Preoperative chemotherapy for non-metastatic colon cancer

National Guideline Alliance (UK)

Preoperative chemotherapy for non-metastatic colon cancer

Colorectal cancer (update)

Evidence review C7

NICE Guideline, No. 151

Authors

National Guideline Alliance (UK).

London: National Institute for Health and Care Excellence (NICE); 2020 Jan.

ISBN-13: 978-1-4731-3657-1

Which people with non-metastatic colon cancer would benefit from preoperative chemotherapy?

This evidence review supports recommendation 1.3.13.

Review question

Which people with non-metastatic colon cancer would benefit from preoperative chemotherapy?

Introduction

Localised and resectable non-metastatic colon cancer has traditionally required an aggressive therapeutic approach through complete oncologic resection with post-operative chemotherapy, with extensive surgical resection needed to achieve negative margins. While preoperative chemotherapy is commonly used for localised oesophageal, gastric and rectal cancers, its use is not well-established for colon cancer as of yet. Preoperative chemotherapy has the potential to provide earlier and more effective eradication of occult micrometastatic disease, minimise the extent of surgery and debulk tumours to reduce the frequency of tumour cell shedding during surgery. Therefore, the aim of this review was to determine which people with non-metastatic colon cancer would benefit from preoperative chemotherapy.

Summary of the protocol

Please see Table 1 for a summary of the population, intervention, comparison and outcomes (PICO) characteristics of this review.

Table 1

Summary of the protocol (PICO table).

For further details see the review protocol in appendix A.

Methods and process

This evidence review was developed using the methods and process described in Developing NICE guidelines: the manual 2014. Methods specific to this review question are described in the review protocol in appendix A.

Declarations of interest were recorded according to NICE’s 2014 conflicts of interest policy until 31 March 2018. From 1 April 2018, declarations of interest were recorded according to NICE’s 2018 conflicts of interest policy. Those interests declared until April 2018 were reclassified according to NICE’s 2018 conflicts of interest policy (see Register of Interests).

Clinical evidence

Included studies

Two studies were included in this review (FOxTROT trial [Agbamu 2012]; Dehal 2017).

The clinical studies included in this evidence review are summarised in Table 2.

One pilot RCT (FOxTROT 2012 [Agbamu 2012]) compared preoperative chemotherapy + surgery + postoperative chemotherapy to surgery + postoperative chemotherapy and 1 retrospective cohort study (Dehal 2017) compared preoperative chemotherapy + surgery to surgery + postoperative chemotherapy.

Expert evidence

The published evidence base is weak and relies on one retrospective study and the pilot phase of the FOxTROT trial. The FOxTROT trial is an international, mainly UK-based, phase III randomised trial that investigates the efficacy of neoadjuvant chemotherapy in colon cancer and is the only trial in the topic to date. The results from FOxTROT were presented to the guideline committee as academic in confidence data by one of the FOxTROT trialists as expert witness evidence. Where outcomes were reported in both the pilot trial and expert evidence presentation, data from the expert evidence presentation were used as these data were most recent and more mature (longer follow-up). Since the expert witness presentation, the results of the trial have been presented in a conference making them publicly available, although not peer-reviewed.

See the summary of expert evidence in appendix M.

Excluded studies

Studies not included in this review and their reasons for exclusion are listed in appendix K.

Summary of clinical studies included in the evidence review

Table 2

Summary of included studies.

See the full evidence tables in appendix D and the forest plots in appendix E.

Quality assessment of clinical outcomes included in the evidence review

See the clinical evidence profiles in appendix F.

Economic evidence

Included studies

A systematic review of the economic literature was conducted but no economic studies were identified which were applicable to this review question.

Excluded studies

A global search of economic evidence was undertaken for all review questions in this guideline. See Supplement 2 for further information.

Economic model

No economic modelling was undertaken for this review because the committee agreed that other topics were higher priorities for economic evaluation.

Evidence statements

Clinical evidence statements

Comparison 1: Preoperative chemotherapy versus no preoperative chemotherapy

Critical outcomes

Disease-free survival

No evidence was identified to inform this outcome.

Overall survival

T3 patients

Very low quality evidence from 1 retrospective cohort study (N=27,575) showed no clinically important difference in 3-year overall survival between those receiving preoperative chemotherapy + surgery compared to surgery + postoperative chemotherapy.

T4a patients

Very low quality evidence from 1 retrospective cohort study (N=27,575) showed no clinically important difference in 3-year overall survival between those receiving preoperative chemotherapy + surgery compared to surgery + postoperative chemotherapy.

T4b patients

Very low quality evidence from 1 retrospective cohort study (N=27,575) showed a clinically important increase in 3-year overall survival between those receiving preoperative chemotherapy + surgery compared to surgery + postoperative chemotherapy.

Resection margins

T4b patients

Very low quality evidence from 1 retrospective cohort study (N=27,575) showed a clinically important decrease in resection margins between those receiving preoperative chemotherapy + surgery compared to surgery + postoperative chemotherapy.

Important outcomes

Any Grade 3 or 4 adverse events

Grade ≥3 adverse events

Very low quality evidence from 1 RCT (N=150) showed no clinically important difference in Grade ≥3 adverse events within 6, 12, 18, or 24 weeks between those receiving preoperative chemotherapy + surgery + postoperative chemotherapy compared to surgery + postoperative chemotherapy.

Anastomotic leak

More recent data for this outcome were available in the expert evidence summary.

Wound infection with or without intra-abdominal abscess

Very low quality evidence from 1 RCT (N=150) showed no clinically important difference in wound infection with or without intra-abdominal abscess between those receiving preoperative chemotherapy + surgery + postoperative chemotherapy compared to surgery + postoperative chemotherapy.

Bronchopneumonia

Very low quality evidence from 1 RCT (N=150) showed no clinically important difference in bronchopneumonia between those receiving preoperative chemotherapy + surgery + postoperative chemotherapy compared to surgery + postoperative chemotherapy.

Deep vein thrombosis

Very low quality evidence from 1 RCT (N=150) showed no clinically important difference in deep vein thrombosis between those receiving preoperative chemotherapy + surgery + postoperative chemotherapy compared to surgery + postoperative chemotherapy.

Neutropenia

Very low quality evidence from 1 RCT (N=150) showed no clinically important difference in neutropenia between those receiving preoperative chemotherapy + surgery + postoperative chemotherapy compared to surgery + postoperative chemotherapy.

Overall quality of life

No evidence was identified to inform this outcome.

Treatment-related mortality

More recent data for this outcome were available in the expert evidence summary.

Local recurrence

No evidence was identified to inform this outcome.

Expert evidence statements

Comparison 1: Preoperative chemotherapy versus no preoperative chemotherapy

Critical outcomes

Disease-free survival

Moderate quality evidence from 1 RCT (N=1052) showed a clinically important decrease in recurrence between those receiving preoperative chemotherapy + surgery + postoperative chemotherapy compared to surgery + postoperative chemotherapy.

Overall survival

No evidence was identified to inform this outcome.

Resection margins

No evidence was identified to inform this outcome.

Important outcomes

Any Grade 3 or 4 adverse events

Anastomotic leak

Moderate quality evidence from 1 RCT (N=1052) showed a clinically important decrease in anastomotic leak between those receiving preoperative chemotherapy + surgery + postoperative chemotherapy compared to surgery + postoperative chemotherapy.

Wound infection with or without intra-abdominal abscess

No evidence was identified to inform this outcome.

Bronchopneumonia

No evidence was identified to inform this outcome.

Pulmonary embolism ± deep vein thrombosis

No evidence was identified to inform this outcome.

Overall quality of life

No evidence was identified to inform this outcome.

Treatment-related mortality

Moderate quality evidence from 1 RCT (N=1052) showed no clinically important difference in treatment-related mortality (postoperative mortality) between those receiving preoperative chemotherapy + surgery + postoperative chemotherapy compared to surgery + postoperative chemotherapy.

Local recurrence

No evidence was identified to inform this outcome.

Economic evidence statements

No economic evidence was identified which was applicable to this review question.

The committee’s discussion of the evidence

Interpreting the evidence

The outcomes that matter most

Disease-free survival and overall survival were considered critical outcomes for decision making because disease progression suggests ineffective control of the localised colon cancer, potentially requiring further treatment and affecting overall survival. Resection margins were also critical as they are indicative of whether further treatment, likely surgical, is needed.

Quality of life was an important outcome because of the impact that different treatment options can have on patients’ functioning and the potential long term adverse effects. Any grade 3 or 4 adverse events and treatment-related mortality were also important outcomes, as they are indicative of the complications of treatments. Additionally, local recurrence was an important outcome because lesions that extend into surrounding structures and organs indicate the need for further surgical resection.

The quality of the evidence

Evidence was available from 1 pilot RCT comparing preoperative chemotherapy + surgery + postoperative chemotherapy to surgery + postoperative chemotherapy and 1 retrospective cohort study comparing preoperative chemotherapy + surgery to surgery + postoperative chemotherapy.

Evidence was available for overall survival, resection margins, any grade 3 or 4 adverse events and treatment-related mortality. There was no evidence for quality of life or local recurrence. The quality of the evidence was assessed using GRADE and was of very low quality. The quality of evidence was downgraded because of methodological limitations affecting the risk of bias and imprecision around the risk estimate.

Methodological limitations leading to risk of bias were due to confounding from differences in baseline characteristics, lack of blinding and allocation concealment.

Indirectness in the study interventions was attributable to numerous protocol violations in both arms of the RCT that potentially diluted the effectiveness of the interventions.

Uncertainty around the risk estimate was due to low event rates and small sample sizes.

An expert witness presented academic in confidence results of the FoXTROT trial which provided expert evidence for the comparison of preoperative chemotherapy + surgery + postoperative chemotherapy versus surgery + postoperative surgery. Evidence was available for disease-free survival, any grade 3 or 4 adverse events and treatment-related mortality. This evidence was assessed using GRADE as moderate quality.

The range in quality of the evidence and lack of evidence for many comparisons and outcomes impacted the decision-making and the strength of the recommendation as there was insufficient evidence to make a strong recommendation or to make recommendations for all subgroups within the population.

Benefits and harms

The evidence indicated that there were benefits for disease-free survival, overall survival and clear resection margins for patients with more advanced (T4b) colonic tumours who received preoperative chemotherapy. No benefit on overall survival was found for patients with T3 or T4a colonic tumours. However, the committee agreed that differentiating between T4a and T4b tumours would be difficult in preoperative clinical staging (imaging), therefore, based on their clinical experience and knowledge they agreed that the recommendation to consider preoperative therapy should cover patients with T4 tumours.

While the expert evidence showed that there was a clinically important decrease in anastomotic leak, otherwise the clinical evidence did not show any clinically important difference between treatment groups in terms of adverse events or treatment-related mortality. From their clinical experience, the committee noted that there is a potential for harm from increased surgical morbidity. The committee was not aware of any evidence regarding treatment decision-making pertaining to the extent of surgical resection (that is, whether decisions should be based on pre- or post-chemotherapy imaging). However, they noted that most clinicians would base their decisions on the extent of surgery on pre-chemotherapy imaging.

Cost effectiveness and resource use

A systematic review of the economic literature was conducted but no relevant studies were identified which were applicable to this review question.

The committee considered that the addition of preoperative chemotherapy would not increase costs for patients with T4 colon cancer as postoperative chemotherapy is current standard of care and costs between pre and post would be similar given the almost identical regimens. The committee acknowledged that preoperative chemotherapy was already being done in some centres and that it would only represent a change for some centres. There would also be increases in overall survival and quality of life through reduced surgical morbidity.

Other factors the committee took into account

The committee acknowledged the FOxTROT trial, which compares preoperative plus post-operative chemotherapy (+/− panitumumab) with standard post-operative chemotherapy. Results from the earlier feasibility trial (FOxTROT trial [Agbamu 2012]) were included in this review. Primary outcomes include 2-year recurrence-free survival and pathological down-staging and secondary outcomes include disease-specific survival and overall survival at 2 years and quality of life by EORTC QLQ C-30 and EuroQol EQ-5D before surgery, before the first post-operative chemotherapy and 1 year post-randomisation. The committee considered expert evidence about the unpublished results of the FOxTROT trial from the primary randomisation (preoperative-and-postoperative chemotherapy versus standard postoperative chemotherapy) to neoadjuvant treatment as data analysis for the substudy (patients with KRAS-wild type tumours randomised 1:1 to preoperative-and-postoperative chemotherapy +/− panitumumab) was not complete. Moderate quality evidence from the primary randomisation phase showed that complete clinical response and tumour downstaging are more likely in those who receive preoperative chemotherapy, although follow-up is not yet long enough to assess long-term outcomes. The results presented to the committee as academic in confidence were since presented at an international conference. See more details in appendix M.

References

FOxTROT trial [Agbamu 2012]
Agbamu D, Day N, Walsh C, et al. (2012) Feasibility of preoperative chemotherapy for locally advanced, operable colon cancer: The pilot phase of a randomised controlled trial. Lancet Oncology 13(11): 1152–1160 [PMC free article: PMC3488188] [PubMed: 23017669]
Dehal 2017
Dehal A, Vuong B, Graff-Baker A, et al. (2017) Neoadjuvant chemotherapy improves survival in patients with clinical T4B colon cancer. Gastroenterology 152 (5): S1209

Appendices

Appendix A. Review protocol

Review protocol for review question: Which people with non-metastatic colon cancer would benefit from preoperative chemotherapy?

Table 3. Review protocol for pre-operative chemotherapy for people with non-metastatic colon cancer

Appendix B. Literature search strategies

Literature search strategies for review question: Which people with non-meta static colon cancer would benefit from preoperative chemotherapy?

Databases: Embase/Medline

Last searched on: 31/10/2018

Table

Database: Cochrane Library

Last searched on: 31/10/2018

Table

Appendix C. Clinical evidence study selection

Clinical study selection for review question: Which people with non-metastatic colon cancer would benefit from preoperative chemotherapy?

Figure 1. Study selection flow chart

Appendix D. Clinical evidence tables

Clinical evidence tables for review question: Which people with non-metastatic colon cancer would benefit from preoperative chemotherapy?

Table 4. Clinical evidence tables (PDF, 384K)

Appendix E. Forest plots

Forest plots for review question: Which people with non-metastatic colon cancer would benefit from preoperative chemotherapy?

Figure 2. Preoperative chemotherapy versus no preoperative chemotherapy - 3-year overall survival; event is death from any cause

Figure 3. Preoperative chemotherapy versus no preoperative chemotherapy - Positive resection margins, T4b patients

Figure 4. Preoperative chemotherapy versus no preoperative chemotherapy – Any Grade 3 or 4 events and wound infection with or without intra-abdominal abscess

Figure 5. Preoperative chemotherapy versus no preoperative chemotherapy – Grade 3 or 4 events; bronchopneumonia, neutropenia, deep vein thrombosis

Appendix F. GRADE tables

GRADE tables for review question: Which people with non-metastatic colon cancer would benefit from preoperative chemotherapy?

Table 5. Clinical evidence profile for comparison preoperative chemotherapy versus no preoperative chemotherapy

Appendix G. Economic evidence study selection

Economic evidence study selection for review question: Which people with non-metastatic colon cancer would benefit from preoperative chemotherapy

A global search of economic evidence was undertaken for all review questions in this guideline. See Supplement 2 for further information.

Appendix H. Economic evidence tables

Economic evidence tables for review question: Which people with non-metastatic colon cancer would benefit from preoperative chemotherapy

No economic evidence was identified which was applicable to this review question. 5

Appendix I. Economic evidence profiles

Economic evidence profiles for review question: Which people with non-metastatic colon cancer would benefit from preoperative chemotherapy?

No economic evidence was identified which was applicable to this review question.

Appendix J. Economic analysis

Economic analysis for review question: Which people with non-metastatic colon cancer would benefit from preoperative chemotherapy?

No economic analysis was conducted for this review question. 5

Appendix K. Excluded studies

Excluded clinical studies for review question: Which people with non-metastatic colon cancer would benefit from preoperative chemotherapy?

Table 6. Excluded studies and reasons for their exclusion

Appendix L. Research recommendations

Research recommendations for review question: Which people with non-meta static colon cancer would benefit from preoperative chemotherapy?

No research recommendations were made for this review question.

Appendix M. Expert evidence

Expert evidence for review question: Which people with non-metastatic colon cancer would benefit from preoperative chemotherapy?

Table 7. Expert evidence: Preliminary findings from the FOxTROT trial (PDF, 216K)

Table 8. Gaps addressed and recommendations supported by expert evidence

Figure 6. Forest plot: Preoperative chemotherapy versus no preoperative chemotherapy - Disease-free survival

Figure 7. Forest plot: Preoperative chemotherapy versus no preoperative chemotherapy - Grade 3 or 4 adverse events: anastomotic leak

Figure 8. Forest plot: Preoperative chemotherapy versus no preoperative chemotherapy - Treatment-related mortality

Table 9. Quality assessment of expert evidence

Final

Evidence reviews

Developed by the National Guideline Alliance part of the Royal College of Obstetricians and Gynaecologists

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.

Bookshelf ID: NBK559941PMID: 32730008

Table 1Summary of the protocol (PICO table)

Population	Adults with localised, resectable, non-metastatic colon cancer Non-metastatic cancer defined as: Tany N1-2 T3 T4 M0 Subgroups by: Disease characteristics: Radiological T stage Radiological N stage Tumour location Colonic obstruction status (no/complete/partly)
Intervention	Preoperative chemotherapy
Comparison	No preoperative chemotherapy
Outcomes	Critical Disease-free survival Overall survival Resection margins Important Any grade 3 or 4 adverse events Overall quality of life Treatment-related mortality Local recurrence

Table 2Summary of included studies

Study

Population

Intervention/Comparison

Outcomes

FOxTROT trial

[Agbamu 2012]

Pilot RCT

N=150 patients with locally advanced (T4 or T3 with extramural depth ≥ 5mm) adenocarcinoma of the colon with staging determined preoperatively by either spiral or multidetector CT

Preoperative chemotherapy + surgery + postoperative chemotherapy versus surgery + postoperative chemotherapy

Grade 3 or 4 adverse events

Dehal 2017

Retrospective cohort study

N=27,575 patients with clinically staged T3 or T4, non-metastatic primary colon cancer who had both surgery and chemotherapy and a tumour with a mucinous, signet ring cell, or adenocarcinoma

Preoperative chemotherapy + surgery versus surgery + postoperative chemotherapy

Overall survival
Positive resection margins

: CT: computed tomography; N: number; RCT: randomised controlled trial; T: tumour stage

Table 3Review protocol for pre-operative chemotherapy for people with non-metastatic colon cancer

Field (based on PRISMA)	Content
Review question in guideline	Which people with non-metastatic colon cancer would benefit from preoperative chemotherapy?
Type of review question	Intervention
Objective of the review	To determine which people with non-metastatic colon cancer would benefit from preoperative chemotherapy.
Eligibility criteria – population/disease/condition/issue/domain	Adults with localised, resectable, non-metastatic colon cancer Non-metastatic cancer defined as: Tany N1-2 T3 T4 M0 Subgroups according to (analysed separately): Disease characteristics: Radiological T stage Radiological N stage Tumour location Colonic obstruction status (no/com-plete/partly)
Eligibility criteria – intervention(s)/exposure(s)/prognostic factor(s)	Preoperative chemotherapy
Eligibility criteria – comparator(s)/control or reference (gold) standard	No preoperative chemotherapy
Outcomes and prioritisation	Critical outcomes: Disease-free survival (minimally important difference [MID]: statistical significance) Overall survival (MID: statistical significance) Resection margins (MID: statistical significance) Important outcomes: Any Grade 3 or 4 adverse events (MID: statistical significance) Overall quality of life measured using validated scales (MID: published MIDs from literature, see below) Treatment-related mortality (MID: statistical significance) Local recurrence (MID: statistical significance) 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 using FACT-G quintiles FACT-C: 5 points FACT-G: 5 points SF-12: > 3.77 for the mental component summary (MCS) and > 3.29 for the physical component summary (PCS) 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 PCS
Eligibility criteria – study design	Systematic reviews Randomised controlled trials Prospective or retrospective comparative cohort studies will only be considered if eligible RCTs are not available
Other inclusion exclusion criteria	Inclusion: English-language All settings will be considered that consider medications and treatments available in the UK Studies published post-2005 Studies conducted post-2005 will be considered for this review question because the guideline committee considered that treatment techniques have evolved and evidence prior to 2005 would no longer be relevant.
Proposed sensitivity/sub-group analysis, or meta-regression	Cohort studies should include multivariate analysis controlling for the following confounding factors: Patient characteristics (i.e. age [life expectancy], comorbidities) Type of chemotherapy Tumour characteristics T stage Tumour location
Selection process – duplicate screening/selection/analysis	Sifting, data extraction, appraisal of methodological quality and GRADE assessment will be performed by the systematic reviewer. Resolution of any disputes will be with the senior systematic reviewer and the Topic Advisor. Quality control will be performed by the senior systematic reviewer. Dual sifting will be undertaken for this question for a random 10% sample of the titles and abstracts identified by the search.
Data management (software)	Pairwise meta-analyses will be performed using Cochrane 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 – databases and dates	Potential sources to be searched: Medline, Medline In-Process, 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 2005
Identify if an update	Not an update
Author contacts	https://www.nice.org.uk/guidance/indevelopment/gid-ng10060 Developer: NGA
Highlight if amendment to previous protocol	For details please see section 4.5 of Developing NICE guidelines: the manual
Search strategy – for one database	For details please see appendix B
Data collection process – forms/duplicate	A standardised evidence table format will be used, and published as appendix D (clinical evidence tables) or H (economic evidence tables).
Data items – define all variables to be collected	For details please see evidence tables in appendix D (clinical evidence tables) or H (economic evidence tables).
Methods for assessing bias at outcome/study level	Standard study checklists were used to critically appraise individual studies. For details please see section 6.2 of 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 for non-randomised studies 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 synthesis (where suitable)	For details please see section 6.4 of Developing NICE guidelines: the manual
Methods for analysis – combining studies and exploring (in)consistency	Synthesis of data: Pairwise meta-analysis of randomised trials will be conducted where appropriate. When meta-analysing continuous data, final and change scores will be pooled if baselines are comparable. If any studies report both, the method used in the majority of studies will be analysed. Minimally important differences: 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 – publication bias, selective reporting bias	For details please see section 6.2 of Developing NICE guidelines: the manual. If sufficient relevant RCT evidence is available, publication bias will be explored using RevMan software to examine funnel plots.
Assessment of confidence in cumulative evidence	For details please see sections 6.4 and 9.1 of Developing NICE guidelines: the manual
Rationale/context – Current management	For details please see the introduction to the evidence review.
Describe contributions of authors and guarantor	A multidisciplinary committee developed the guideline. The committee was convened by The NGA and 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 funding/support	The NGA is funded by NICE and hosted by the Royal College of Obstetricians and Gynaecologists
Name of sponsor	The NGA is funded by NICE and hosted by the Royal College of Obstetricians and Gynaecologists
Roles of sponsor	NICE funds the NGA to develop guidelines for those working in the NHS, public health, and social care in England
PROSPERO registration number	Not registered

: CCTR: Cochrane Central Register of Controlled Trials; CDSR: Cochrane Database of Systematic Reviews; CENTRAL: Cochrane Central Register of Controlled Trials; DARE: Database of Abstracts of Reviews of Effects; EuroQol five dimensions questionnaire; EORTC QLQ-C30: European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 Items; EORTC QLQ-CR29: European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire colorectal cancer module (29 items); EORTC QLQ-CR38: European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire colorectal cancer module (38 items); FACT-C: Functional Assessment of Cancer Therapy questionnaire (colorectal cancer); FACT-G: Functional Assessment of Cancer Therapy questionnaire (general); GRADE: Grading of Recommendations Assessment, Development and Evaluation; HTA: Health Technology Assessment; M0: no distant metastasis; MCS: mental component summary; MID: minimally important difference; N: nodal stage; NGA: National Guideline Alliance; NHS: National health service; NICE: National Institute for Health and Care Excellence; PCS: physical component summary; RCT: randomised controlled trial; RevMan5: Review Manager version 5; RoB: risk of bias; ROBINS-I: Risk Of Bias In Non-randomised Studies - of Interventions; ROBIS: risk of bias in systematic reviews; SD: standard deviation; SF-12: 12-Item Short Form Survey; SF-36: 36-Item Short Form Survey; T: tumour stage

#	Search
1	exp colonic neoplasms/ use ppez
2	exp colon tumor/ use emez
3	((colon or colonic) adj3 (adenocarcinoma* or cancer* or carcinoma* or malignan* or neoplas* or oncolog* or tumo?r*)).tw.
4	or/1-3
5	(local* advanc* or locali?ed or non-metasta* or non metasta* or operable or operative or resectable).tw.
6	(t3 or t4 or m0 or N1 or N2).tw.
7	or/5-6
8	preoperative chemotherapy/ use emez
9	neoadjuvant chemotherapy/ use emez
10	Neoadjuvant Therapy/ use ppez
11	((preop* or pre?op* or neoadjuvant) adj3 (chemotherap* or therap* or treat*)).tw.
12	or/8-11
13	4 and 7 and 12
14	Letter/ use ppez
15	letter.pt. or letter/ use emez
16	note.pt.
17	editorial.pt.
18	Editorial/ use ppez
19	News/ use ppez
20	exp Historical Article/ use ppez
21	Anecdotes as Topic/ use ppez
22	Comment/ use ppez
23	Case Report/ use ppez
24	case report/ or case study/ use emez
25	(letter or comment*).ti.
26	or/14-25
27	randomized controlled trial/ use ppez
28	randomized controlled trial/ use emez
29	random*.ti,ab.
30	or/27-29
31	26 not 30
32	animals/ not humans/ use ppez
33	animal/ not human/ use emez
34	nonhuman/ use emez
35	exp Animals, Laboratory/ use ppez
36	exp Animal Experimentation/ use ppez
37	exp Animal Experiment/ use emez
38	exp Experimental Animal/ use emez
39	exp Models, Animal/ use ppez
40	animal model/ use emez
41	exp Rodentia/ use ppez
42	exp Rodent/ use emez
43	(rat or rats or mouse or mice).ti.
44	or/31-43
45	13 not 44
46	limit 45 to (yr=“2005 - current” and english language)
47	remove duplicates from 46

#	Search
1	MeSH descriptor: [Colonic Neoplasms] explode all trees
2	((colon or colonic) near/3 (adenocarcinoma* or cancer* or carcinoma* or malignan* or neoplas* or oncolog* or tumo?r*)):kw,ti,ab
3	#1 or #2
4	(local* advanc* or locali?ed or non-metasta* or non metasta* or operable or operative or resectable):kw,ti,ab
5	(t3 or t4 or m0 or N1 or N2):kw,ti,ab
6	#4 or #5
7	MeSH descriptor: [Neoadjuvant Therapy] this term only
8	((preop* or pre?op* or neoadjuvant) near/3 (chemotherap* or therap* or treat*)):kw,ti,ab
9	#7 or #8
10	#3 and #6 and #9 with Cochrane Library publication date Between Jan 2005 and Dec 2018

Figure 1Study selection flow chart

Figure 2Preoperative chemotherapy versus no preoperative chemotherapy - 3-year overall survival^*; event is death from any cause

CI: confidence interval; CT: chemotherapy; IV: inverse variance; SE: standard error; T: tumour stage

*: propensity score matched for age, gender, race, insurance status, comorbidity score, hospital type, tumour histology, grade, N stage, tumour location, number of nodes examined, margin, and extent of surgery

Figure 3Preoperative chemotherapy versus no preoperative chemotherapy - Positive resection margins^*, T4b patients

CI: confidence interval; CT: chemotherapy; IV: inverse variance; SE: standard error; T: tumour stage

*: adjusted for age, gender, race, insurance status, comorbidity score, hospital type, tumour histology, grade, N stage, extent of surgery, and tumour location

Figure 4Preoperative chemotherapy versus no preoperative chemotherapy – Any Grade 3 or 4 events and wound infection with or without intra-abdominal abscess

CI: confidence interval; CT: chemotherapy; FOxTROT: Fluoropyrimidine, Oxaliplatin and Targeted-Receptor pre-Operative Therapy for patients with high-risk, operable colon cancer; M-H: Mantel Haenszel

Figure 5Preoperative chemotherapy versus no preoperative chemotherapy – Grade 3 or 4 events; bronchopneumonia, neutropenia, deep vein thrombosis

CI: confidence interval; CT: chemotherapy; FOxTROT: Fluoropyrimidine, Oxaliplatin and Targeted-Receptor pre-Operative Therapy for patients with high-risk, operable colon cancer; M-H: Mantel Haenszel

Table 5Clinical evidence profile for comparison preoperative chemotherapy versus no preoperative chemotherapy

Quality assessment							No of patients		Effect		Quality	Importance
No of studies	Design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	Preop CT	No preop CT	Relative (95% CI)	Absolute	Quality	Importance
Disease-free survival
0	No evidence available	-	-	-	-	-	-	-	-	-	-	CRITICAL
3-year overall survival, event is death from any cause (propensity score matched for age, gender, race, insurance status, comorbidity score, hospital type, tumour histology, grade, N stage, tumour location, number of nodes examined, margin, and extent of surgery) - T3 patients
1	observational studies¹	serious²	no serious inconsistency	no serious indirectness	no serious imprecision	none	15,999	383	HR 1.15 (0.92 to 1.44)	At 3 years no preop CT^a 84.5%, preop CT 82.4% (78.5% to 85.6%)	VERY LOW	CRITICAL
3-year overall survival, event is death from any cause (propensity score matched for age, gender, race, insurance status, comorbidity score, hospital type, tumour histology, grade, N stage, tumour location, number of nodes examined, margin, and extent of surgery) – T4a patients
1	observational studies¹	serious²	no serious inconsistency	no serious indirectness	no serious imprecision	none	2,241	48	HR 1.43 (0.85 to 2.41)	At 3 years no preop CT^a 73.2%, preop CT 64.0% (47.1% to 76.7%	VERY LOW	CRITICAL
3-year overall survival, event is death from any cause (propensity score matched for age, gender, race, insurance status, comorbidity score, hospital type, tumour histology, grade, N stage, tumour location, number of nodes examined, margin, and extent of surgery) - T4b patients
1	observational studies¹	serious²	no serious inconsistency	no serious indirectness	no serious imprecision	none	2,330	273	HR 0.77 (0.60 to 0.99)	At 3 years no preop CT^a 69.1%, preop CT 75.2% (69.4% to 80.1%)	VERY LOW	CRITICAL
Positive resection margins, T4b patients (adjusted for age, gender, race, insurance status, comorbidity score, hospital type, tumour histology, grade, N stage, extent of surgery, and tumour location)
1	observational studies	serious²	no serious inconsistency	no serious indirectness	no serious imprecision	none	2,987	350	OR 0.95 (0.91 to 0.99)	12 fewer per 1000 (from 24 fewer to 4 fewer)	VERY LOW	CRITICAL
Any Grade 3 or 4 adverse events - Grade ≥ 3 toxicity within 6 weeks
1	randomised trials	serious³	no serious inconsistency	serious⁴	serious⁵	none	32/94 (34%)	12/39 (30.8%)	RR 1.11 (0.64 to 1.91)	34 more per 1000 (from 111 fewer to 280 more)	VERY LOW	IMPORTANT
Any Grade 3 or 4 adverse events - Grade ≥ 3 adverse events within 12 weeks
1	randomised trials	serious³	no serious inconsistency	serious⁴	serious⁵	none	14/81 (17.3%)	9/38 (23.7%)	RR 0.73 (0.35 to 1.53)	64 fewer per 1000 (from 154 fewer to 126 more)	VERY LOW	IMPORTANT
Any Grade 3 or 4 adverse events - Grade ≥ 3 adverse events within 18 weeks
1	randomised trials	serious³	no serious inconsistency	serious⁴	serious⁵	none	18/75 (24%)	8/34 (23.5%)	RR 1.02 (0.49 to 2.11)	5 more per 1000 (from 120 fewer to 261 more)	VERY LOW	IMPORTANT
Any Grade 3 or 4 adverse events - Grade ≥ 3 adverse events within 24 weeks
1	randomised trials	serious³	no serious inconsistency	serious⁴	serious⁵	none	47/95 (49.5%)	20/39 (51.3%)	RR 0.96 (0.67 to 1.39)	21 fewer per 1000 (from 169 fewer to 200 more)	VERY LOW	IMPORTANT
Any Grade 3 or 4 adverse events - Wound infection with or without intra-abdominal abscess
1	randomised trials	serious³	no serious inconsistency	serious⁴	serious⁵	none	13/99 (13.1%)	4/51 (7.8%)	RR 1.67 (0.58 to 4.87)	53 more per 1000 (from 33 fewer to 304 more)	VERY LOW	IMPORTANT
Any Grade 3 or 4 adverse events - Bronchopneumonia
1	randomised trials	serious³	no serious inconsistency	serious⁴	serious⁵	none	2/99 (2%)	0/51 (0%)	Peto OR 4.60 (0.24, 86.57)	20 more per 1000 (from 60 fewer to 20 more)	VERY LOW	IMPORTANT
Any Grade 3 or 4 adverse events - Neutropenia
1	randomised trials	serious³	no serious inconsistency	serious⁴	serious⁵	none	1/99 (1%)	0/51 (0%)	Peto OR 4.55 (0.07, 285.04)	10 more per 1000 (from 30 fewer to 50 more)	VERY LOW	IMPORTANT
Any Grade 3 or 4 adverse events – Deep vein thrombosis
1	randomised trials	serious³	no serious inconsistency	serious⁴	serious⁵	none	2/99 (2%)	0/51 (0%)	Peto OR 4.60 (0.24, 86.57)	20 more per 1000 (from 60 fewer to 20 more)	VERY LOW	IMPORTANT
Overall quality of life
0	No evidence available	-	-	-	-	-	-	-	-	-	-	IMPORTANT
Local recurrence
0	No evidence available	-	-	-	-	-	-	-	-	-	-	IMPORTANT

: CI: confidence interval; CT: chemotherapy; HR: hazard ratio; OR: odds ratio; RR: risk ratio

1: Subgroups based on propensity score match at a rate of 80, 70 and 78% respectively for T3, T4a, and T4b patients were used in the analysis (Dehal 2017)

2: Quality of evidence downgraded by 1 because high risk of confounding despite use of propensity score matching and bias in the selection of participants (Dehal 2017)

3: Quality of evidence downgraded by 2 due to lack of allocation concealment and blinding (FOxTROT trial [Agbamu 2012])

4: Quality of evidence downgraded by 1 due to numerous protocol violations in both arms (FOxTROT trial [Agbamu 2012])

5: Quality of evidence downgraded by 1 because of imprecision of the effect estimate (< 300 events for dichotomous outcomes or < 400 patients for continuous outcomes).

a: The absolute risk at 3 years in the control group taken from Dehal 2017

Table 6Excluded studies and reasons for their exclusion

Study	Reason for exclusion
Anonymous, FOxTROT: safety and feasibility of neoadjuvant chemotherapy in locally advanced, resectable colon cancer based on the phase III of a randomised controlled trial, Colorectal disease. Conference: 12th scientific and annual meeting of the european society of coloproctology. Germany, 19, 3, 2017	Waiting for full text of paper to be published in 2019; results from pilot study reported in Agbamu 2012
Arredondo J., Gonzalez I., Baixauli J., Martinez P., Rodriguez J., Pastor C., Ribelles M. J., Sola J. J., Hernandez-Lizoain J. L., Tumor response assessment in locally advanced colon cancer after neoadjuvant chemotherapy, Journal of Gastrointestinal Oncology, 5, 104–111, 2014 [PMC free article: PMC3999636] [PubMed: 24772338]	Not comparative
Arredondo J., Martinez P., Baixauli J., Pastor C., Rodriguez J., Pardo F., Rotellar F., Chopitea A., Hernandez-Lizoain J. L., Analysis of surgical complications of primary tumor resection after neoadjuvant treatment in stage IV colon cancer, Journal of Gastrointestinal Oncology, 5, 148–153, 2014 [PMC free article: PMC3999633] [PubMed: 24772343]	Not comparative; population not relevant - all had liver metastases
Arredondo J., Pastor C., Baixauli J., Rodriguez J., Gonzalez I., Vigil C., Chopitea A., Hernandez-Lizoain J. L., Preliminary outcome of a treatment strategy based on perioperative chemotherapy and surgery in patients with locally advanced colon cancer, Colorectal Disease, 15, 552–557, 2013 [PubMed: 23398577]	Not comparative
Artac M., Turhal N. S., Kocer M., Karabulut B., Bozcuk H., Yalcin S., Karaagac M., Gunduz S., Isik N., Uygun K., Do high-risk features support the use of adjuvant chemotherapy in stage II colon cancer? A Turkish Oncology Group study, Tumori, 100, 143–8, 2014 [PubMed: 24852857]	Intervention not relevant - adjuvant chemotherapy vs no adjuvant chemotherapy
Blencowe N. S., Chana P., Whistance R. N., Stevens D., Wong, N. A. C. S., Falk S. J., Blazeby J. M., Outcome reporting in neoadjuvant surgical trials: A systematic review of the literature and proposals for new standards, Journal of the National Cancer InstituteJ Natl Cancer Inst, 106 (9) (no pagination), 2014 [PubMed: 25106656]	Systematic review - studies assessed individually
Chaves J. A., Neoadjuvant chemotherapy in locally advanced colon cancer -ELECLA trial, Colorectal disease. Conference: 11th scientific and annual meeting of the european society of coloproctology. Italy, 18, 126, 2016	Abstract - trial still in progress
Cukier M., Smith A. J., Milot L., Chu W., Chung H., Fenech D., Herschorn S., Ko Y., Rowsell C., Soliman H., Ung Y. C., Wong C. S., Neoadjuvant chemoradiotherapy and multivisceral resection for primary locally advanced adherent colon cancer: A single institution experience, European Journal of Surgical Oncology, 38, 677–682, 2012 [PubMed: 22632848]	Not comparative
Dehal A., Graff-Baker A. N., Vuong B., Fischer T., Klempner S. J., Chang S. C., Grunkemeier G. L., Bilchik A. J., Goldfarb M., Neoadjuvant Chemotherapy Improves Survival in Patients with Clinical T4b Colon Cancer, Journal of Gastrointestinal Surgery, 22, 242–249, 2018 [PubMed: 28933016]	Conference abstract, full text not available
Deng Y., Zhang J., Cai Y., Hu H., Ling J., Xiao J., Huang M., Kang L., Wang L., Lan P., Wang J., Neoadjuvant chemotherapy alone with mFOLFOXIRI in locally advanced rectal cancer: A single-arm phase II study, Journal of Clinical Oncology. Conference, 34, 2016	Abstract - trial still in progress
Engstrom P. F., Arnoletti J. P., Benson, Iii A. B., Chen Y. J., Choti M. A., Cooper H. S., Covey A., Dilawari R. A., Early D. S., Enzinger P. C., Fakih M. G., Fleshman Jr J., Fuchs C., Grem J. L., Kiel K., Knol J. A., Leong L. A., Lin E., Mulcahy M. F., Rao S., Ryan D. P., Saltz L., Shibata D., Skibber J. M., Sofocleous C., Thomas J., Venook A. P., Willett C., Colon cancer, JNCCN Journal of the National Comprehensive Cancer Network, 7, 778–831, 2009 [PubMed: 19755046]	Clinical practice guideline
Gray R. G., Morton D., Brown G., Ferry D. R., Magill L., Quirke P., Seymour M. T., Warren B., FOxTROT: Randomized phase II study of neoadjuvant chemotherapy with or without an anti-EGFR monoclonal antibody for locally advanced, operable colon cancer, Journal of Clinical Oncology. Conference, 28, 2010	Abstract
Hansen T. F., Kjaer-Frifeldt S., Lindebjerg J., Rafaelsen S. R., Jensen L. H., Jakobsen A., Sorensen F. B., Tumor-stroma ratio predicts recurrence in patients with colon cancer treated with neoadjuvant chemotherapy, Acta Oncologica, 57, 528–533, 2018 [PubMed: 28980848]	Not comparative
Jakobsen A., Andersen F., Fischer A., Jensen L. H., Jorgensen J. C. R., Larsen O., Lindebjerg J., Ploen J., Rafaelsen S. R., Vilandt J., Neoadjuvant chemotherapy in locally advanced colon cancer. A phase II trial, Acta Oncologica, 54, 17471753, 2015 [PubMed: 25920359]	Not comparative
Karoui M., Rullier A., Luciani A., Bonnetain F., Auriault M. L., Sarran A., Monges G., Trillaud H., Le Malicot K., Leroy K., et al.,, Neoadjuvant FOLFOX 4 versus FOLFOX 4 with Cetuximab versus immediate surgery for high-risk stage II and III colon cancers: a multicentre randomised controlled phase II trial - the PRODIGE 22 - ECKINOXE trial, BMC Cancer, 15, 2015 [PMC free article: PMC4497499] [PubMed: 26156156]	Abstract - expected study completion date February 2021
Karoui M., Rullier A., Luciani A., Bonnetain F., Auriault M. L., Sarran A., Monges G., Trillaud H., Le Malicot K., Leroy K., Sobhani I., Bardier A., Moreau M., Brindel I., Seitz J. F., Taieb J., Neoadjuvant FOLFOX 4 versus FOLFOX 4 with Cetuximab versus immediate surgery for high-risk stage II and III colon cancers: a multicentre randomised controlled phase II trial--the PRODIGE 22--ECKINOXE trial, BMC Cancer, 15, 511, 2015 [PMC free article: PMC4497499] [PubMed: 26156156]	Abstract - expected study completion date February 2021
Karoui M., Rullier A., Mariette C., Maillard E., Bardier A., Poizat F., Luciani A., Sarran A., Legoux J. L., De Chaisemartin C., et al.,, Neoadjuvant FOLFOX 4 versus FOLFOX 4 plus cetuximab versus immediate surgery for high-risk stage II and III colon cancers: a phase II multicentre randomised controlled trial (PRODIGE 22), Annals of oncology. Conference: 42nd ESMO congress, ESMO 2017. Spain, 28, v159, 2017	Abstract - estimated study completion date February 2021
Nct,, Neoadjuvant Chemotherapy Verse Surgery Alone After Stent Placement for Obstructive Colonic Cancer, Https://clinicaltrials.gov/show/nct02972541, 2016	Clinical trial entry
Nct,, Neoadjuvant FOLFOX Chemotherapy for Patients With Locally Advanced Colon Cancer, Https://clinicaltrials.gov/show/nct03426904, 2018	Clinical trial entry
Nct,, Fluorouracil and Oxaliplatin With or Without Panitumumab In Treating Patients With High-Risk Colon Cancer That Can Be Removed by Surgery, Https://clinicaltrials.gov/show/nct00647530, 2008	Clinical trial entry
Nct,, Perioperative Versus Postoperative CapOX Chemotherapy for Locally Advanced Colon Cancer, Https://clinicaltrials.gov/show/nct03125980, 2017	Clinical trial entry
Nct,, Neoadjuvant Chemotherapy for the Treatment of Resectable Locally Advanced Colon Cancer, Https://clinicaltrials.gov/show/nct02882269, 2016	Clinical trial entry
Nct,, Neoadjuvant Chemotherapy Versus Standard Treatment in Patients With Locally Advanced Colon Cancer, Https://clinicaltrials.gov/show/nct01918527, 2013	Clinical trial entry
Park S., Park J., Kim H., Choi G., Pilot study of neoadjuvant chemotherapy with three cycles of capox for treatment of locally advanced colon cancer, Diseases of the colon and rectum. Conference: 2018 american society of colon and rectal surgeons annual meeting, ASCRS 2018. United states, 61, e279, 2018	Abstract - full text unavailable
Sekiya S., Imamura K., Takeuchi S., Teramura K., Watanabe Y., Tamoto E., Takada M., Kinoshita Y., Anbo Y., Nakamura F., Kashimura N., Noguchi H., Miura K., Hirano S., Pathological complete response of locally advanced colon cancer after preoperative radiotherapy: a case report and narrative review of the literature, Surgical Case Reports, 4, 58, 2018 [PMC free article: PMC6002327] [PubMed: 29904815]	Case study and narrative review
Tresallet C., Benoist S., Nordlinger B., Adjuvant and neoadjuvant treatment in resectable and non-resectable metastatic colon cancer, European Journal of Cancer, Supplement, 3, 275–281, 2005	Patients had metastatic disease
Trojan J., Lubomierski N., Lehnert T., Engels K., Zeuzem S., Bechstein W. O., Neoadjuvant treatment with cetuximab, 5-Fluorouracil, folinic Acid and oxaliplatin in unresectable retroperitoneal recurrent colon cancer, Zeitschrift fur Gastroenterologie, 46, 776–9, 2008 [PubMed: 18759201]	Full text in German; case report
Zhou Z., Nimeiri H. S., Benson A. B., 3rd, Preoperative chemotherapy for locally advanced resectable colon cancer - a new treatment paradigm in colon cancer?, Annals of Translational Medicine, 1, 11, 2013 [PMC free article: PMC4200631] [PubMed: 25332956]	Narrative review

Table 8Gaps addressed and recommendations supported by expert evidence

Expert testimony	Gaps addressed	Recommendations supported
Preliminary findings from the FOxTROT trial	The published evidence base is weak and relies on one retrospective study and the pilot phase of the FOxTROT trial. The FOxTROT trial is a UK Phase III randomised trial that investigates the efficacy of neoadjuvant chemotherapy in colon cancer and is the only trial in the topic to date. However, the timeline of the guideline does not allow us to wait for the full results to be published later this year.	1.3.13

: FOxTROT: Fluoropyrimidine, Oxaliplatin and Targeted-Receptor pre-Operative Therapy for patients with high-risk, operable colon cancer

Figure 6Forest plot: Preoperative chemotherapy versus no preoperative chemotherapy - Disease-free survival

CI: confidence interval; CT: chemotherapy; E: expected; M-H: Mantel-Haenszel; O: observed; Preop: preoperative; V: variance

Figure 7Forest plot: Preoperative chemotherapy versus no preoperative chemotherapy - Grade 3 or 4 adverse events: anastomotic leak

CI: confidence interval; CT: chemotherapy; DVT: deep vein thrombosis; M-H: Mantel-Haenszel; Preop: preoperative

Figure 8Forest plot: Preoperative chemotherapy versus no preoperative chemotherapy - Treatment-related mortality

CI: confidence interval; CT: chemotherapy; M-H: Mantel-Haenszel; Preop: preoperative;

Table 9Quality assessment of expert evidence

Quality assessment							No of patients		Effect		Quality	Importance
No of studies	Design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	Preop CT	No preop CT	Relative (95% CI)	Absolute	Quality	Importance
Disease-free survival
1	randomised trials	no serious risk of bias	no serious inconsistency	no serious indirectness	serious¹	none	95/698 (13.6%)	61/354 (17.2%)	HR 0.74 (0.53, 1.04)	42 fewer per 1000 (from 77 fewer to 6 more)	MODERATE	CRITICAL
Overall survival
0	No evidence available	-	-	-	-	-	-	-	-	-	-	CRITICAL
Positive resection margins, T4b patients
0	No evidence available	-	-	-	-	-	-	-	-	-	-	CRITICAL
Any Grade 3 or 4 adverse events
0	No evidence available	-	-	-	-	-	-	-	-	-	-	IMPORTANT
Any Grade 3 or 4 adverse events - Anastomotic leak
1	randomised trials	no serious risk of bias	no serious inconsistency	no serious indirectness	serious¹	none	32/682 (4.7%)	26/350 (7.4%)	RR 0.63 (0.38, 1.04)	27 fewer pre 1000 (from 68 fewer to 136 more)	MODERATE	IMPORTANT
Any Grade 3 or 4 adverse events - Wound infection
0	No evidence available	-	-	-	-	-	-	-	-	-	-	IMPORTANT
Any Grade 3 or 4 adverse events – Bronchopneumonia
0	No evidence available	-	-	-	-	-	-	-	-	-	-	IMPORTANT
Any Grade 3 or 4 adverse events – Pulmonary embolism ± deep vein thrombosis
0	No evidence available	-	-	-	-	-	-	-	-	-	-	IMPORTANT
Overall quality of life
0	No evidence available	-	-	-	-	-	-	-	-	-	-	IMPORTANT
Treatment-related mortality (postoperative death rate)
1	randomised trials	no serious risk of bias	no serious inconsistency	no serious indirectness	serious¹	none	3/682 (0.4%)	1/350 (0.3%)	RR 1.52 [0.16, 14.57]	1 more per 1000 (from 2 fewer to 387 more)	MODERATE	IMPORTANT
Local recurrence
0	No evidence available	-	-	-	-	-	-	-	-	-	-	IMPORTANT

: CI: confidence interval; CT: chemotherapy; HR: hazard ratio; OR: odds ratio; RR: risk ratio

1: Quality of evidence downgraded by 1 because of imprecision of the effect estimate (< 300 events for dichotomous outcomes or < 400 patients for continuous outcomes).