committee on Cancer; ASA: American Society of Anestheologists; BMI: body mass index; c: clinical; CEA: carcinoembryonic antigen; 2 cGy: centigray unit; CI: confidence interval; CRM: circumferential resection margin; CT: computed tomography; EORTC: European Organisation for Research and Treatment of 3 Cancer; EQ-5D: EuroQol five dimensions questionnaire; EQ-VAS: EuroQol visual analogue scale; FSFI: Female Sexual Function Index; Gy: Gray unit; HR: hazard ratio; IIEF: 4 International Index of Erectile Function; IQR: interquartile range; IPSS: International Prostate Symptom score; LAP: laparoscopic resection; L-TME: laparoscopic total mesorectal 5 excision; ml: millilitre; M0-1: distant metastasis stage; MRI: magnetic resonance imaging; N0-2: nodal stage; N: number; NR: not reported; p: pathological; OPEN: open resection; 6 OR: odds ratio; PME: partial mesorectal excision; QLQ-C30: Quality of Life Questionnaire Core 30 Items; QLQ-CR38: Quality of Life Questionnaire colorectal cancer module (38 7 items); RCT: randomised controlled trial; ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions; R-TME: robotic total mesorectal excision; SD: 8 standard deviation; SF-36: 36-Item Short Form Survey; T0-4: tumour stage; TME: total mesorectal excision; TNM: cancer classification system, standing for tumour, nodal and 9 metastasis stages; VAS: visual analogue scale 10
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1 Appendix E – Forest plots
2 Forest plots for review question: What is the optimal surgery for rectal cancer?
3 Figure 2: Comparison 1: Laparoscopic versus open surgery for rectal cancer – Overall survival (median 3.2 to 9.2 years of follow-up, 4 event is death from any cause)
5 6 CI: confidence interval; O-E: observed minus expected; V: variance
7
8
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1 Figure 3: Comparison 1: Laparoscopic versus open surgery for rectal cancer – Quality of life - Global quality of life score (QLQ-C30; 2 scale 0-100; better indicated by higher values)
3 4 CI: confidence interval; IV: inverse variance; QLQ-C30: Quality of Life Questionnaire Core 30 Items; SE: standard error
5 Figure 4: Comparison 1: Laparoscopic versus open surgery for rectal cancer – Quality of life - Global health status (EQ-VAS; scale 0- 6 100; better indicated by higher values)
7 8 CI: confidence interval; EQ-VAS: EuroQol visual analogue scale; IV: inverse variance; SE: standard error
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1 Figure 5: Comparison 1: Laparoscopic versus open surgery for rectal cancer – Quality of life - Sexual functioning (QLQ-CR38; scale 0- 2 100; better indicated by higher values)
3 4 CI: confidence interval; IV: inverse variance; QLQ-CR38: Quality of Life Questionnaire colorectal cancer module (38 items); SE: standard error
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1 Figure 6: Comparison 1: Laparoscopic versus open surgery for rectal cancer – Quality of life - Sexual enjoyment (QLQ-CR38; scale 0- 2 100; better indicated by higher values)
3 4 CI: confidence interval; IV: inverse variance; QLQ-CR38: Quality of Life Questionnaire colorectal cancer module (38 items); SE: standard error
5 Figure 7: Comparison 1: Laparoscopic versus open surgery for rectal cancer – Quality of life - Female sexual problems (QLQ-CR38; 6 scale 0-100; better indicated by lower values)
7 8 CI: confidence interval; IV: inverse variance; QLQ-CR38: Quality of Life Questionnaire colorectal cancer module (38 items); SE: standard error
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1 Figure 8: Comparison 1: Laparoscopic versus open surgery for rectal cancer – Quality of life - Overall level of sexual function decreased 2 ‘quite a lot’ or ‘severely’ as a result of surgery in women (FSFI)
3 4 CI: confidence interval; FSFI: Female Sexual Function Index; M-H: Mantel Haenszel method
5 Figure 9: Comparison 1: Laparoscopic versus open surgery for rectal cancer – Quality of life - Male sexual problems (QLQ-CR38; scale 6 0-100; better indicated by lower values)
7 8 CI: confidence interval; IV: inverse variance; QLQ-CR38: Quality of Life Questionnaire colorectal cancer module (38 items); SE: standard error
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1 Figure 10: Comparison 1: Laparoscopic versus open surgery for rectal cancer – Quality of life - Overall sexual dysfunction median 3 2 years after surgery among previously sexually active men (IIEF)
3 4 CI: confidence interval; IIEF: International Index of Erectile Function; M-H: Mantel Haenszel method
5 Figure 11: Comparison 1: Laparoscopic versus open surgery for rectal cancer – Quality of life - A severe change in overall level of 6 sexual function perceived in men (IIEF)
7 8 CI: confidence interval; IIEF: International Index of Erectile Function; M-H: Mantel Haenszel method
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1 Figure 12: Comparison 1: Laparoscopic versus open surgery for rectal cancer – Quality of life - Micturitional symptoms (QLQ-CR38; 2 scale 0-100; better indicated by lower values)
3 4 CI: confidence interval; IV: inverse variance; QLQ-CR38: Quality of Life Questionnaire colorectal cancer module (38 items); SE: standard error
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Figure 13: Comparison 1: Laparoscopic versus open surgery for rectal cancer – Positive resection margins
CI: confidence interval; CRM: circumferential resection margin; M-H: Mantel Haenszel method
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Figure 14: Comparison 1: Laparoscopic versus open surgery for rectal cancer – Positive radial resection margin ≤ 2 mm
CI: confidence interval
Figure 15: Comparison 1: Laparoscopic versus open surgery for rectal cancer – Positive resection margin (“cancer cell found in the cut margin”)
CI: confidence interval; M-H: Mantel Haenszel method
Figure 16: Comparison 1: Laparoscopic versus open surgery for rectal cancer – Local recurrence (time to event outcome; median 3.2 to 4 years of follow-up)
CI: confidence interval; O-E: observed minus expected; V: variance
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Figure 17: Comparison 1: Laparoscopic versus open surgery for rectal cancer – Local or locoregional recurrence (median 3 to 7.5 years of follow-up)
CI: confidence interval; M-H: Mantel Haenszel method
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Figure 18: Comparison 1: Laparoscopic versus open surgery for rectal cancer – Length of hospital stay (days)
CI: confidence interval; IV: inverse variance; SD: standard deviation
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Figure 19: Comparison 1: Laparoscopic versus open surgery for rectal cancer – Operative mortality
CI: confidence interval; M-H: Mantel Haenszel method
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Figure 20: Comparison 1: Laparoscopic versus open surgery for rectal cancer – 90-day operative mortality
CI: confidence interval; M-H: Mantel Haenszel method
Figure 21: Comparison 1: Laparoscopic versus open surgery for rectal cancer – Anastomotic leak
CI: confidence interval; M-H: Mantel Haenszel method
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Figure 22: Comparison 1: Laparoscopic versus open surgery for rectal cancer – Surgical site infection
CI: confidence interval; M-H: Mantel Haenszel method
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Figure 23: Comparison 1: Laparoscopic versus open surgery for rectal cancer – Blood loss (ml)
CI: confidence interval; IV: inverse variance; SD: standard deviation
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Figure 24: Comparison 2: Robotic versus open surgery for rectal cancer – overall survival (median follow-up 3 years)
CI: confidence interval; O-E: observed minus expected; V: variance
Figure 25: Comparison 2: Robotic versus open surgery for rectal cancer – Quality of life - Sexual dysfunction in men ≤65 years
CI: confidence interval; M-H: Mantel Haenszel method; VAS: visual analogue scale
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Figure 26: Comparison 2: Robotic versus open surgery for rectal cancer – Positive resection margins
CI: confidence interval; CRM: circumferential resection margin; M-H: Mantel Haenszel method
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Figure 27: Comparison 2: Robotic versus open surgery for rectal cancer – positive resection margin (R1)
CI: confidence interval
Figure 28: Comparison 3: Robotic versus laparoscopic surgery for rectal cancer – overall survival (median follow-up 3 to 5 years )
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CI: confidence interval; O-E: observed minus expected; V: variance
Figure 29: Comparison 3: Robotic versus laparoscopic surgery for rectal cancer – Quality of life - Sexual function mean score at 12 months (QLQ-CR38; scale 0-100; better indicated by higher values)
CI: confidence interval; IV: inverse variance; QLQ-CR38: Quality of Life Questionnaire colorectal cancer module (38 items); SD: standard deviation
Figure 30: Comparison 3: Robotic versus laparoscopic surgery for rectal cancer – Quality of life – Female sexual function adjusted mean score difference at 6 months (FSFI; scale 2-36; better indicated by higher values)
CI: confidence interval; FSFI: Female Sexual Function Index; IV: inverse variance; SE: standard error
Figure 31: Comparison 3: Robotic versus laparoscopic surgery for rectal cancer – Quality of life – Male sexual function adjusted mean score difference at 6 months (IIEF; scale 5-75; better indicated by higher values)
CI: confidence interval; IIEF: International Index of Erectile Function; IV: inverse variance; SE: standard error
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Figure 32: Comparison 3: Robotic versus laparoscopic surgery for rectal cancer – Quality of life – Bladder function adjusted mean score difference at 6 months (IPSS; scale 0-35; better indicated by lower values)
CI: confidence interval; IPSS: International Prostate Symptom Score; IV: inverse variance; SE: standard error
Figure 33: Comparison 3: Robotic versus laparoscopic surgery for rectal cancer – Positive resection margins
CI: confidence interval; CRM: circumferential resection margin; M-H: Mantel Haenszel method
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Figure 34: Comparison 3: Robotic versus laparoscopic surgery for rectal cancer – Positive proximal resection margin
CI: confidence interval; M-H: Mantel Haenszel method
Figure 35: Comparison 3: Robotic versus laparoscopic surgery for rectal cancer – Positive distal resection margin
CI: confidence interval
Figure 36: Comparison 3: Robotic versus laparoscopic surgery for rectal cancer – Length of hospital stay (days)
CI: confidence interval; IV: inverse variance; SD: standard deviation
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Figure 37: Comparison 3: Robotic versus laparoscopic surgery for rectal cancer – 30-day operative mortality
CI: confidence interval; M-H: Mantel Haenszel method
Figure 38: Comparison 3: Robotic versus laparoscopic surgery for rectal cancer – Anastomotic leak
CI: confidence interval; M-H: Mantel Haenszel method
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Figure 39: Comparison 3: Robotic versus laparoscopic surgery for rectal cancer – Surgical site infection
CI: confidence interval; M-H: Mantel Haenszel method
Figure 40: Comparison 4: Transanal total mesorectal excision versus laparoscopic surgery for rectal cancer – Overall survival (median 5 years of follow-up)
CI: confidence interval; O-E: observed minus expected; TaTME: transanal total mesorectal excision; V: variance
Figure 41: Comparison 4: Transanal total mesorectal excision versus laparoscopic surgery for rectal cancer – Quality of life - Sexual activity maintained at median 3.2 years after treatment (in previously sexually active participants)
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CI: confidence interval; M-H: Mantel Haenszel method; TaTME: transanal total mesorectal excision
Figure 42: Comparison 4: Transanal total mesorectal excision versus laparoscopic surgery for rectal cancer – Quality of life - Sexual dysfunction at median 3.2 years after treatment (FSFI score ≤19) in previously sexually active women
CI: confidence interval; FSFI: Female Sexual Function Index; M-H: Mantel Haenszel method; TaTME: transanal total mesorectal excision
Figure 43: Comparison 4: Comparison 4: Transanal total mesorectal excision versus laparoscopic surgery for rectal cancer – Quality of life - Normal ejaculatory function at median 3.2 years after treatment in previously sexually active men (IIEF)
CI: confidence interval; IIEF: International Index of Erectile Function; M-H: Mantel Haenszel method; TaTME: transanal total mesorectal excision
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Figure 44: Comparison 4: Transanal total mesorectal excision versus laparoscopic surgery for rectal cancer – Positive resection margins
CI: confidence interval; CRM: circumferential resection margin; M-H: Mantel Haenszel method; TaTME: transnal total mesorectal excision
Figure 45: Comparison 4: Transanal total mesorectal excision versus laparoscopic surgery for rectal cancer – Postoperative mortality
CI: confidence interval; TaTME: transanal total mesorectal excision
Figure 46: Comparison 4: Transanal total mesorectal excision versus laparoscopic surgery for rectal cancer – Anastomotic leak and/or abscess
CI: confidence interval; M-H: Mantel Haenszel method; TaTME: transanal total mesorectal excision
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1 Appendix F – GRADE tables
2 GRADE tables for review question: What is the optimal surgery for rectal cancer?
3 Table 9: Clinical evidence profile for comparison 1: Laparoscopic versus open surgery for rectal cancer
Quality assessment No of patients Effect No of Design Risk of Inconsistency Indirectness Imprecision Other Laparoscopic Open Relative Absolute studie bias consideratio surgery surgery (95% CI) Importan s ns Quality ce Overall survival (median 3.2 to 9.2 years of follow-up; event is death from any cause) 9 randomised no no serious serious3 no serious none 1,601 1,130 HR 0.83 At 5 years MODERATE CRITICAL trials serious inconsistency imprecision (0.70 to open 85%2, risk of 0.99) laparoscopic bias 87.4% (85.1% to 89.2%) Quality of life - Global quality of life (QLQ-C30) - Change from baseline at 4 weeks (range of scores: 0-100; Better indicated by higher values) 1 randomised serious5 no serious serious3 serious6 none 230 108 - MD 0.3 VERY LOW CRITICAL trials inconsistency higher (4.7 lower to 5.3 higher) Quality of life - Global quality of life (QLQ-C30) - Change from baseline at 6 months (range of scores: 0-100; Better indicated by higher values) 1 randomised serious5 no serious serious3 serious6 none 221 106 - MD 2.2 VERY LOW CRITICAL trials inconsistency lower (6.8 lower to 2.4 higher)
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Quality assessment No of patients Effect No of Design Risk of Inconsistency Indirectness Imprecision Other Laparoscopic Open Relative Absolute studie bias consideratio surgery surgery (95% CI) Importan s ns Quality ce Quality of life - Global quality of life (QLQ-C30) - Change from baseline at 12 months (range of scores: 0-100; Better indicated by higher values) 1 randomised serious5 no serious serious3 serious6 none 208 97 - MD 1.8 VERY LOW CRITICAL trials inconsistency lower (6.1 lower to 2.5 higher) Quality of life - Global health status (EQ-VAS) - Change from baseline at 4 weeks (range of scores: 0-100; Better indicated by higher values) 1 randomised serious5 no serious serious3 serious1 none 232 104 - MD 1.6 VERY LOW CRITICAL trials inconsistency higher (3.3 lower to 6.5 higher) Quality of life - Global health status (EQ-VAS) - Change from baseline at 6 months (range of scores: 0-100; Better indicated by higher values) 1 randomised serious5 no serious serious3 serious1 none 219 102 - MD 1.7 VERY LOW CRITICAL trials inconsistency higher (2.4 lower to 5.8 higher) Quality of life - Global health status (EQ-VAS) - Change from baseline at 12 months (range of scores: 0-100; Better indicated by higher values) 1 randomised serious5 no serious serious3 serious1 none 206 91 - MD 0.6 VERY LOW CRITICAL trials inconsistency higher (3.4 lower to 4.6 higher) Quality of life - General health score (SF-36) - At 12 months (range of scores: 0-100; Better indicated by higher values) 1 randomised serious5 no serious serious3 serious1 none 83 85 - Laparoscopi VERY LOW CRITICAL trials inconsistency c: 74 Open 65 p=0.0001 Quality of life - General health score (SF-36) - At 24 months after surgery (range of scores: 0-100; Better indicated by higher values) 1 randomised serious5 no serious serious3 serious1 none 83 85 - Laparoscopi VERY LOW CRITICAL trials inconsistency c: 72 Open: 65 Not significant (p-value not reported)
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Quality assessment No of patients Effect No of Design Risk of Inconsistency Indirectness Imprecision Other Laparoscopic Open Relative Absolute studie bias consideratio surgery surgery (95% CI) Importan s ns Quality ce Quality of life - Sexual functioning (QLQ-CR38) - Change from baseline at 4 weeks (range of scores: 0-100; Better indicated by higher values) 1 randomised serious5 no serious serious3 serious6 none 207 98 - MD 2.5 VERY LOW CRITICAL trials inconsistency higher (0.3 lower to 5.3 higher) Quality of life - Sexual functioning (QLQ-CR38) - Change from baseline at 6 months (range of scores: 0-100; Better indicated by higher values) 1 randomised serious5 no serious serious3 serious6 none 206 96 - MD 0.8 VERY LOW CRITICAL trials inconsistency lower (5.5 lower to 3.9 higher) Quality of life - Sexual functioning (QLQ-CR38) - Change from baseline at 12 months (range of scores: 0-100; Better indicated by higher values) 1 randomised serious5 no serious serious3 serious6 none 197 89 - MD 3.1 VERY LOW CRITICAL trials inconsistency higher (1.7 lower to 7.9 higher) Quality of life - Sexual functioning (QLQ-CR38) - Change from baseline at 24 months (range of scores: 0-100; Better indicated by higher values) 1 randomised serious5 no serious serious3 serious6 none 141 64 - MD 4.6 VERY LOW CRITICAL trials inconsistency higher (1.7 lower to 10.9 higher) Quality of life - Sexual enjoyment (QLQ-CR38) - Change from baseline at 6 months (range of scores: 0-100; Better indicated by higher values) 1 randomised serious5 no serious serious3 very serious7 none 72 37 - MD 0.7 VERY LOW CRITICAL trials inconsistency higher (13.6 lower to 15 higher) Quality of life - Sexual enjoyment (QLQ-CR38) - Change from baseline at 12 months (range of scores: 0-100; Better indicated by higher values) 1 randomised serious5 no serious serious3 very serious7 none 87 38 - MD 8 higher VERY LOW CRITICAL trials inconsistency (5 lower to 21 higher) Quality of life - Sexual enjoyment (QLQ-CR38) - Change from baseline at 24 months (range of scores: 0-100; Better indicated by higher values) 1 randomised serious5 no serious serious3 very serious7 none 41 21 - MD 2.1 VERY LOW CRITICAL trials inconsistency lower (17.2 lower to 13 higher)
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Quality assessment No of patients Effect No of Design Risk of Inconsistency Indirectness Imprecision Other Laparoscopic Open Relative Absolute studie bias consideratio surgery surgery (95% CI) Importan s ns Quality ce Quality of life - Female sexual problems (QLQ-CR38) - Change from baseline at 6 months (range of scores: 0-100; Better indicated by lower values) 1 randomised serious5 no serious serious3 very serious5 none 19 10 - MD 5.1 VERY LOW CRITICAL trials inconsistency higher (16.5 lower to 26.7 higher) Quality of life - Female sexual problems (QLQ-CR38) - Change from baseline at 12 months (range of scores: 0-100; Better indicated by lower values) 1 randomised serious5 no serious serious3 very serious7 none 19 14 - MD 0.9 VERY LOW CRITICAL trials inconsistency higher (20.8 lower to 22.6 higher) Quality of life - Female sexual problems (QLQ-CR38) - Change from baseline at 24 months (range of scores: 0-100; Better indicated by lower values) 1 randomised serious5 no serious serious3 very serious7 none 7 5 - MD 11.8 VERY LOW CRITICAL trials inconsistency higher (18.9 lower to 42.5 higher) Quality of life - Overall level of sexual function decreased ‘quite a lot’ or ‘severely’ as a result of surgery in women (FSFI) 1 randomised serious5 no serious serious3 serious1 none 8/29 3/17 RR 1.56 99 more per VERY LOW CRITICAL trials inconsistency (27.6%) (17.6%) (0.48 to 1000 (from 5.11) 92 fewer to 725 more) Quality of life - Male sexual problems (QLQ-CR38) - Change from baseline at 4 weeks (range of scores: 0-100; Better indicated by lower values) 1 randomised serious5 no serious serious3 very serious7 none 91 41 - MD 6.5 VERY LOW CRITICAL trials inconsistency lower (19.9 lower to 6.9 higher) Quality of life - Male sexual problems (QLQ-CR38) - Change from baseline at 6 months (range of scores: 0-100; Better indicated by lower values) 1 randomised serious5 no serious serious3 very serious7 none 116 47 - MD 6.9 VERY LOW CRITICAL trials inconsistency lower (20.5 lower to 6.7 higher) Quality of life - Male sexual problems (QLQ-CR38) - Change from baseline at 12 months (range of scores: 0-100; Better indicated by lower values) 1 randomised serious5 no serious serious3 serious6 none 117 50 - MD 9.8 VERY LOW CRITICAL trials inconsistency lower (22.3 lower to 2.7 higher)
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Quality assessment No of patients Effect No of Design Risk of Inconsistency Indirectness Imprecision Other Laparoscopic Open Relative Absolute studie bias consideratio surgery surgery (95% CI) Importan s ns Quality ce Quality of life - Male sexual problems (QLQ-CR38) - Change from baseline at 24 months (range of scores: 0-100; Better indicated by lower values) 1 randomised serious5 no serious serious3 very serious7 none 78 37 - MD 1.1 VERY LOW CRITICAL trials inconsistency higher (12.2 lower to 14.4 higher) Quality of life - Overall sexual dysfunction median 3 years after surgery among previously sexually active men (IIEF) 1 randomised serious5 no serious serious3 serious1 none 7/15 1/22 RR 10.27 421 more VERY LOW CRITICAL trials inconsistency (46.7%) (4.5%) (1.4 to per 1000 75.1) (from 18 more to 1000 more) Quality of life - A severe change in overall level of sexual function perceived in men (IIEF) 1 randomised serious5 no serious serious3 serious1 none 23/56 6/26 RR 1.78 180 more VERY LOW CRITICAL trials inconsistency (41.1%) (23.1%) (0.83 to per 1000 3.84) (from 39 fewer to 655 more) Quality of life - Micturitional symptoms (QLQ-CR38) - Change from baseline at 4 weeks (range of scores: 0-100; Better indicated by lower values) 1 randomised serious5 no serious serious3 serious6 none 219 103 - MD 0.9 VERY LOW CRITICAL trials inconsistency higher (4.4 lower to 6.2 higher) Quality of life - Micturitional symptoms (QLQ-CR38) - Change from baseline at 6 months (range of scores: 0-100; Better indicated by lower values) 1 randomised serious5 no serious serious3 serious6 none 219 101 - MD 1 lower VERY LOW CRITICAL trials inconsistency (5 lower to 3 higher) Quality of life - Micturitional symptoms (QLQ-CR38) - Change from baseline at 12 months (range of scores: 0-100; Better indicated by lower values) 1 randomised serious5 no serious serious3 serious6 none 209 95 - MD 2.2 VERY LOW CRITICAL trials inconsistency higher (2 lower to 6.4 higher) Quality of life - Micturitional symptoms (QLQ-CR38) - Change from baseline at 24 months (range of scores: 0-100; Better indicated by lower values) 1 randomised serious5 no serious serious3 serious6 none 170 79 - MD 2.4 VERY LOW CRITICAL trials inconsistency higher (2.4
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Quality assessment No of patients Effect No of Design Risk of Inconsistency Indirectness Imprecision Other Laparoscopic Open Relative Absolute studie bias consideratio surgery surgery (95% CI) Importan s ns Quality ce lower to 7.2 higher) Quality of life - Bladder function at 2 weeks, 3, 6, and 18 months after surgery (IPSS and QLQ-CR38) 1 randomised serious5 no serious serious3 serious1 none 98 50 - "No VERY LOW CRITICAL trials inconsistency differences in bladder function were detected at any time point between the laparoscopic and open rectal groups." Positive CRM 9 randomised no no serious no serious serious1 none 93/1,181 55/1,065 RR 1.35 18 more per MODERATE CRITICAL trials serious inconsistency indirectness (7.9%) (5.2%) (0.98 to 1000 (from 1 risk of 1.86) fewer to 44 bias more) Positive CRM (<2 mm) 1 randomised no no serious serious3 serious1 none 56/588 30/300 RR 0.95 5 fewer per LOW CRITICAL trials serious inconsistency (9.5%) (10%) (0.63 to 1000 (from risk of 1.45) 37 fewer to bias 45 more) Positive distal resection margin 5 randomised no no serious no serious serious1 none 8/682 (1.2%) 5/665 RR 1.50 4 more per MODERATE CRITICAL trials serious inconsistency indirectness (0.75%) (0.50 to 1000 (from 4 risk of 4.54) fewer to 27 bias more) Positive radial resection margin (≤1 mm) 1 randomised no no serious no serious serious1 none 29/240 17/222 RR 1.58 44 more per MODERATE CRITICAL trials serious inconsistency indirectness (12.1%) (7.7%) (0.89 to 1000 (from 8 risk of 2.79) fewer to 137 bias more)
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Quality assessment No of patients Effect No of Design Risk of Inconsistency Indirectness Imprecision Other Laparoscopic Open Relative Absolute studie bias consideratio surgery surgery (95% CI) Importan s ns Quality ce Positive radial resection margin (≤2 mm) 1 randomised serious4 no serious serious3 serious1 none 0/20 (0%) 4/20 (20%) Peto odds 173 fewer VERY LOW CRITICAL trials inconsistency ratio 0.11 per 1000 (0.01, 0.88) (from 198 fewer to 20 fewer) Positive resection margin ("cancer cell found in the cut margins") 1 randomised serious4 no serious no serious serious1 none 0/82 0/89 RD 0.00 (- 0 fewer per LOW CRITICAL trials inconsistency indirectness (0%) (0%) 0.02, 0.02) 1000 (from 20 fewer to 20 more) Local recurrence (time to event outcome; median 3.2 to 4 years of follow-up) 3 randomised no no serious no serious serious1 none 7/350 13/351 HR 0.57 At 3 years MODERATE IMPORTA trials serious inconsistency indirectness (3.9%) (3.1%) (0.25 to open 4.9%8, NT risk of 1.26) laparoscopic bias 2.8% (1.2% to 6.6 %) Local or locoregional recurrence (median 3 to 7.5 years of follow-up) 9 randomised no no serious serious3 serious1 none 68/1,414 46/1,106 RR 1.13 5 more per LOW IMPORTA trials serious inconsistency (4.8%) (4.2%) (0.78 to 1000 (from 9 NT risk of 1.62) fewer to 26 bias more) Length of hospital stay (days) - Anterior resection or abdominoperineal resection 4 randomised no very serious9 serious3 no serious none 1,060 690 - MD 0.25 VERY LOW IMPORTA trials serious imprecision lower (0.91 NT risk of lower to 0.4 bias higher) 1 randomised no no serious serious serious1 none 253 128 - Laparoscopi LOW IMPORTA trials serious inconsistency c: median 11 NT risk of (IQR 9-15) bias Open: median 13 (IQR 9-18) No difference
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Quality assessment No of patients Effect No of Design Risk of Inconsistency Indirectness Imprecision Other Laparoscopic Open Relative Absolute studie bias consideratio surgery surgery (95% CI) Importan s ns Quality ce between groups, narratively reported. Length of hospital stay (days) - Sphincter-preserving surgery 4 randomised serious5 no serious serious3 no serious none 281 291 - MD 4.95 LOW IMPORTA trials inconsistency imprecision lower (5.89 NT to 4.01 lower) 1 randomised no no serious serious3 no serious none 238 237 - Laparoscopi MODERATE IMPORTA trials serious inconsistency imprecision c: median 8 NT risk of (IQR 6-12) bias Open: median 8 (IQR 6-12) p=0.21 1 randomised no no serious no serious serious1 none 170 170 - Laparoscopi MODERATE IMPORTA trials serious inconsistency indirectness c: median 8 NT risk of (IQR 7-12) bias Open: median 9 (IQR 8-12) p=0.056 Length of hospital stay (days) - Abdominoperineal resection 1 randomised no no serious serious3 serious1 none 51 48 - Laparoscopi LOW IMPORTA trials serious inconsistency c: mean NT risk of 10.8 (range bias 5-27) Open: mean 11.5 (range 5-38) p=0.55 30-day mortality 4 randomised no no serious serious3 serious1 none 12/1,209 11/844 RR 0.71 4 fewer per LOW IMPORTA trials serious inconsistency (0.99%) (1.3%) (0.31 to 1000 (from 9 NT 1.6)
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Quality assessment No of patients Effect No of Design Risk of Inconsistency Indirectness Imprecision Other Laparoscopic Open Relative Absolute studie bias consideratio surgery surgery (95% CI) Importan s ns Quality ce risk of fewer to 8 bias more) 90-day mortality 1 randomised no no serious no serious serious1 none 0/170 0/170 RD 0.00 (- 0 fewer per MODERATE IMPORTA trials serious inconsistency indirectness (0%) (0%) 0.01, 0.01) 1000 (from NT risk of 10 fewer to bias 10 more) Operative mortality (timeframe not defined) 6 randomised no no serious serious3 serious1 none 17/585 27/823 RR 1.03 1 fewer per LOW IMPORTA trials serious inconsistency (2.9%) (3.3%) (0.57 to 1000 (from NT risk of 1.86) 14 fewer to bias 28 more) Anastomotic leak 10 randomised no no serious serious3 serious1 none 85/1,418 64/1,198 RR 0.94 3 fewer per LOW IMPORTA trials serious inconsistency (6%) (5.3%) (0.68 to 1000 (from NT risk of 1.29) 17 fewer to bias 15 more) Surgical site infection 10 randomised no no serious serious3 serious1 none 97/1,572 86/1,106 RR 0.79 16 fewer per LOW IMPORTA trials serious inconsistency (6.2%) (7.8%) (0.6 to 1000 (from NT risk of 1.05) 31 fewer to bias 4 more) Blood loss (ml) - Anterior resection or abdominoperineal resection 3 randomised no serious10 no serious no serious none 357 338 - MD 100.71 MODERATE IMPORTA trials serious indirectness imprecision lower NT risk of (132.25 to bias 69.17 lower) 1 randomised no no serious serious3 no serious none 699 345 - Laparoscopi MODERATE IMPORTA trials serious inconsistency imprecision c: median NT risk of 200 (IQR bias 100-400) Open: median 400 (IQR 200- 700)
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Quality assessment No of patients Effect No of Design Risk of Inconsistency Indirectness Imprecision Other Laparoscopic Open Relative Absolute studie bias consideratio surgery surgery (95% CI) Importan s ns Quality ce p<0.0001 Blood loss (ml) - Sphincter-preserving surgery 4 randomised no no serious serious3 no serious none 281 291 - MD 183 MODERATE IMPORTA trials serious inconsistency imprecision lower NT risk of (276.09 to bias 89.91 lower) 1 randomised no no serious serious3 no serious none 238 237 - Laparoscopi MODERATE IMPORTA trials serious inconsistency imprecision c: median NT risk of 100 (IQR bias 50-200) Open: median 150 (55-300) p=0.02 1 randomised no no serious no serious serious1 none 170 170 - Laparoscopi MODERATE IMPORTA trials serious inconsistency indirectness c: median NT risk of 200 (IQR bias 100-300) Open: median 217.5 (IQR 150-400) p=0.006 Blood loss (ml) - Abdominoperinal resection 1 randomised no no serious serious3 serious1 none 51 48 - Laparoscopi LOW IMPORTA trials serious inconsistency c: mean NT risk of 321.7 (range bias 0-3000) Open: mean 555.6 (range 0-4720) p=0.093 1 CI: confidence interval; CRM: circumferential resection margin; EQ-VAS: EuroQol visual analogue scale; FSFI: Female Sexual Function Index; HR: hazard ratio; IIEF: International 2 Index of Erectile Function questionnaire; IPSS: International Prostate Symptom score; IQR: interquartile range; MD: mean difference; QLQ-C30: Quality of Life Questionnaire Core 3 30 Items; QLQ-CR38: Quality of Life Questionnaire colorectal cancer module (38 items); RD: risk difference; RR: relative risk; SF-36: 36-item Short Form health survey 4 1 Quality of evidence downgraded by 1 because of imprecision of the effect estimate (<300 events for dichotomous outcomes or sample size <400 for continuous outcomes).
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1 2 Survival percentage at 5 years in the control group estimated using 5-year survival data from Ng 2014 and Ng 2008, and 3-year survival data from COREAN trial (Jeong 2014) 2 and 10-year survival data from Ng 2009. 3 3 Quality of evidence downgraded by 1 because a considerable proportion of the population had or likely had (not clearly reported) early (T1-2N0M0 or stage 0/I) rectal cancer. 4 4 Quality of evidence downgraded by 1 because of risk of selection bias (method of randomisation or allocation concealment were not reported). 5 5 Quality of evidence downgraded by 1 because of risk of detection bias (there was no blinding of intervention which might affect assessment of outcome). 6 6 Quality of evidence downgraded by 1 because the imprecision of the effect estimate (95% CI crosses 1 MID). 7 7 Quality of evidence downgraded by 2 because of the imprecision of the effect estimate (95% CI crosses 2 MIDs). 8 8 Local recurrence percentage at 3 years in the control group taken from COREAN trial (Jeong 2014). 9 9 Quality of evidence downgraded by 2 because of serious heterogeneity. 10 10 Quality of evidence downgraded by 1 because of heterogeneity.
11 Table 10: Clinical evidence profile for comparison 2: Robotic versus open surgery for rectal cancer
Quality assessment No of patients Effect No of Design Risk of Inconsistency Indirectness Imprecision Other Robotic Open Relative Absolute studie bias considerations surgery surgery (95% CI) Qualit s y Importance Overall survival (median follow-up 3 years; event is death from any cause) 2 observational serious1 no serious serious2 serious3 none 596 1,156 HR 0.98 At 3 years VERY CRITICAL studies inconsistency (0.68 to open LOW 1.42) 92%, robotic 92% (89% to 95%)5 Quality of life - Moderate or severe sexual dysfunction in men ≤65 years (VAS 2-5) 1 observational very no serious serious2 serious3 none 27/141 108/332 RR 0.59 133 fewer VERY CRITICAL studies serious1,4 inconsistency (19.1%) (32.5%) (0.41 to per 1000 LOW 0.85) (from 49 fewer to 192 fewer) Quality of life - Severe sexual dysfunction in men ≤65 years (VAS 4-5) 1 observational very no serious serious2 serious3 none 13/141 37/332 RR 0.83 19 fewer VERY CRITICAL studies serious1,4 inconsistency (9.2%) (11.1%) (0.45 to per 1000 LOW 1.51) (from 61 fewer to 57 more) Quality of life - Moderate sexual dysfunction in men ≤65 years (VAS 2-3)
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Quality assessment No of patients Effect No of Design Risk of Inconsistency Indirectness Imprecision Other Robotic Open Relative Absolute studie bias considerations surgery surgery (95% CI) Qualit s y Importance 1 observational very no serious serious2 serious3 none 14/141 71/332 RR 0.46 115 fewer VERY CRITICAL studies serious1,4 inconsistency (9.9%) (21.4%) (0.27 to per 1000 LOW 0.8) (from 43 fewer to 156 fewer) Positive resection margin 1 observational serious1 no serious serious2 no serious none 106/1,937 1,256/14,735 RR 0.64 31 fewer VERY CRITICAL studies inconsistency imprecision (5.5%) (8.5%) (0.53 to per 1000 LOW 0.78) (from 19 fewer to 40 fewer) Positive CRM (≤1 mm) 1 observational serious1 no serious serious2 serious3 none 8/533 26/1,095 RR 0.63 9 fewer VERY CRITICAL studies inconsistency (1.5%) (2.4%) (0.29 to per 1000 LOW 1.39) (from 17 fewer to 9 more) Postive resection margin (R1) 1 observational serious1 no serious serious2 serious3 none 0/65 2/55 Peto 32 fewer VERY CRITICAL studies inconsistency (0%) (3.6%) odds per 1000 LOW ratio (from 36 0.11 fewer to (0.01, 28 more) 1.81) Positive distal resection margin (≤5 mm) 1 observational serious1 no serious serious2 serious3 none 5/533 13/1,095 RR 0.79 2 fewer VERY CRITICAL studies inconsistency (0.94%) (1.2%) (0.28 to per 1000 LOW 2.2) (from 9 fewer to 14 more) Local recurrence 0 No RCT ------IMPORTANT evidence available
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Quality assessment No of patients Effect No of Design Risk of Inconsistency Indirectness Imprecision Other Robotic Open Relative Absolute studie bias considerations surgery surgery (95% CI) Qualit s y Importance Length of hospital stay (days) 0 No RCT ------IMPORTANT evidence available Operative mortality 0 No RCT ------IMPORTANT evidence available Treatment-related complications 0 No RCT ------IMPORTANT evidence available 1 CI: confidence interval; CRM: circumferential resection margin; R1: positive resection margin; RCT: randomised controlled trial; RR relative risk; VAS: visual analogue scale 2 1 Quality of evidence downgraded by 1 because of risk of bias due to lack of adjustment for confounding or case mix. 3 2 Quality of evidence downgraded by 1 because a considerable proportion of the population had or likely had (not clearly reported) early (T1-2N0M0 or stage 0/I) rectal cancer. 4 3 Quality of evidence downgraded by 1 because of imprecision of the effect estimate (less than 300 events for dichotomous outcomes or sample size less than 400 for continuous 5 outcomes). 6 4 Quality of evidence downgraded by 1 because of no blinding. 7 5 Estimated using the 3 year overall survival in the open surgery group from Kim 2016
8 Table 11: Clinical evidence profile for comparison 3: Robotic versus laparoscopic surgery for rectal cancer
Quality assessment No of patients Effect No of Design Risk of Inconsistency Indirectness Imprecision Other Robotic Lapar Relative Absolute studie bias considerations surgery oscopi (95% CI) s c surger Qualit y y Importance Overall survival (median follow-up 3 to 5 years; event is death from any cause) 8 observational serious1 no serious serious2 serious3 none 1,471 1,300 HR 1.07 At 3 years VERY CRITICAL studies inconsistency (0.87 to laparoscop LOW 1.31) ic 94%,
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Quality assessment No of patients Effect No of Design Risk of Inconsistency Indirectness Imprecision Other Robotic Lapar Relative Absolute studie bias considerations surgery oscopi (95% CI) s c surger Qualit y y Importance robotic 94% (92% to 95%)7 Quality of life - Global health status (QLQ-C30) 1 randomised serious4 no serious serious2 serious3 none 66 73 No - VERY CRITICAL trials inconsistency differenc LOW e between the two groups at 3 weeks, 3 months, and 12 months after surgery. Quality of life - Sexual function mean score at 12 months (QLQ-CR38) (range of scores: 0-100; Better indicated by higher values) 1 randomised serious4 no serious serious2 serious3 none 66 73 - MD 12.2 VERY CRITICAL trials inconsistency higher LOW (1.37 to 23.03 higher) Quality of life – Female sexual function at 6 months (FSFI) (range of scores: 2-36; Better indicated by higher values) 1 randomised serious4,5 no serious serious2 serious3 none 25 29 - Adjusted6 VERY CRITICAL trials inconsistency MD -1.23 LOW (-6.00 to 3.54) Quality of life – Male sexual function at 6 months (IIEF) (range of scores: 5-75; Better indicated by lower values) 1 randomised serious4,5 no serious serious2 serious3 none 97 84 - Adjusted6 VERY CRITICAL trials inconsistency MD -0.80 LOW (-5.70 to 4.10) Quality of life – Bladder function at 6 months (IPSS) (range of scores 0-35; Better indicated by lower values)
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Quality assessment No of patients Effect No of Design Risk of Inconsistency Indirectness Imprecision Other Robotic Lapar Relative Absolute studie bias considerations surgery oscopi (95% CI) s c surger Qualit y y Importance 1 randomised serious4,5 no serious serious2 serious3 none 175 176 - Adjusted6 VERY CRITICAL trials inconsistency MD -0.74 LOW (-2.07 to 0.59) Positive CRM (≤1 mm) 2 randomised serious5 no serious serious2 serious3 none 16/301 (5.3%) 18/297 RR 0.88 7 fewer per VERY CRITICAL trials inconsistency (6.1%) (0.46 to 1000 (from LOW 1.69) 33 fewer to 42 more) Positive proximal resection margin 1 randomised serious5 no serious serious2 serious3 none 0/235 (0%) 0/224 RD 0 .00 0 fewer per VERY CRITICAL trials inconsistency (0%) (-0.01., 1000 (from LOW 0.01) 10 fewer to 10 more Positive distal resection margin 1 randomised serious5 no serious serious2 serious3 none 0/235 (0%) 1/224 Peto 4 fewer per VERY CRITICAL trials inconsistency (0.45% odds 1000 (from LOW ) ratio 0 fewer to 0.13 24more) (0.00, 6.50) Local recurrence 0 No RCT ------IMPORTANT evidence available Length of hospital stay (days) 2 randomised serious5 no serious serious2 serious3 none 303 307 - MD 0.27 VERY IMPORTANT trials inconsistency lower (1.21 LOW lower to 0.66 higher) 30-day operative mortality
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Quality assessment No of patients Effect No of Design Risk of Inconsistency Indirectness Imprecision Other Robotic Lapar Relative Absolute studie bias considerations surgery oscopi (95% CI) s c surger Qualit y y Importance 1 randomised serious5 no serious serious2 serious3 none 2/236 (0.85%) 2/230 RR 0.97 0 fewer per VERY IMPORTANT trials inconsistency (0.87% (0.14 to 1000 (from LOW ) 6.86) 7 fewer to 51 more) Anastomotic leak 2 randomised serious5 no serious serious2 serious3 none 30/246 (12.2%) 23/254 RR 1.34 31 more VERY IMPORTANT trials inconsistency (9.1%) (0.8 to per 1000 LOW 2.24) (from 18 fewer to 112 more) Surgical site infection within 30 days 1 randomised serious5 no serious serious2 serious3 none 21/236 (8.9%) 19/230 RR 1.08 7 more per VERY IMPORTANT trials inconsistency (8.3%) (0.6 to 1000 (from LOW 1.95) 33 fewer to 78 more) Surgical site infection between 30 days and 6 months after surgery 1 randomised serious5 no serious serious2 serious3 none 4/236 (1.7%) 8/230 RR 0.49 18 fewer VERY IMPORTANT trials inconsistency (3.5%) (0.15 to per 1000 LOW 1.6) (from 30 fewer to 21 more) Blood loss (ml) 1 randomised no no serious serious2 serious3 none 66 73 - Robotic: LOW IMPORTANT trials serious inconsistency median risk of 100 (range bias 0-1,000) Laparosco pic: median 50 (range 0- 300) p<0.0001 1 CI: confidence interval; CRM: circumferential resection margin; FSFI: Female Sexual Function Index; IIEF: International Index of Erectile Function; IPSS: International Prostate 2 Symptom Score; MD: mean difference; QLQ-C30: Quality of Life Questionnaire Core 30 Items; QLQ-CR38: Quality of Life Questionnaire colorectal cancer module (38 items); RCT:
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1 randomised controlled trial; RD: risk difference; RR: relative risk 2 1 Quality of evidence downgraded by 1 because of risk of bias due to lack of adjustment for confounding or case mix. 3 2 Quality of evidence downgraded by 1 because considerable proportion of the population had or likely had (not clear from the paper) early (T1-2N0M0 or stage 0-I) rectal cancer. 4 3 Quality of evidence downgraded by 1 because of imprecision of the effect estimate (less than 300 events for dichotomous outcomes or sample size less than 400 for continuous 5 outcomes). 6 4 Quality of evidence downgraded by 1 because of no blinding. 7 5 Quality of evidence downgraded by 1 because details about randomisation and allocation concealment were not reported. 8 6 Adjusted for baseline scores and stratification factors (surgeon, sex, preoperative therapy, intended procedure and BMI). 9 7 Estimated using the 3 year overall survival in the laparascopic surgery group from Kim 2016
10 Table 12: Clinical evidence profile for comparison 4: Transanal total mesorectal excision versus laparoscopic surgery for rectal cancer
Quality assessment No of patients Effect No of Design Risk of Inconsistency Indirectness Imprecision Other TaTME Laparo Relative Absolute studie bias considerations scopic (95% CI) s surger Qualit y y Importance Overall survival (median 5 years of follow-up; event is death from any cause) 1 randomised no no serious serious1 serious2 none 7/50 13/50 HR 0.50 At 5 years LOW CRITICAL trials serious inconsistency (14%) (26%) (0.20 to laparoscopi risk of 1.24) c 74.4%3, bias TaTME 86.3% (69.3% to 94.3%) Quality of life - Sexual activity maintained at median 3.2 years after treatment (in previously sexually active participants) 1 randomised serious4 no serious serious1 serious2 none 20/28 9/23 RR 1.83 325 more VERY CRITICAL trials inconsistency (71.4%) (39.1%) (1.04 to per 1000 LOW 3.2) (from 16 more to 861 more) Quality of life - Sexual dysfunction at median 3.2 years after treatment (FSFI score ≤19) in previously sexually active women 1 randomised serious4 no serious serious1 serious2 none 2/5 2/3 RR 0.6 267 fewer VERY CRITICAL trials inconsistency (40%) (66.7%) (0.16 to per 1000 LOW 2.29) (from 560 fewer to 860 more) Quality of life - Erectile function score at median 3.2 years after treatment (IIEF) (range of scores: 5-25; Better indicated by higher values) 1 randomised serious4 no serious serious1 serious2 none 23 16 - TaTME: VERY CRITICAL trials inconsistency median LOW
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Quality assessment No of patients Effect No of Design Risk of Inconsistency Indirectness Imprecision Other TaTME Laparo Relative Absolute studie bias considerations scopic (95% CI) s surger Qualit y y Importance 17.5 (range 5-25) Laparoscop ic: median 7 (range 5- 21) p=0.119 Quality of life - Normal ejaculatory function at median 3.2 years after treatment in previously sexually active men (IIEF) 1 randomised serious4 no serious serious1 serious2 none 14/21 7/16 RR 1.52 227 more VERY CRITICAL trials inconsistency (66.7%) (43.8%) (0.81 to per 1000 LOW 2.87) (from 83 fewer to 818 more) Quality of life - Urinary function quality of life score at median 3.2 years after treatment (IPSS) (range of scores: 0-6; Better indicated by lower values) 1 randomised serious4 no serious serious1 serious2 none 38 34 - TaTME: VERY CRITICAL trials inconsistency median 1 LOW (range 0-6) Laparoscop ic: median 1 (range 0- 5) p=0.967 Quality of life - Urinary function total score at median 3.2 years after treatment (IPSS) (range of scores: 0-35; Better indicated by lower values) 1 randomised serious4 no serious serious1 serious2 none 38 34 - TaTME: VERY CRITICAL trials inconsistency median 5.5 LOW (range 0- 23) Laparoscop ic: median 3.5 (range 0-27) p=0.821 R1 resection (positive CRM)
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Quality assessment No of patients Effect No of Design Risk of Inconsistency Indirectness Imprecision Other TaTME Laparo Relative Absolute studie bias considerations scopic (95% CI) s surger Qualit y y Importance 1 randomised no no serious serious1 serious2 none 2/50 9/50 RR 0.22 140 fewer LOW CRITICAL trials serious inconsistency (4%) (18%) (0.05 to per 1000 risk of 0.98) (from 4 bias fewer to 171 fewer) Positive distal margin 1 randomised no no serious serious1 serious2 none 1/50 4/50 RR 0.25 60 fewer LOW CRITICAL trials serious inconsistency (2%) (8%) (0.03 to per 1000 risk of 2.16) (from 78 bias fewer to 93 more) Local recurrence 1 randomised no no serious serious1 serious2 none 50 50 Insufficie At 5 years LOW IMPORTANT trials serious inconsistency nt data laparoscopi risk of to c 4.8%, bias calculate TaTME 2.6 (2.3% to 7.5%) Length of hospital stay (days) 1 randomised no no serious serious1 serious2 none 50 50 - TaTME: LOW IMPORTANT trials serious inconsistency median 7 risk of (range 3- bias 54) Laparoscop ic: median 8 (range 2- 29) p=0.281 Postoperative mortality 1 randomised no no serious serious1 serious2 none 0/50 1/50 Peto 17 fewer LOW IMPORTANT trials serious inconsistency (0%) (2%) odds per 1000 risk of ratio (from 0 bias 0.14 fewer to (0.00, 102 more) 6.82)
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Quality assessment No of patients Effect No of Design Risk of Inconsistency Indirectness Imprecision Other TaTME Laparo Relative Absolute studie bias considerations scopic (95% CI) s surger Qualit y y Importance Anastomotic leak and/or abscess 1 randomised no no serious serious1 serious2 none 1/50 5/50 RR 0.2 80 fewer LOW IMPORTANT trials serious inconsistency (2%) (10%) (0.02 to per 1000 risk of 1.65) (from 98 bias fewer to 65 more) Surgical site infection 0 No evidence ------IMPORTANT available Blood loss (ml) 0 No evidence ------IMPORTANT available 1 CI: confidence interval; CRM: circumferential resection margin; FSFI: Female Sexual Function Index; HR: hazard ratio; IIEF: International Index of Erectile Function questionnaire; 2 IPSS: International Prostate Symptom score; MD: mean difference; R1: positive margin; RR: relative risk; TaTME: transanal total mesorectal excision 3 1 Quality of evidence downgraded by 1 because considerable proportion of the population likely had (not clear from the paper) early (T1-2N0M0 or stage 0-I) rectal cancer. 4 2 Quality of evidence downgraded by 1 because of imprecision of the effect estimate (less than 300 events for dichotomous outcomes or sample size less than 400 for continuous 5 outcomes). 6 3 Survival percentage at 5 years in the control group taken from the Bordeaux’ trial (Denost 2018). 7 4 Quality of evidence downgraded by 1 because of no blinding.
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1 Appendix G – Economic evidence study selection
2 Economic evidence study selection for review question: What is the optimal 3 surgical technique for rectal cancer? 4 A global search of economic evidence was undertaken for all review questions in this 5 guideline. See Supplement 2 for further information. 6
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1 Appendix H – Economic evidence tables
2 Economic evidence study selection for review question: What is the optimal 3 surgical technique for rectal cancer? 4 No economic evidence was identified which was applicable to this review question. 5
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1 Appendix I – Economic evidence profiles
2 Economic evidence profiles for review question: What is the optimal surgical 3 technique for rectal cancer? 4 No economic evidence was identified which was applicable to this review question.
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1 Appendix J – Economic analysis
2 Economic evidence analysis for review question: What is the optimal surgical 3 technique for rectal cancer? 4 An economic analysis was undertaken to estimate the cost-effectiveness of surgical 5 techniques for rectal cancer.
6 Methods 7 The analysis was developed in Microsoft Excel® and was conducted from the perspective of 8 the NHS and Personal Social Services (PSS) as outlined in the NICE Reference Case (see 9 Developing NICE guidelines: the manual). The model considered a lifetime horizon with 10 future costs and benefits discounted at a rate of 3.5% (as recommended in the NICE 11 reference case).
12 Clinical data and model approach 13 The economic analysis was based on clinical effectiveness data for each of the surgical 14 techniques, which was sourced from the clinical evidence review. However, only the 15 comparison between the open and laparoscopic approach provided sufficient data for all the 16 key outcomes of interest for the economic analysis (overall survival, local recurrence and 17 complications). As a result, a decision was made to separately consider two comparisons in 18 the analysis. In the first, a comparison is made between the open and laparoscopic approach 19 based on evidence from the clinical evidence review. In the second, all four surgical 20 approaches are considered using available data from the clinical evidence review in 21 combination with assumptions to fill in the missing data. The second analysis was therefore 22 considered to be more speculative and the conclusions that can be drawn from the analysis 23 were limited. 24 The clinical values applied in the analysis are detailed in the relevant sections below. In all 25 cases it should be noted that there is considerable uncertainty around the estimates (as 26 shown by the reported Cis). Furthermore, it should be noted that the four way comparison 27 relies on making some assumptions were values were missing and also necessitates making 28 indirect treatment comparisons which further increases uncertainty.
29 Model Structure 30 A partitioned survival analysis was developed to estimate the expected life expectancy, 31 quality adjusted life years (QALYs) and costs associated with the approaches considered in 32 this economic analysis. A partitioned survival analysis divides the model cohort between 33 different health states based on survival curves derived for overall survival (OS) and 34 recurrence free survival (RFS) derived from the accompanying clinical evidence review. The 35 expected OS and RFS are then calculated from the area under the respective curves. For 36 our model, 3 mutually exclusive health states were derived for the cohort to be partitioned 37 into: 38 • alive without progressed disease (equal to the area under the RFS curve) 39 • alive with progressed disease (equal to the area between the RFS curve and the OS 40 curve) 41 • death (area above the OS curve). 42 An illustrative example of the structure of the partitioned survival analysis is shown in Figure 43 47.
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Figure 47: Illustrative example of partitioned survival analysis
1 A partitioned survival analysis approach was chosen over other modelling approaches, for 2 example, a state transition model as only absolute survival estimates at limited set time 3 points were reported by the identified studies and these were the only survival estimates 4 synthesised and reported by the meta-analyses in the accompanying clinical evidence 5 review. Consequently all OS and RFS estimates in the model were derived from these 6 outcomes. Given the scarcity of the time points at which these were reported it was difficult to 7 estimate plausible transition probabilities for use in a state transition model. It was also 8 possible to extrapolate survival beyond that reported by the studies in the accompanying 9 clinical evidence review. This approach is widely used in models of the cost effectiveness of 10 oncology interventions. A review of recent NICE technology appraisals in oncology found that 11 this approach was used in 73% of submissions (Woods 2017). 12 While not a consideration in choosing the most appropriate modelling approach, a partitioned 13 survival analysis is a more intuitive modelling approach for metastases in cancer than state 14 transition models. Evidence from trials and observational studies where survival is a key 15 outcome are almost exclusively reported as median overall and progression-free survival 16 with accompanying hazard ratio and Kaplan Meier survival curves. As these are the primary 17 inputs for partitioned survival analysis the inputs can be easily compared with those 18 observed in the included trials and other external sources. The model can also be more 19 easily compared, for validity, with any potential future study which consider the relevant 20 interventions.
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1 A partitioned survival analysis was performed for both interventions considered in the 2 economic evaluation and for the two further interventions considered in the further 3 speculative analysis and the total time spent in each health state for the model cohort was 4 calculated. Each health state was assigned a quality of life weighting so that survival could 5 be adjusted to QALYs. 6 The economic component of the model was built and run in Microsoft Excel 2013. The model 7 had a cycle length of 1 year. The model had a time horizon of 36 years for which, based on 8 Office of National Statistics (ONS) life tables, over 99.9% of a general population sample 9 would have died. This percentage would be even higher for a population with rectal cancer. 10 The model would therefore comfortably cover a sufficient time horizon to capture all 11 outcomes, QALYs and costs. The model took a NHS and Personal Social Services 12 perspective (PSS) and only outcomes relevant to either organisation were considered. 13 For the reporting of outcomes in the model the open approach was considered the 14 comparator and laparoscopic approach the intervention. Costs and outcomes are reported 15 on a per person basis.
16 Overall survival 17 Overall survival estimates for the comparison between the open and laparoscopic surgical 18 approach were based upon values from the clinical evidence review. Absolute survival 19 estimates showed that 85.0% of patients were alive at five years following treatment with the 20 open surgical approach. The laparoscopic approach was found to reduce overall mortality in 21 comparison to the open approach with an estimated HR of 0.83 (95% CI 0.70-0.99). 22 Overall survival estimates for the comparison between all four surgical approaches were also 23 based upon values from the clinical evidence review. Overall survival values for the open and 24 laparoscopic approach were based on the same methodology used in the two-way 25 comparison between these approaches. Overall survival with the robotic approach was 26 based on an estimated RR of 1.02. This value was estimated from absolute 3 year survival 27 estimates obtained from 1 study (Rouanet 2018) the clinical evidence review which gave 28 survival rates of 88.4% and 84.1% for the laparoscopic and robotic approach, respectively. 29 Overall survival for the TaTME approach was based on the HR of 0.5 (95% CI 0.20-1.24) 30 reported in the clinical evidence review for the comparison between TaTME and the 31 laparoscopic approach. All calculations follow the usual proportional hazard assumptions.
32 Local recurrence 33 Local recurrence estimates for the comparison between the open and laparoscopic surgical 34 approach were based upon values from the clinical evidence review. Absolute estimates 35 from 1 study (Jeong 2014) identified in the accompanying clinical evidence review showed 36 that 4.9% of patients had local recurrence at 3 years following treatment with the open 37 surgical approach. From this study, the laparoscopic approach had lower local recurrence in 38 comparison to the open approach and estimated a HR of 0.40 (95% CI 0.13-1.26). This 39 estimate was chosen for use in the economic model over the pooled estimate from the 40 clinical evidence review as this was the largest and most recent study identified and was 41 considered most applicable to technologies used today. The pooled estimate of 0.57 (95% CI 42 0.25-1.26) would be less favourable to a laparoscopic approach however both estimates 43 have 95% confidence intervals that pass the line of no effect. 44 Local recurrence estimates for the comparison between all four surgical approaches were 45 also based upon values from the clinical evidence review. Local recurrence values for the 46 open and laparoscopic approach were based on the same methodology used in the two-way 47 comparison between these approaches. Local recurrence estimates were not available for 48 the robotic approach. It was therefore assumed that it would be equivalent to local 49 recurrence with the laparoscopic approach. A RR estimate of 1.00 was therefore applied. 50 Local recurrence with the TaTME approach was based on an estimated RR of 0.54. This
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1 value was estimated from absolute local recurrence estimates obtained from the clinical 2 evidence review which gave local recurrence rates of 4.8% and 2.6% at 5 years for the 3 laparoscopic and robotic approach, respectively. As with overall survival the usual 4 proportional hazard assumptions apply.
5 Complications 6 The accompanying clinical evidence review found evidence for 3 types of surgical 7 complications in this comparison: anastomical leak, surgical site infection and excess blood 8 loss. Excess blood loss is not an uncommon occurrence in surgery and it was likely that in all 9 but rare severe cases there will be limited impact on quality of life and costs. This 10 complication was therefore not included in the economic model. Other complications which 11 were highlighted as important such as reduction in sexual function and bladder problems, 12 even though they would have a significant impact upon quality of life were not included in the 13 model. This is because the accompanying evidence review did not find any evidence around 14 these outcomes and it is uncertain, from clinical opinion, whether these would be more 15 favourable in either open or laparoscopic groups. 16 All complications were assumed to have only a short impact upon quality of life and 17 morbidity. No longer-term morbidity was modelled. Whilst anastomical leaks can lead to 18 operative mortality this would beincluded in the perioperative mortality model inputs. 19 The proportion of treatment related complications were estimated for the comparison 20 between the open and laparoscopic surgical approach using values from the clinical 21 evidence review. Absolute estimates for patients treated with the open approach showed that 22 5.3% had an anastomotic leak and 7.8% had a surgical site infection. Complications after the 23 laparoscopic approach were estimated using RRs from the clinical evidence review which 24 suggest that the laparoscopic approach reduces complications with RRs of 0.94 (95% CI 25 0.68-1.29) and 0.79 (95% CI 0.60-1.05) for anastomotic leak and surgical site infection, 26 respectively. 27 Complication estimates for the comparison between all four surgical approaches were also 28 based upon values from the clinical evidence review. Complication estimates for the open 29 and laparoscopic approach were based on the same methodology used in the two-way 30 comparison between these approaches. The proportion of patients with an anastomotic leak 31 after treatment with the robotic approach was based on a reported RR of 1.34 (95% CI 0.80- 32 2.24) in comparison to the laparoscopic approach. There was no data on the proportion of 33 patients with a surgical site infection after treatment with the robotic approach. Therefore this 34 was assumed to be equivalent to laparoscopic approach (i.e. assuming RR of 1.00). The 35 proportion of patients with an anastomotic leak after treatment with the TaTME approach was 36 based on a reported RR of 0.20 (95% CI 0.02-1.65) in comparison to the laparoscopic 37 approach. There was no data on the proportion of patients with a surgical site infection after 38 treatment with the TaTME approach. Therefore this was assumed to be equivalent to 39 laparoscopic approach (i.e. assuming RR of 1.00).
40 Costs 41 The costs considered in the model reflect the perspective of the analysis, thus only costs that 42 are relevant to the UK NHS & PSS were included. Where possible, all costs were estimated 43 in 2016/17 prices. All costs used in the model are presented in Table 13 with the exception of 44 palliative care costs which are presented in Table 14. 45 The majority of costs were sourced from NHS reference costs 2016/17 by applying tariffs 46 associated with the appropriate Healthcare Resource Groups (HRG) code. However, note 47 that the cost of the surgical procedure in NHS reference costs (FF31: complex large intestine 48 procedures, 19 years and over) is the same regardless of the approach taken. Therefore this 49 cost was not estimated using the procedure code from NHS reference costs and an 50 alternative approach was adopted in order to differentiate the various surgical techniques.
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1 Surgical equipment costs 2 Surgical equipment costs were estimated using data from a cost-effectiveness analysis of 3 surgical approaches in prostate cancer (Ramsay 2012), with costs inflated to 2016 prices. 4 Equipment costs were estimated to be £1,502, £1,605, £4,628 and £1,815 for the open, 5 laparoscopic, robotic, and TaTME approaches, respectively. Operative time costs were 6 estimated using average theatre time estimates from the studies included in the clinical 7 evidence review. A cost for an hour of operating theatre time was sourced the cost- 8 effectiveness analysis from Ramsay 2012 and inflated to 2016 prices (£1,266). Length of 9 stay costs were estimated using data on the number of days for each procedure from the 10 studies included in the clinical evidence review combined with the cost of an excess bed day 11 from NHS reference costs 2016/17. The length of hospital stay was meta-analysed by type of 12 resection in the clinical evidence review given heterogeneity. This economic analysis does 13 not investigate the cost effectiveness of the interventions by these subgroup so a pooled 14 estimate of all length of stays was used in the economic model. This distribution was given a 15 wide uniform distribution in the probabilistic sensitivity analysis given the considerations 16 around heterogeneity.
17 Complication costs 18 Complication costs were estimated using the different costs associated with complication and 19 co-morbidity (CC) scores for the surgical procedure from NHS reference costs. The 20 difference between CC score 0-2 (used as a best estimate for no complications) and a 21 weighted average of the other CC scores associated with complex large intestine procedures 22 (FF31) was used as an estimate of complication costs.
23 Systemic chemotherapy costs 24 Systemic chemotherapy costs were estimated assuming that patients would be treated with 6 25 cycles of FOLFIRI or FOLFOX. The chemotherapy delivery costs were sourced from NHS 26 Reference Costs 2015/16 (assuming day case delivery) and drug costs were sourced from 27 eMit.
28 Inpatient and outpatient management costs 29 The cost of palliative care was estimated using estimates from a costing report by the 30 Nuffield Trust (Georghiou 2014). A cost of £7,287 was applied based on the average 31 resource use of patients with cancer in the last three months of life.
32 Table 13: Costs and cost weightings used in the economic model Weight Cost Source Complex Large Intestine Procedures, 19 years and over with CC Score 9+ NHS Reference costs (FF31A) 3% £13,567.94 2016/17 with CC Score 6-8 NHS Reference costs (FF31B) 6% £10,626.33 2016/17 with CC Score 3-5 NHS Reference costs (FF31C) 22% £8,810.93 2016/17 with CC Score 0-2 NHS Reference costs (FF31D) 70% £7,370.66 2016/17 Weighted average 100% £8,026.32 Complex Large Intestine Procedures, 19 years and over-Excess bed days with CC Score 9+ NHS Reference costs (FF31A) 6% £247.57 2016/17 with CC Score 6-8 NHS Reference costs (FF31B) 18% £298.73 2016/17
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Weight Cost Source with CC Score 3-5 NHS Reference costs (FF31C) 23% £354.04 2016/17 with CC Score 0-2 NHS Reference costs (FF31D) 53% £326.78 2016/17 Weighted average 100% £323.36 Operative and length of stay costs Operative time cost £1,265.90 Ramsay 2012 per hour of surgery LOS - cost per day £323.36 Ramsay 2012 Open approach Equipment cost £1,501.93 Ramsay 2012 Operative time 181 minutes Ramsay 2012 Operative time cost £3,813.41 LOS - number of days 9.68 days Ramsay 2012 LOS cost £3,130.12 Total cost of open £8,445.46 approach Laparoscopic approach Equipment cost £1,605.41 Ramsay 2012 Operative time 225 minutes Ramsay 2012 Operative time cost £4,744.40 LOS - number of days 8.27 days Ramsay 2012 LOS cost £2,674.18 Total cost of £9,024.00 laparoscopic approach Robotic approach Equipment cost £4,627.63 Ramsay 2012 Operative time 282 minutes Ramsay 2012 Operative time cost £5,950.57 LOS - number of days 7.77 days Ramsay 2012 LOS cost £2,512.50 Total cost of robotic £13,090.70 approach TaTME approach Equipment cost £1,814.81 Ramsay 2012 Operative time 205 minutes Ramsay 2012 Operative time cost £4,329.50 Surgeon cost per £107.00 Ramsay 2012 working hour Cost for second £365.95 Ramsay 2012 surgeon LOS - number of days 7.24 days Ramsay 2012 LOS cost £2,339.91
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Weight Cost Source Total cost of TaTME £8,850.16 approach Systemic chemotherapy costs FOLFOX Deliver complex £385.99 NHS Reference costs chemotherapy at first attendance 2016/17 Dexamethasone 8mg £1.52 eMit Ondansetron 16mg £0.17 eMit Chlorphenamine 10mg £3.01 eMit Oxaliplatin 85mg/m2 £16.04 eMit Folinic Acid 350mg £10.42 eMit Fluorouracil 400mg/m2 £3.94 eMit Fluorouracil £8.36 eMit 2400mg/m2 Cost per cycle £429.45 Total cost for 6 £2,576.72 cycles FOLFIRI Deliver complex £385.99 NHS Reference costs chemotherapy at first attendance 2016/17 Atropine 250mcg £0.12 eMit Irinotecan 180mg/m2 £17.35 eMit Folinic Acid 350mg £10.42 eMit Fluorouracil 400mg/m2 £3.94 eMit Fluorouracil £8.36 eMit 2400mg/m2 Cost per cycle £426.18 Total cost for 6 £2,557.09 cycles Average cost of £2,566.91 systemic chemotherapy regimens 1 FOLFIRI: folinic acid, fluorouracil and irinotecan; FOLFOX: folnic acif, fluorouracil and oxaliplatin; LOS: length of 2 stay; CC: clinical complications; eMit: Drugs and pharmaceutical electronic market information tool
3 Cost of palliative care 4 Given the life expectancy of the model cohort and that the majority of patients would die as a 5 result of their disease a one off cost of palliative care was applied to the entirety of the cohort 6 during their final year of life. This is to represent the increase in resource use experienced 7 during the final months of a patient’s life. This one off cost was taken from Georghiou 2014. 8 The study used medical records of over 1,836 patients with cancer at multiple UK hospitals 9 and hospices to estimate resource use and publically available UK costs to estimate a total 10 cost for the final 90 days of life. An average cost for patients with cancer was used from the 11 report. These costs are presented in Table 14.
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1 Table 14: Costs of palliative care for patients with cancer from Georghiou 2014 Type of care Cost Cost of all hospital contacts £5,890 Local authority-funded care £444 District nursing care £588 GP contacts £365 Total palliative care cost per patient £7,287
2 The above costs includes ‘local authority-funded care’. The methods of calculation from the 3 original report may include costs, such as personal contributions to care, which are not 4 strictly covered by the NHS & PSS perspective used for this economic model. A deterministic 5 sensitivity analysis was therefore undertaken which removed this cost from the total palliative 6 care cost estimate.
7 Health-related quality of life 8 As recommended in the NICE reference case, the model estimates effectiveness in terms of 9 quality adjusted life years (QALYs). These are estimated by combining life year estimates 10 with quality of life (QoL) values associated with being in a particular health state. 11 QoL data for all comparisons were sourced from Rao 2017, a cost-effectiveness analysis that 12 estimated QoL for recurrences (0.78) and for being recurrence free (0.86).
13 Sensitivity analysis 14 Uncertainty was assessed in the economic model through deterministic and probabilistic 15 sensitivity analysis. A series of deterministic sensitivity analyses were conducted, whereby 16 an input parameter was changed, the model was re-run and the new cost-effectiveness 17 result was recorded. This form of analysis is a useful way of estimating uncertainty and 18 determining the key drivers of the model results. 19 Probabilistic sensitivity analysis (PSA) was conducted to assess the combined parameter 20 uncertainty in the model. In this analysis, the mean values that were utilised in the base-case 21 were replaced with values drawn from distributions around the mean values.
22 Results
23 Overall and recurrence free survival 24 Overall (Figure 48) and recurrence free survival (Figure 49), based on the deterministic point 25 estimates, were unsurprisingly in line with the HRs and RRs used as inputs. There is over a 26 20 percentage point difference between TaTME and the open approach for both overall and 27 recurrence free survival at the greatest point of difference although the uncertainty around 28 the TaTME estimates of both types of survival should be noted.
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1 Figure 48: Overall survival estimated in the economic model
2
3 Figure 49: Recurrence free survival estimated in the economic model
4 5 Base-case results 6 The base case resultsof the analysis, based on the point estimates of the model inputs, are 7 shown in Table 15 and Table 16 for the two-way and four-way comparison respectively. The 8 results of the two way comparison show the laparoscopic approach to be more effective 9 (1.26 QALYs) and less costly than the open approach (£921) and it is therefore dominant. 10 These results are driven by improvements in overall survival which are clinically significant.
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1 In the four-way comparison, alternative approaches were compared using a net monetary 2 benefit approach assuming a threshold of £20,000 per QALY. The results show the TaTME 3 approach to be the least costly approach. All other strategies are found to be more costly and 4 less effective than TaTME and are therefore dominated. Consequently, net monetary benefit 5 was negative for all other interventions. However it should be noted for TaTME that the 6 results are driven by improvements in overall survival and recurrence which were based on a 7 hazard ratio for which the 95% confidence interval passed the line of no effect. It is therefore 8 plausible that TaTME may result in lower QALYs and higher costs (through increased 9 recurrence) compared to alternative approaches. These results should therefore be 10 considered speculative.
11 Table 15: Base case results for two-way comparison Strategy Cost QALYs ICER (cost Total Incremental Total Incremental per QALY Open £11,963 - 9.08 - - Laparoscopic £11,042 -£921 10.34 1.26 Dominant 12 ICER: incremental cost-effectiveness ratio; QALYs: quality adjusted life years
13 Table 16: Base case results for four-way comparison Strategy Cost QALYs ICER (cost NMB per QALY Total Incremental Total Incremental TaTME £9,812 - 11.15 - - Laparoscopic £11,042 £1,230 10.34 -0.81 Dominated -£17,395 Open £11,963 £2,151 9.08 -2.07 Dominated -£43,575 Robotic £15,612 £5,800 9.92 -1.24 Dominated -£30,503 14 ICER: incremental cost-effectiveness ratio; QALYs: quality adjusted life years NMB Net monetary benefit 15 Disaggregated costs are presented in Table 17. The majority of total costs (>60% of total 16 costs) for all interventions is the upfront treatment cost of the surgical procedure.Systemic 17 chemotherapy and palliative care costs are zero for both robotic and TaTME given the 18 assumptions around disease specific mortality.
19 Table 17: Disaggregated costs for four-way analysis Upfront Complication Recurrence Systemic Palliative treatment costs costs chemotherap care costs costs y TaTME £8,850 £259 £1,154 £0 £0 Laparoscopic £9,024 £404 £1,182 £319 £907 Open £8,445 £475 £1,209 £805 £2,284 Robotic £8,850 £259 £1,154 £0 £0 20
21 Deterministic sensitivity results 22 A series of deterministic sensitivity analyses were conducted whereby an input parameter is 23 changed, the model is re-run and the new cost-effectiveness result is recorded. This is a 24 useful way of estimating uncertainty and determining the key drivers of the model result. The 25 results of the deterministic sensitivity analyses are presented in Table 18 and Table 19 for 26 the two-way and four-way comparison, respectively. 27 In the two-way comparison, it can again be seen that the conclusion of the analysis remains 28 unchanged in the majority of modelled scenarios with the laparoscopic approach found to be 29 cost effective. Notably this includes a scenario in which only statistically significant effects
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1 are modelled. The conclusion of the analysis was found to change when the upper HR for 2 overall survival was applied (meaning that overall survival is better with the open approach). 3 In the four-way comparison, it can again be seen that the conclusion of the analysis remains 4 unchanged in the majority of modelled scenarios with TaTME found to be cost effective. 5 However, notably, this does not include a scenario in which only statistically significant 6 effects are modelled (in which the laparoscopic approach is found to be cost effective). The 7 laparoscopic approach was also found to be cost effective when the upper HR for overall 8 survival for TaTME was applied or when overall survival was assumed to be equivalent with 9 laparoscopic and TaTME. The open approach was found to be cost effective when the upper 10 HR for overall survival for TaTME and the laparoscopic approach was applied.
11 Table 18: Deterministic sensitivity results for two-way comparison Modelled scenario Optimal strategy Base case Laparoscopic Overall survival – lower HR Laparoscopic Overall survival – upper HR Laparoscopic Local recurrence – lower RR Laparoscopic Local recurrence – upper RR Laparoscopic Complications – lower RR Laparoscopic Complications – upper RR Laparoscopic Statistically significant changes only Laparoscopic Number of robotic procedures per year = 50 Laparoscopic Number of robotic procedures per year = 100 Laparoscopic Number of robotic procedures per year = 200 Laparoscopic Complication costs + 50% Laparoscopic Complication costs - 50% Laparoscopic No systemic chemotherapy costs Laparoscopic No palliative care costs Laparoscopic No recurrence disutility Laparoscopic 12 HR: hazard ratio; RR: relative risk
13 Table 19: Deterministic sensitivity results for four-way comparison Modelled scenario Optimal strategy Base case TaTME Overall survival – lower HR for laparoscopic TaTME Overall survival – upper HR for laparoscopic TaTME Overall survival – lower HR for TaTME TaTME Overall survival – upper HR for TaTME Laparoscopic Overall survival with TaTME equivalent to laparoscopic Laparoscopic Overall survival – upper HR for TaTME and laparoscopic Open Absolute overall survival with robotic 10% higher TaTME Absolute overall survival with robotic 10% lower TaTME Local recurrence – lower RR for laparoscopic TaTME Local recurrence – upper RR for laparoscopic TaTME Absolute local recurrence with TaTME 10% higher TaTME Absolute local recurrence with TaTME 10% lower TaTME Local recurrence with TaTME equivalent to laparoscopic TaTME Complications – lower RR TaTME
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Modelled scenario Optimal strategy Complications – upper RR TaTME Statistically significant changes only Laparoscopic Number of robotic procedures per year = 50 TaTME Number of robotic procedures per year = 100 TaTME Number of robotic procedures per year = 200 TaTME Complication costs + 50% TaTME Complication costs - 50% TaTME No systemic chemotherapy costs TaTME No palliative care costs TaTME No recurrence disutility TaTME 1 HR: hazard ratio; RR: relative risk; TaTME: transanal total mesorectal excision; TME: total mesorectal excision
2 Probabilistic sensitivity results 3 The results of 10,000 runs of the PSA are shown using ICER scatterplots and cost- 4 effectiveness acceptability curves (CEAC). The ICER scatter plots show the incremental 5 costs and QALYs associated with each of the 10,000 runs of the PSA along with the mean 6 result. The CEAC graphs show the probability of each strategy being considered cost- 7 effective at the various cost-effectiveness thresholds on the x axis. 8 Figure 50 shows the ICER scatterplot for the comparison between the open and laparoscopic 9 surgical approach. It can be seen that, while the results are spread across all four domains of 10 the scatterplot, the majority of the results reside on the East side of the graph. This indicates 11 that in the majority of cases, the laparoscopic approach was found to be more effective. 12 Furthermore, it can be seen that the majority of the cost effectiveness pairs reside below the 13 cost-effectiveness threshold line (£20,000 per QALY) meaning that in the majority of cases, 14 the laparoscopic strategy was found to be cost effective. 15 Figure 51 shows the CEAC for the comparison between the open and laparoscopic surgical 16 approach. It can be seen that the likelihood of the laparoscopic approach being deemed 17 cost-effective increases as the cost-effectiveness threshold increases. At the NICE threshold 18 of £20,000 per QALY, the laparoscopic approach was found to have a 9% probability of 19 being cost effective, while the open approach has a 2% probability of being cost effective. 20 Figure 52 shows the CEAC for the comparison between all four surgical approaches. It can 21 be seen that the likelihood of the TaTME strategy being cost-effective increases as the cost- 22 effectiveness threshold increases while the likelihood of all other strategies being cost- 23 effective decrease. At the NICE threshold of £20,000 per QALY, the TaTME strategy was 24 found to have an 86% probability of being cost effective, while the laparoscopic, open and 25 robotic approach were found to have a 13%, 2% and 0% probability of being cost effective, 26 respectively.
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1 Figure 50: ICER scatterplot for the comparison between the open and laparoscopic 2 surgical approach
3 4 CE: cost-effectiveness; QALYs: quality-adjusted live years
5 Figure 51: Cost-effectiveness acceptability curve (CEAC) for the comparison between 6 the open and laparoscopic surgical approach
7
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1 Figure 52: Cost-effectiveness acceptability curve (CEAC) for the comparison between 2 all four surgical approaches
3 4 TaTME: transanal total mesorectal excision
5 Conclusions 6 The results of the analysis suggest that the laparoscopic approach may be cost effective for 7 rectal cancer surgery. However, there is some uncertainty around the approach, largely 8 driven by the uncertainty around some of the clinical effectiveness estimates especially 9 around recurrence. A speculative analysis comparing the open, laparoscopic, robotic and 10 TaTME approaches suggests that the TaTME may be cost-effective. However, the lack of 11 clear data as well as the assumptions required to run this four-way comparison severely limit 12 the conclusions that can be drawn from the analysis.
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1 Appendix K – Excluded studies
2 Excluded clinical studies for review question: What is the optimal surgical 3 technique for rectal cancer?
4 Table 20: Excluded studies and reasons for their exclusion Study Reason for exclusion Anon. Short-term surgical outcomes and patient A conference abstract quality of life between robotic and laparoscopic extralevator abdominoperineal excision for adenocarcinoma of the rectum Abdujapparov A, Ten Y, Korakhadjaev B. The A conference abstract results of neoadjuvant chemoradiation therapy in combined treatment of rectal cancer. European Journal of Cancer. 2017;72:S50. Abraha I, Aristei C, Palumbo I, Lupattelli M, Wrong comparison: (comparison potentially Trastulli S, Cirocchi R, et al. Preoperative relevant for review C1). A systematic review and radiotherapy and curative surgery for the meta-analysis of RCTs comparing preoperative management of localised rectal carcinoma. radiotherapy and surgery versus surgery alone. Cochrane Database Syst Rev. 2018;10:CD002102. Agha, A., Benseler, V., Hornung, M., Gerken, A non-randomised study comparing M., Iesalnieks, I., Furst, A., Anthuber, M., Jauch, laparoscopic and open surgery. K. W., Schlitt, H. J., Long-term oncologic outcome after laparoscopic surgery for rectal cancer, Surgical Endoscopy and Other Interventional Techniques, 28, 1119-1125, 2014 Agha, A., Furst, A., Iesalnieks, I., Fichtner-Feigl, A non-randomised study comparing S., Ghali, N., Krenz, D., Anthuber, M., Jauch, K. laparoscopic and open surgery. W., Piso, P., Schlitt, H. J., Conversion rate in 300 laparoscopic rectal resections and its influence on morbidity and oncological outcome, International Journal of Colorectal Disease, 23, 409-417, 2008 Ahmad, N. Z., Racheva, G., Elmusharaf, H., A Systematic review of laparoscopic versus open systematic review and meta-analysis of rectal surgery including both RCTs and non- randomized and non-randomized studies RCTs and studies published pre-2000. Included comparing laparoscopic and open RCTs checked for relevance. abdominoperineal resection for rectal cancer, Colorectal Disease, 15, 269-277, 2013 Alecu, L., Stanciulea, O., Poesina, D., No comparison group. Tomulescu, V., Vasilescu, C., Popescu, I., Robotically performed total mesorectal excision for rectal cancer, Chirurgia (Bucuresti), 110, 137-43, 2015 Ali, S., Taylor, B. M., Schlachta, C. M., Insufficient number of participants to get Evaluation of pilot experience with robotic- meaningful data. (Robot group included a total assisted proctectomy and coloanal anastomosis of 3 participants.) for rectal cancer, Canadian journal of surgery, Journal canadien de chirurgie. 58, 188-192, 2015 Allaix, M. E., Giraudo, G., Ferrarese, A., Arezzo, A non-randomised study comparing A., Rebecchi, F., Morino, M., 10-Year Oncologic laparoscopic and open surgery. Outcomes After Laparoscopic or Open Total Mesorectal Excision for Rectal Cancer, World Journal of Surgery, 40, 3052-3062, 2016
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Lelong, B., Bege, T., Esterni, B., Guiramand, J., A non-randomised study comparing Turrini, O., Moutardier, V., Magnin, V., Monges, laparoscopic and open surgery. G., Pernoud, N., Blache, J. L., Giovannini, M., Delpero, J. R., Short-term outcome after laparoscopic or open restorative mesorectal excision for rectal cancer: A comparative cohort study, Diseases of the Colon and Rectum, 50, 176-183, 2007 Leung, K. L., Kwok, S. P., Lam, S. C., Lee, J. F., This study is among people with rectosigmoid Yiu, R. Y., Ng, S. S., Lai, P. B., Lau, W. Y., cancer, therefore, not the right population. Laparoscopic resection of rectosigmoid carcinoma: prospective randomised trial, Lancet, 363, 1187-92, 2004 Leung, K. L., Lai, P. B., Ho, R. L., Meng, W. C., This study is among people with rectosigmoid Yiu, R. Y., Lee, J. F., Lau, W. Y., Systemic cancer, therefore, not the right population. cytokine response after laparoscopic-assisted resection of rectosigmoid carcinoma: A prospective randomized trial, Ann Surg, 231, 506-11, 2000 Leung, Kl, Yiu, Ry, Lai, Pb, Lee, Jf, Thung, Kh, A non-randomised study comparing Lau, Wy, Laparoscopic-assisted resection of laparoscopic and open surgery. colorectal carcinoma: five-year audit, Diseases of the Colon and Rectum, 42, 327-32; discussion 332-3, 1999 Levic, K., Donatsky, A. M., Bulut, O., Non-randomised study comparing robotic versus Rosenberg, J., A Comparative Study of Single- laparoscopic surgery. RCT evidence is available Port Laparoscopic Surgery Versus Robotic- for critical outcomes, apart from overall survival, Assisted Laparoscopic Surgery for Rectal therefore, data from non-randomised studies will Cancer, Surgical Innovation, 22, 368-375, 2015 only be considered for overall survival. This study does not report overall survival. Lezoche, E., Guerrieri, M., De Sanctis, A., A non-randomised study comparing Campagnacci, R., Baldarelli, M., Lezoche, G., laparoscopic and open surgery. Paganini, A. M., Long-term results of laparoscopic versus open colorectal resections for cancer in 235 patients with a minimum follow-up of 5 years, Surgical Endoscopy and Other Interventional Techniques, 20, 546-553, 2006 Li, S., Chi, P., Lin, H., Lu, X., Huang, Y., Long- A non-randomised study comparing term outcomes of laparoscopic surgery versus laparoscopic and open surgery. open resection for middle and lower rectal cancer: An NTCLES study, Surgical Endoscopy and Other Interventional Techniques, 25, 3175- 3182, 2011 Li, S., Jiang, F., Tu, J., Zheng, X., Long-term A non-randomised study comparing oncologic outcomes of laparoscopic versus open laparoscopic and open surgery. surgery for middle and lower rectal cancer, PLoS ONE, 10 (9) (no pagination), 2015 Lim, D. R., Bae, S. U., Hur, H., Min, B. S., Baik, Population not according to protocol: 45% of S. H., Lee, K. Y., Kim, N. K., Long-term participants in one arm with stage 0-I rectal oncological outcomes of robotic versus cancer. laparoscopic total mesorectal excision of mid- low rectal cancer following neoadjuvant chemoradiation therapy, Surgical Endoscopy and Other Interventional Techniques, 31, 1728- 1737, 2017 Lin Y, Lin H, Xu Z, Zhou S, Chi P. Comparative Wrong comparison (compares preoperative Outcomes of Preoperative Chemoradiotherapy chemoradiotherapy with/without postoperative and Selective Postoperative Chemoradiotherapy chemotherapy)
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DRAFT FOR CONSULTATION Optimal surgical technique for rectal cancer
in Clinical Stage T3N0 Low and Mid Rectal Cancer. J Invest Surg. 2018:1-9. Liu, F. L., Lin, J. J., Ye, F., Teng, L. S., Hand- Hand-assisted laparoscopic colorectal surgery is assisted laparoscopic surgery versus the open rarely performed in England and therefore not approach in curative resection of rectal cancer, relevant for this review. Journal of International Medical Research, 38, 916-922, 2010 Liu, L., Cao, Y., Zhang, G., Zhang, L., Wang, P., A non-randomised study comparing Gong, J., Long-term outcomes after laparoscopic and open surgery. laparoscopic total mesorectal excision for advanced rectal cancer, South African Journal of Surgery, 49, 186-189, 2011 Liu, Y., Lu, X. M., Niu, Y. F., Tao, K. X., Wang, A non-randomised study comparing G. B., Application of laparoscopic total laparoscopic and open surgery. mesorectal excision combined with sphincter- preserving surgery in low or ultralow rectal cancer, Journal of Innovative Optical Health Sciences, 9 (5) (no pagination), 2016 Liu, Z., Kang, L., Huang, M., Luo, Y., Wang, L., A non-randomised study comparing Lan, P., Cui, J., Wang, J., Open surgery against laparoscopic and open surgery. laparoscopic surgery for mid-rectal or low-rectal cancer of male patients: Better postoperative genital function of laparoscopic surgery, Surgical Laparoscopy, Endoscopy and Percutaneous Techniques, 25, 444-448, 2015 Lujan, J., Parrila, P., Authors' reply: Randomized Author's reply. The trial this comment refers to is clinical trial comparing laparoscopic and open included in the review. surgery in patients with rectal cancer (Br J Surg 2009; 96: 982-989), British Journal of Surgery, 96, 1496, 2009 Lujan, J., Valero, G., Biondo, S., Espin, E., A non-randomised study comparing Parrilla, P., Ortiz, H., Laparoscopic versus open laparoscopic and open surgery. surgery for rectal cancer: Results of a prospective multicentre analysis of 4,970 patients, Surgical Endoscopy and Other Interventional Techniques, 27, 295-302, 2013 Marks, J. H., Montenegro, G. A., Salem, J. F., Non-randomised study comparing TaTME to Shields, M. V., Marks, G. J., Transanal laparoscopic surgery. Evidence on critical TATA/TME: a case-matched study of taTME outcomes already available from a RCT. versus laparoscopic TME surgery for rectal cancer, Techniques in Coloproctology, 20, 467- 473, 2016 Matsuhashi, N., Takahashi, T., Tanahashi, T., A non-randomised study comparing Matsui, S., Imai, H., Tanaka, Y., Yamaguchi, K., laparoscopic and open surgery. Osada, S., Yoshida, K., Safety and feasibility of laparoscopic intersphincteric resection for a lower rectal tumor, Oncology Letters, 14, 4142- 4150, 2017 Matsumoto, A, Arita, K, Tashiro, M, Haruki, S, A non-randomised study comparing Usui, S, Laparoscopic versus open resection for laparoscopic and open surgery. rectal cancer (RA and RB) based on 10 year data: results of our hospital study in 217 rectal cancer patients, Surgical endoscopy and other interventional techniques., 29, S102, 2015 Milsom, Jw, Böhm, B, Hammerhofer, Ka, Fazio, Published 1998. Includes both colon and rectal V, Steiger, E, Elson, P, A prospective, tumours and results are not stratified according randomized trial comparing laparoscopic versus to tumour location. conventional techniques in colorectal cancer
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Chemotherapy and Radiochemotherapy vs. Radiochemotherapy. 2015 NCT. Phase III Study Comparing Preoperative A clinical trial record; no results (no data) Chemoradiotherapy Alone Versus Neoadjuvant Chemotherapy With Folfirinox Regimen Followed by Preoperative Chemoradiotherapy for Patients With Resectable Locally Advanced Rectal Cancer. 2013 NCT. Preoperative Chemoradiotheray for Rectal Wrong comparison for this research question. A Cancer. 2009 clinical trial record; no results (no data) (linked to Park et al., 2012 [evidence review C1]) Neijenhuis, Pa, Buurma, M, Reimers, M, Kroon, A non-randomised study comparing Hm, Laparoscopic colorectal surgery leads to laparoscopic and open surgery. increased overall survival when compared to a conventional open approach, Surgical endoscopy and other interventional techniques., 29, S104, 2015 Ng, S. S. M., Lee, J. F. Y., Yiu, R. Y. C., Li, J. C. This is a pooled analysis of 3 randomised trials M., Hon, S. S. F., Mak, T. W. C., Leung, W. W., from the same hospital in Hong Kong. The three Leung, K. L., Long-term oncologic outcomes of trials focused on different rectal tumour locations laparoscopic versus open surgery for rectal (lower, middle, upper), and the type of surgery cancer: A pooled analysis of 3 randomized was therefore different (APR or AR). All of these controlled trials, Annals of Surgery, 259, 139- trials have been included in this review. 147, 2014 Nienhuser H, Heger P, Schmitz R, Kulu Y, A systematic review and meta-analysis Diener MK, Klose J, et al. Short- and Long-Term comparing laparoscopic and open surgery. Oncological Outcome After Rectal Cancer Included studies checked. Surgery: a Systematic Review and Meta- Analysis Comparing Open Versus Laparoscopic Rectal Cancer Surgery. J Gastrointest Surg. 2018;22(8):1418-33. Nonaka, T., Fukuda, A., Maekawa, K., A non-randomised study comparing Nagayoshi, S., Tokunaga, T., Takatsuki, M., laparoscopic and open surgery. Kitajima, T., Taniguchi, K., Fujioka, H., Clinical and oncological outcomes of laparoscopic versus open surgery for advanced rectal cancer, Anticancer Research, 36, 5419-5424, 2016 Odermatt, M., Flashman, K., Khan, J., Parvaiz, A non-randomised study comparing A., Laparoscopic-assisted abdominoperineal laparoscopic and open surgery. resection for low rectal cancer provides a shorter length of hospital stay while not affecting the recurrence or survival: a propensity score- matched analysis, Surgery Today, 46, 798-806, 2016 Ohtani H, Maeda K, Nomura S, Shinto O, A systematic review and meta-analysis Mizuyama Y, Nakagawa H, et al. Meta-analysis comparing robotic and laparoscopic surgery. of Robot-assisted Versus Laparoscopic Surgery Included studies checked. for Rectal Cancer. In Vivo. 2018;32(3):611-23. Ohtani, H., Tamamori, Y., Azuma, T., Mori, Y., Systematic review of laparoscopic versus open Nishiguchi, Y., Maeda, K., Hirakawa, K., A Meta- rectal surgery, all included studies checked for analysis of the Short- and Long-Term Results of relevance but not all studies are relevant to our Randomized Controlled Trials That Compared review according to protocol. Laparoscopy-Assisted and Conventional Open Surgery for Rectal Cancer, Journal of Gastrointestinal Surgery, 15, 1375-1385, 2011 Pai, A., Marecik, S. J., Park, J. J., Melich, G., No comparison group. Sulo, S., Prasad, L. M., Oncologic and Clinicopathologic Outcomes of Robot-Assisted
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DRAFT FOR CONSULTATION Optimal surgical technique for rectal cancer
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Der Peet, D. L., Meijerink, W. J. H. J., Cuesta, M. A., Laparoscopic versus open total mesorectal excision: A comparative study on short-term outcomes: A single-institution experience regarding anterior resections and abdominoperineal resections, Digestive Surgery, 24, 367-374, 2007 Veenhof, A. A. F. A., Sietses, C., Von Blomberg, A sub-study of the COLOR II trial. No relevant B. M. E., Van Hoogstraten, I. M. W., Vd Pas, M. outcomes reported. H. G. M., Meijerink, W. J. H. J., Vd Peet, D. L., Vd Tol, M. P., Bonjer, H. J., Cuesta, M. A., The surgical stress response and postoperative immune function after laparoscopic or conventional total mesorectal excision in rectal cancer: A randomized trial, International Journal of Colorectal Disease, 26, 53-59, 2011 Veltcamp Helbach M, Koedam TWA, Knol JJ, A non-randomised study comparing Velthuis S, Bonjer HJ, Tuynman JB, et al. laparoscopic and transanal total mesorectal Quality of life after rectal cancer surgery: excision. differences between laparoscopic and transanal total mesorectal excision. Surg Endosc. 2019;33(1):79-87. Velthuis, S., Nieuwenhuis, D. H., Ruijter, T. E., Non-randomised study comparing TaTME to Cuesta, M. A., Bonjer, H. J., Sietses, C., laparoscopic surgery. Evidence on critical Transanal versus traditional laparoscopic total outcomes already available from a RCT. mesorectal excision for rectal carcinoma, Population not according to protocol: Around Surgical Endoscopy, 28, 3494-9, 2014 half of participants with T1-2 and more than half with N0, T4 were excluded. Vennix, S., Pelzers, L., Bouvy, N., Beets, G. L., Systematic review of laparoscopic versus open Pierie, J. P., Wiggers, T., Breukink, S., rectal surgery, all included studies checked for Laparoscopic versus open total mesorectal relevance but not all studies are relevant to our excision for rectal cancer, The Cochrane review according to protocol. database of systematic reviews, 4, CD005200, 2014 Wang F, Fan W, Peng J, Lu Z, Pan Z, Li L, et al. Wrong comparison (compares any preoperative Total mesorectal excision with or without therapy with surgery alone) preoperative chemoradiotherapy for resectable mid/low rectal cancer: a long-term analysis of a prospective, single-center, randomized trial. Cancer Commun (Lond). 2018;38(1):73. Wang X, Zheng B, Lu X, Bai R, Feng L, Wang Wrong comparison (a systematic review of short Q, et al. Preoperative short-course radiotherapy course radiotherapy with long course and long-course radiochemotherapy for locally radiotherapy) advanced rectal cancer: Meta-analysis with trial sequential analysis of long-term survival data. PLoS One. 2018;13(7):e0200142. Wang, Y. W., Huang, L. Y., Song, C. L., Zhuo, A non-randomised study comparing C. H., Shi, D. B., Cai, G. X., Xu, Y., Cai, S. J., Li, laparoscopic and open surgery. X. X., Laparoscopic vs open abdominoperineal resection in the multimodality management of low rectal cancers, World Journal of Gastroenterology, 21, 10174-10183, 2015 Wang, Z., Zhang, X. M., Liang, J. W., Hu, J. J., A non-randomised study comparing Zeng, W. G., Zhou, Z. X., Evaluation of short- laparoscopic and open surgery. term outcomes after laparoscopically assisted abdominoperineal resection for low rectal cancer, ANZ journal of surgery, 84, 842-846, 2014
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DRAFT FOR CONSULTATION Optimal surgical technique for rectal cancer
Westerholm, J., Garcia-Osogobio, S., A non-randomised study comparing Farrokhyar, F., Cadeddu, M., Anvari, M., laparoscopic and open surgery. Midterm outcomes of laparoscopic surgery for rectal cancer, Surgical Innovation, 19, 81-88, 2012 Wu QB, Deng XB, Zhang XB, Kong LH, Zhou A non-randomised study comparing ZG. & Wang ZQ.Short-Term and Long-Term laparoscopic and open surgery. Outcomes of Laparoscopic Versus Open Surgery for Low Rectal Cancer. J Laparoendosc Adv Surg Tech A, 2018, 28, 637-644. Wu, Y., Sun, X., Qi, J., Wei, G., Cui, F., Gao, Q., A non-randomised study comparing Yu, J., Wang, K., Zheng, J., Comparative study laparoscopic and open surgery. of short-and long-term outcomes of laparoscopic-assisted versus open rectal cancer resection during and after the learning curve period, Medicine (United States), 96 (19) (no pagination), 2017 Xanthis A, Greenberg D, Jha B, Olafimihan O, Wrong intervention Miller R, Fearnhead N, et al. Local recurrence after 'standard' abdominoperineal resection: do we really need ELAPE? Ann R Coll Surg Engl. 2018;100(2):111-5. Xiao, J., Teng, W. H., Liu, S., Wei, C., Liu, W. J., Wrong comparison Chen, S., Zang, W. D. Short-course radiotherapy with delayed surgery versus conventional chemoradiotherapy: Comparison of short-term outcomes in patients with rectal cancer. 2018 Xiong, B., Ma, L., Huang, W., Zhao, Q., Cheng, Systematic review of robotic versus laparoscopic Y., Liu, J., Robotic versus laparoscopic total rectal surgery, not all studies are relevant to our mesorectal excision for rectal cancer: a meta- review according protocol. analysis of eight studies, Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract, 19, 516-526, 2015 Xiong, B., Ma, L., Zhang, C., Cheng, Y., Robotic Systematic review of robotic versus laparoscopic versus laparoscopic total mesorectal excision for rectal surgery, not all studies are relevant to our rectal cancer: A meta-analysis, Journal of review according protocol. Surgical Research, 188, 404-414, 2014 Xu J, Wei Y, Ren L, Feng Q, Chen J, Zhu D, et A conference abstract al. 482PD Robot-assisted vs laparoscopic vs open abdominoperineal resections for low rectal cancer: Short-term outcomes of a single-center prospective randomized controlled trial. Annals of Oncology. 2017;28(suppl_5). Yang, Y., Wang, F., Zhang, P., Shi, C., Zou, Y., Systematic review of TaTME versus Qin, H., Ma, Y., Robot-assisted versus laparoscopic rectal surgery, not all studies are conventional laparoscopic surgery for colorectal relevant to our review according protocol. disease, focusing on rectal cancer: A meta- analysis, Annals of Surgical Oncology, 19, 3727- 3736, 2012 Yu, J, Zhang, C, Wang, Yn, Hu, Yf, Cheng, X, Li, A non-randomised study comparing Gx, Laparoscopic versus open total mesorectal laparoscopic and open surgery. excision for the middle-lower rectal cancer: a clinical comparative study, Zhonghua wei chang wai ke za zhi [Chinese journal of gastrointestinal surgery], 12, 573-576, 2009
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DRAFT FOR CONSULTATION Optimal surgical technique for rectal cancer
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Zhou, Z; Li, L; Shu, Y; Yu, Y; Cheng, Z; Lei, W;, Full text in Chinese. [Laparoscopic total mesorectal excision for low or ultralow anterior resection of rectal cancer with anal sphincter preservation], Zhonghua wai ke za zhi [Chinese journal of surgery], 40, 899- 901, 2007
1 2
219 Colorectal cancer (update): evidence reviews for the optimal surgical technique for rectal cancer DRAFT (July 2019)
DRAFT FOR CONSULTATION Optimal surgical technique for rectal cancer
1 Appendix L – Research recommendations
2 Research recommendations for review question: What is the optimal surgical 3 technique for rectal cancer? 4 No research recommendations were made for this review question.
220 Colorectal cancer (update): evidence reviews for the optimal surgical technique for rectal cancer DRAFT (July 2019)