Colorectal cancer (update) - C7 Preoperative chemotherapy for non-metastatic colon cancer - NICE
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National Institute for Health and Care
Excellence
Final
Colorectal cancer (update)
[C7] Preoperative chemotherapy for
non-metastatic colon cancer
NICE guideline NG151
Evidence reviews
January 2020
Final
Developed by the National Guideline
Alliance part of the Royal College of
Obstetricians and GynaecologistsFINAL 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 ap- plied 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 dis- crimination, 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 North- ern Ireland Executive. All NICE guidance is subject to regular review and may be updated or withdrawn. Copyright © NICE 2020. All rights reserved. Subject to Notice of Rights. ISBN: 978-1-4731-3657-1
FINAL
Preoperative chemotherapy in non-metastatic colon cancer
Contents
Which people with non-metastatic colon cancer would benefit from preoperative
chemotherapy?............................................................................................................. 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 outcomes included in the evidence review ............. 8
Economic evidence ............................................................................................... 8
Economic model .................................................................................................... 8
Evidence statements ............................................................................................. 9
The committee’s discussion of the evidence........................................................ 11
References .......................................................................................................... 13
Appendices ........................................................................................................................ 14
Appendix A – Review protocol ...................................................................................... 14
Review protocol for review question: Which people with non-metastatic colon
cancer would benefit from preoperative chemotherapy? .......................... 14
Appendix B – Literature search strategies .................................................................... 19
Literature search strategies for review question: Which people with non-
metastatic colon cancer would benefit from preoperative
chemotherapy? ........................................................................................ 19
Appendix C – Clinical evidence study selection ............................................................ 21
Clinical study selection for review question: Which people with non-metastatic
colon cancer would benefit from preoperative chemotherapy? ................. 21
Appendix D – Clinical evidence tables .......................................................................... 22
Clinical evidence tables for review question: Which people with non-metastatic
colon cancer would benefit from preoperative chemotherapy? ................. 22
Appendix E – Forest plots............................................................................................. 29
Forest plots for review question: Which people with non-metastatic colon
cancer would benefit from preoperative chemotherapy? .......................... 29
Appendix F – GRADE tables ........................................................................................ 33
GRADE tables for review question: Which people with non-metastatic colon
cancer would benefit from preoperative chemotherapy? .......................... 33
Appendix G – Economic evidence study selection ........................................................ 37
Economic evidence study selection for review question: Which people with
non-metastatic colon cancer would benefit from preoperative
chemotherapy .......................................................................................... 37
Appendix H – Economic evidence tables ...................................................................... 38
4FINAL
Preoperative chemotherapy in non-metastatic colon cancer
Economic evidence tables for review question: Which people with non-
metastatic colon cancer would benefit from preoperative chemotherapy .. 38
Appendix I – Economic evidence profiles ..................................................................... 39
Economic evidence profiles for review question: Which people with non-
metastatic colon cancer would benefit from preoperative
chemotherapy? ........................................................................................ 39
Appendix J – Economic analysis .................................................................................. 40
Economic analysis for review question: Which people with non-metastatic
colon cancer would benefit from preoperative chemotherapy? ................. 40
Appendix K – Excluded studies .................................................................................... 41
Excluded clinical studies for review question: Which people with non-
metastatic colon cancer would benefit from preoperative
chemotherapy? ........................................................................................ 41
Appendix L – Research recommendations ................................................................... 45
Research recommendations for review question: Which people with non-
metastatic colon cancer would benefit from preoperative
chemotherapy? ........................................................................................ 45
Appendix M – Expert evidence ..................................................................................... 46
Expert evidence for review question: Which people with non-metastatic colon
cancer would benefit from preoperative chemotherapy? .......................... 46
5FINAL
Preoperative chemotherapy in non-metastatic colon cancer
1 Which people with non-metastatic co-
2 lon cancer would benefit from preoper-
3 ative chemotherapy?
4 This evidence review supports recommendation 1.3.13.
5 Review question
6 Which people with non-metastatic colon cancer would benefit from preoperative
7 chemotherapy?
8 Introduction
9 Localised and resectable non-metastatic colon cancer has traditionally required an
10 aggressive therapeutic approach through complete oncologic resection with post-op-
11 erative chemotherapy, with extensive surgical resection needed to achieve negative
12 margins. While preoperative chemotherapy is commonly used for localised oesopha-
13 geal, gastric and rectal cancers, its use is not well-established for colon cancer as of
14 yet. Preoperative chemotherapy has the potential to provide earlier and more effec-
15 tive eradication of occult micrometastatic disease, minimise the extent of surgery and
16 debulk tumours to reduce the frequency of tumour cell shedding during surgery.
17 Therefore, the aim of this review was to determine which people with non-metastatic
18 colon cancer would benefit from preoperative chemotherapy.
19 Summary of the protocol
20 Please see Table 1 for a summary of the population, intervention, comparison and
21 outcomes (PICO) characteristics of this review.
22 Table 1: Summary 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:
o Radiological T stage
o Radiological N stage
• Tumour location
• Colonic obstruction status (no/complete/partly)
Intervention Preoperative chemotherapy
Comparison No preoperative chemotherapy
Outcomes Critical
• Disease-free survival
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Preoperative chemotherapy in non-metastatic colon cancer
• Overall survival
• Resection margins
Important
• Any grade 3 or 4 adverse events
• Overall quality of life
• Treatment-related mortality
• Local recurrence
1 For further details see the review protocol in appendix A.
2 Methods and process
3 This evidence review was developed using the methods and process described in
4 Developing NICE guidelines: the manual 2014. Methods specific to this review ques-
5 tion are described in the review protocol in appendix A.
6 Declarations of interest were recorded according to NICE’s 2014 conflicts of interest
7 policy until 31 March 2018. From 1 April 2018, declarations of interest were recorded
8 according to NICE’s 2018 conflicts of interest policy. Those interests declared until
9 April 2018 were reclassified according to NICE’s 2018 conflicts of interest policy (see
10 Register of Interests).
11 Clinical evidence
12 Included studies
13 Two studies were included in this review (FOxTROT trial [Agbamu 2012]; Dehal
14 2017).
15 The clinical studies included in this evidence review are summarised in Table 2.
16 One pilot RCT (FOxTROT 2012 [Agbamu 2012]) compared preoperative chemother-
17 apy + surgery + postoperative chemotherapy to surgery + postoperative chemother-
18 apy and 1 retrospective cohort study (Dehal 2017) compared preoperative chemo-
19 therapy + surgery to surgery + postoperative chemotherapy.
20 Expert evidence
21 The published evidence base is weak and relies on one retrospective study and the
22 pilot phase of the FOxTROT trial. The FOxTROT trial is an international, mainly UK-
23 based, phase III randomised trial that investigates the efficacy of neoadjuvant chem-
24 otherapy in colon cancer and is the only trial in the topic to date. The results from
25 FOxTROT were presented to the guideline committee as academic in confidence
26 data by one of the FOxTROT trialists as expert witness evidence. Where outcomes
27 were reported in both the pilot trial and expert evidence presentation, data from the
28 expert evidence presentation were used as these data were most recent and more
29 mature (longer follow-up). Since the expert witness presentation, the results of the
30 trial have been presented in a conference making them publicly available, although
31 not peer-reviewed.
32 See the summary of expert evidence in appendix M.
7
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Preoperative chemotherapy in non-metastatic colon cancer
1 Excluded studies
2 Studies not included in this review and their reasons for exclusion are listed in appen-
3 dix K.
4 Summary of clinical studies included in the evidence review
5 Table 2: Summary of included studies
Intervention/Com- Outcomes
Study Population parison
FOxTROT trial N=150 patients with Preoperative chemo- • Grade 3 or 4 ad-
locally advanced (T4 therapy + surgery + verse events
[Agbamu 2012] or T3 with extramu- postoperative chem-
ral depth ≥ 5mm) ad- otherapy versus sur-
enocarcinoma of the gery + postoperative
Pilot RCT colon with staging chemotherapy
determined preoper-
UK atively by either spi-
ral or multidetector
CT
Dehal 2017 N=27,575 patients Preoperative chemo- • Overall survival
with clinically staged therapy + surgery • Positive resection
Retrospective cohort T3 or T4, non-meta- versus surgery + margins
study static primary colon postoperative chem-
cancer who had both otherapy
US surgery and chemo-
therapy and a tu-
mour with a mucin-
ous, signet ring cell,
or adenocarcinoma
6 CT: computed tomography; N: number; RCT: randomised controlled trial; T: tumour stage
7 See the full evidence tables in appendix D and the forest plots in appendix E.
8 Quality assessment of clinical outcomes included in the evidence review
9 See the clinical evidence profiles in appendix F.
10 Economic evidence
11 Included studies
12 A systematic review of the economic literature was conducted but no economic stud-
13 ies were identified which were applicable to this review question.
14 Excluded studies
15 A global search of economic evidence was undertaken for all review questions in this
16 guideline. See Supplement 2 for further information.
17 Economic model
18 No economic modelling was undertaken for this review because the committee
19 agreed that other topics were higher priorities for economic evaluation.
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1 Evidence statements
2 Clinical evidence statements
3 Comparison 1: Preoperative chemotherapy versus no preoperative chemother-
4 apy
5 Critical outcomes
6 Disease-free survival
7 No evidence was identified to inform this outcome.
8 Overall survival
9 T3 patients
10 • Very low quality evidence from 1 retrospective cohort study (N=27,575) showed
11 no clinically important difference in 3-year overall survival between those receiving
12 preoperative chemotherapy + surgery compared to surgery + postoperative chem-
13 otherapy.
14 T4a patients
15 • Very low quality evidence from 1 retrospective cohort study (N=27,575) showed
16 no clinically important difference in 3-year overall survival between those receiving
17 preoperative chemotherapy + surgery compared to surgery + postoperative chem-
18 otherapy.
19 T4b patients
20 • Very low quality evidence from 1 retrospective cohort study (N=27,575) showed a
21 clinically important increase in 3-year overall survival between those receiving pre-
22 operative chemotherapy + surgery compared to surgery + postoperative chemo-
23 therapy.
24 Resection margins
25 T4b patients
26 • Very low quality evidence from 1 retrospective cohort study (N=27,575) showed a
27 clinically important decrease in resection margins between those receiving pre-
28 operative chemotherapy + surgery compared to surgery + postoperative chemo-
29 therapy.
30 Important outcomes
31 Any Grade 3 or 4 adverse events
32 Grade ≥3 adverse events
33 • Very low quality evidence from 1 RCT (N=150) showed no clinically important dif-
34 ference in Grade ≥3 adverse events within 6, 12, 18, or 24 weeks between those
35 receiving preoperative chemotherapy + surgery + postoperative chemotherapy
36 compared to surgery + postoperative chemotherapy.
37 Anastomotic leak
38 • More recent data for this outcome were available in the expert evidence summary.
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1 Wound infection with or without intra-abdominal abscess
2 • Very low quality evidence from 1 RCT (N=150) showed no clinically important dif-
3 ference in wound infection with or without intra-abdominal abscess between those
4 receiving preoperative chemotherapy + surgery + postoperative chemotherapy
5 compared to surgery + postoperative chemotherapy.
6 Bronchopneumonia
7 • Very low quality evidence from 1 RCT (N=150) showed no clinically important dif-
8 ference in bronchopneumonia between those receiving preoperative chemother-
9 apy + surgery + postoperative chemotherapy compared to surgery + postoperative
10 chemotherapy.
11 Deep vein thrombosis
12 • Very low quality evidence from 1 RCT (N=150) showed no clinically important dif-
13 ference in deep vein thrombosis between those receiving preoperative chemother-
14 apy + surgery + postoperative chemotherapy compared to surgery + postoperative
15 chemotherapy.
16 Neutropenia
17 • Very low quality evidence from 1 RCT (N=150) showed no clinically important dif-
18 ference in neutropenia between those receiving preoperative chemotherapy + sur-
19 gery + postoperative chemotherapy compared to surgery + postoperative chemo-
20 therapy.
21 Overall quality of life
22 No evidence was identified to inform this outcome.
23 Treatment-related mortality
24 • More recent data for this outcome were available in the expert evidence summary.
25 Local recurrence
26 No evidence was identified to inform this outcome.
27 Expert evidence statements
28 Comparison 1: Preoperative chemotherapy versus no preoperative chemother-
29 apy
30 Critical outcomes
31 Disease-free survival
32 • Moderate quality evidence from 1 RCT (N=1052) showed a clinically important de-
33 crease in recurrence between those receiving preoperative chemotherapy + sur-
34 gery + postoperative chemotherapy compared to surgery + postoperative chemo-
35 therapy.
36 Overall survival
37 No evidence was identified to inform this outcome.
38 Resection margins
39 No evidence was identified to inform this outcome.
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Preoperative chemotherapy in non-metastatic colon cancer
1 Important outcomes
2 Any Grade 3 or 4 adverse events
3 Anastomotic leak
4 • Moderate quality evidence from 1 RCT (N=1052) showed a clinically important de-
5 crease in anastomotic leak between those receiving preoperative chemotherapy +
6 surgery + postoperative chemotherapy compared to surgery + postoperative
7 chemotherapy.
8 Wound infection with or without intra-abdominal abscess
9 • No evidence was identified to inform this outcome.
10 Bronchopneumonia
11 • No evidence was identified to inform this outcome.
12 Pulmonary embolism ± deep vein thrombosis
13 • No evidence was identified to inform this outcome.
14 Overall quality of life
15 No evidence was identified to inform this outcome.
16 Treatment-related mortality
17 • Moderate quality evidence from 1 RCT (N=1052) showed no clinically important
18 difference in treatment-related mortality (postoperative mortality) between those
19 receiving preoperative chemotherapy + surgery + postoperative chemotherapy
20 compared to surgery + postoperative chemotherapy.
21 Local recurrence
22 No evidence was identified to inform this outcome.
23 Economic evidence statements
24 No economic evidence was identified which was applicable to this review question.
25 The committee’s discussion of the evidence
26 Interpreting the evidence
27 The outcomes that matter most
28 Disease-free survival and overall survival were considered critical outcomes for deci-
29 sion making because disease progression suggests ineffective control of the local-
30 ised colon cancer, potentially requiring further treatment and affecting overall sur-
31 vival. Resection margins were also critical as they are indicative of whether further
32 treatment, likely surgical, is needed.
33 Quality of life was an important outcome because of the impact that different treat-
34 ment options can have on patients’ functioning and the potential long term adverse
35 effects. Any grade 3 or 4 adverse events and treatment-related mortality were also
36 important outcomes, as they are indicative of the complications of treatments. Addi-
37 tionally, local recurrence was an important outcome because lesions that extend into
38 surrounding structures and organs indicate the need for further surgical resection.
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Colorectal cancer (update): evidence review for preoperative chemotherapy in non-
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Preoperative chemotherapy in non-metastatic colon cancer
1 The quality of the evidence
2 Evidence was available from 1 pilot RCT comparing preoperative chemotherapy +
3 surgery + postoperative chemotherapy to surgery + postoperative chemotherapy and
4 1 retrospective cohort study comparing preoperative chemotherapy + surgery to sur-
5 gery + postoperative chemotherapy.
6 Evidence was available for overall survival, resection margins, any grade 3 or 4 ad-
7 verse events and treatment-related mortality. There was no evidence for quality of life
8 or local recurrence. The quality of the evidence was assessed using GRADE and
9 was of very low quality. The quality of evidence was downgraded because of meth-
10 odological limitations affecting the risk of bias and imprecision around the risk esti-
11 mate.
12 Methodological limitations leading to risk of bias were due to confounding from differ-
13 ences in baseline characteristics, lack of blinding and allocation concealment.
14 Indirectness in the study interventions was attributable to numerous protocol viola-
15 tions in both arms of the RCT that potentially diluted the effectiveness of the interven-
16 tions.
17 Uncertainty around the risk estimate was due to low event rates and small sample
18 sizes.
19 An expert witness presented academic in confidence results of the FoXTROT trial
20 which provided expert evidence for the comparison of preoperative chemotherapy +
21 surgery + postoperative chemotherapy versus surgery + postoperative surgery. Evi-
22 dence was available for disease-free survival, any grade 3 or 4 adverse events and
23 treatment-related mortality. This evidence was assessed using GRADE as moderate
24 quality.
25 The range in quality of the evidence and lack of evidence for many comparisons and
26 outcomes impacted the decision-making and the strength of the recommendation as
27 there was insufficient evidence to make a strong recommendation or to make recom-
28 mendations for all subgroups within the population.
29 Benefits and harms
30 The evidence indicated that there were benefits for disease-free survival, overall sur-
31 vival and clear resection margins for patients with more advanced (T4b) colonic tu-
32 mours who received preoperative chemotherapy. No benefit on overall survival was
33 found for patients with T3 or T4a colonic tumours. However, the committee agreed
34 that differentiating between T4a and T4b tumours would be difficult in preoperative
35 clinical staging (imaging), therefore, based on their clinical experience and
36 knowledge they agreed that the recommendation to consider preoperative therapy
37 should cover patients with T4 tumours.
38 While the expert evidence showed that there was a clinically important decrease in
39 anastomotic leak, otherwise the clinical evidence did not show any clinically im-
40 portant difference between treatment groups in terms of adverse events or treatment-
41 related mortality. From their clinical experience, the committee noted that there is a
42 potential for harm from increased surgical morbidity. The committee was not aware of
43 any evidence regarding treatment decision-making pertaining to the extent of surgical
44 resection (that is, whether decisions should be based on pre- or post-chemotherapy
45 imaging). However, they noted that most clinicians would base their decisions on the
46 extent of surgery on pre-chemotherapy imaging.
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1 Cost effectiveness and resource use
2 A systematic review of the economic literature was conducted but no relevant studies
3 were identified which were applicable to this review question.
4 The committee considered that the addition of preoperative chemotherapy would not
5 increase costs for patients with T4 colon cancer as postoperative chemotherapy is
6 current standard of care and costs between pre and post would be similar given the
7 almost identical regimens. The committee acknowledged that preoperative chemo-
8 therapy was already being done in some centres and that it would only represent a
9 change for some centres. There would also be increases in overall survival and qual-
10 ity of life through reduced surgical morbidity.
11 Other factors the committee took into account
12 The committee acknowledged the FOxTROT trial, which compares preoperative plus
13 post-operative chemotherapy (+/- panitumumab) with standard post-operative chem-
14 otherapy. Results from the earlier feasibility trial (FOxTROT trial [Agbamu 2012])
15 were included in this review. Primary outcomes include 2-year recurrence-free sur-
16 vival and pathological down-staging and secondary outcomes include disease-spe-
17 cific survival and overall survival at 2 years and quality of life by EORTC QLQ C-30
18 and EuroQol EQ-5D before surgery, before the first post-operative chemotherapy
19 and 1 year post-randomisation. The committee considered expert evidence about the
20 unpublished results of the FOxTROT trial from the primary randomisation (preopera-
21 tive-and-postoperative chemotherapy versus standard postoperative chemotherapy)
22 to neoadjuvant treatment as data analysis for the substudy (patients with KRAS-wild
23 type tumours randomised 1:1 to preoperative-and-postoperative chemotherapy +/-
24 panitumumab) was not complete. Moderate quality evidence from the primary ran-
25 domisation phase showed that complete clinical response and tumour downstaging
26 are more likely in those who receive preoperative chemotherapy, although follow-up
27 is not yet long enough to assess long-term outcomes. The results presented to the
28 committee as academic in confidence were since presented at an international con-
29 ference. See more details in appendix M.
30 References
31 FOxTROT trial [Agbamu 2012]
32 Agbamu D, Day N, Walsh C, et al. (2012) Feasibility of preoperative chemotherapy
33 for locally advanced, operable colon cancer: The pilot phase of a randomised con-
34 trolled trial. Lancet Oncology 13(11): 1152-1160
35 Dehal 2017
36 Dehal A, Vuong B, Graff-Baker A, et al. (2017) Neoadjuvant chemotherapy improves
37 survival in patients with clinical T4B colon cancer. Gastroenterology 152 (5): S1209
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Preoperative chemotherapy in non-metastatic colon cancer
1 Appendices
2 Appendix A – Review protocol
3 Review protocol for review question: Which people with non-metastatic co-
4 lon cancer would benefit from preoperative chemotherapy?
5 Table 3: Review protocol for pre-operative chemotherapy for people with non-
6 metastatic colon cancer
Field (based on PRISMA) Content
Review question in guideline Which people with non-metastatic colon can-
cer would benefit from preoperative chemo-
therapy?
Type of review question Intervention
Objective of the review To determine which people with non-meta-
static colon cancer would benefit from pre-
operative chemotherapy.
Eligibility criteria – population/dis- Adults with localised, resectable, non-meta-
ease/condition/issue/domain static colon cancer
Non-metastatic cancer defined as:
• Tany N1-2
• T3
• T4
• M0
Subgroups according to (analysed sepa-
rately):
• Disease characteristics:
o Radiological T stage
o Radiological N stage
• Tumour location
• Colonic obstruction status (no/com-
plete/partly)
Eligibility criteria – intervention(s)/expo- Preoperative chemotherapy
sure(s)/prognostic factor(s)
Eligibility criteria – comparator(s)/control No preoperative chemotherapy
or reference (gold) standard
Outcomes and prioritisation Critical outcomes:
• Disease-free survival (minimally important
difference [MID]: statistical significance)
• Overall survival (MID: statistical signifi-
cance)
• Resection margins (MID: statistical signifi-
cance)
Important outcomes:
• Any Grade 3 or 4 adverse events (MID: sta-
tistical significance)
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Preoperative chemotherapy in non-metastatic colon cancer
Field (based on PRISMA) Content
• Overall quality of life measured using vali-
dated scales (MID: published MIDs from lit-
erature, see below)
• Treatment-related mortality (MID: statistical
significance)
• Local recurrence (MID: statistical signifi-
cance)
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 eligi-
ble 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 consid-
ered 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, Cohort studies should include multivariate
or meta-regression analysis controlling for the following confound-
ing factors:
• Patient characteristics (i.e. age [life expec-
tancy], comorbidities)
• Type of chemotherapy
• Tumour characteristics
o T stage
o Tumour location
Selection process – duplicate screen- Sifting, data extraction, appraisal of methodo-
ing/selection/analysis logical quality and GRADE assessment will be
performed by the systematic reviewer. Reso-
lution of any disputes will be with the senior
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Field (based on PRISMA) Content
systematic reviewer and the Topic Advisor.
Quality control will be performed by the senior
systematic reviewer.
Dual sifting will be undertaken for this ques-
tion for a random 10% sample of the titles and
abstracts identified by the search.
Data management (software) Pairwise meta-analyses will be performed us-
ing 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 as-
sessment using checklists and generating bib-
liographies/citations.
Information sources – databases and Potential sources to be searched: Medline,
dates Medline In-Process, CCTR, CDSR, DARE,
HTA, Embase
Limits (e.g. date, study design):
• Apply standard animal/non-English lan-
guage 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/indevelop-
ment/gid-ng10060Developer: NGA
Highlight if amendment to previous proto- For details please see section 4.5 of Develop-
col ing 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 ta-
bles).
Data items – define all variables to be col- For details please see evidence tables in ap-
lected pendix D (clinical evidence tables) or H (eco-
nomic evidence tables).
Methods for assessing bias at out- Standard study checklists were used to criti-
come/study level cally 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.
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Field (based on PRISMA) Content
The risk of bias across all available evidence
was evaluated for each outcome using an ad-
aptation of the ‘Grading of Recommendations
Assessment, Development and Evaluation
(GRADE) toolbox’ developed by the interna-
tional GRADE working group
http://www.gradeworkinggroup.org/
Criteria for quantitative synthesis (where For details please see section 6.4 of Develop-
suitable) ing NICE guidelines: the manual
Methods for analysis – combining studies Synthesis of data:
and exploring (in)consistency 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 indica-
tors 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, For details please see section 6.2 of Develop-
selective reporting bias ing NICE guidelines: the manual.
If sufficient relevant RCT evidence is availa-
ble, publication bias will be explored using
RevMan software to examine funnel plots.
Assessment of confidence in cumulative For details please see sections 6.4 and 9.1 of
evidence Developing NICE guidelines: the manual
Rationale/context – Current management For details please see the introduction to the
evidence review.
Describe contributions of authors and A multidisciplinary committee developed the
guarantor 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 un-
dertook systematic literature searches, ap-
praised the evidence, conducted meta-analy-
sis and cost-effectiveness analysis where ap-
propriate, and drafted the guideline in collabo-
ration 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 Gy-
naecologists
Name of sponsor The NGA is funded by NICE and hosted by
the Royal College of Obstetricians and Gy-
naecologists
17
Colorectal cancer (update): evidence review for preoperative chemotherapy in non-
metastatic colon cancer FINAL (January 2020)FINAL
Preoperative chemotherapy in non-metastatic colon cancer
Field (based on PRISMA) Content
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
1 CCTR: Cochrane Central Register of Controlled Trials; CDSR: Cochrane Database of Systematic Re-
2 views; CENTRAL: Cochrane Central Register of Controlled Trials; DARE: Database of Abstracts of Re-
3 views of Effects; EuroQol five dimensions questionnaire; EORTC QLQ-C30: European Organisation for
4 Research and Treatment of Cancer Quality of Life Questionnaire Core 30 Items; EORTC QLQ-CR29:
5 European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire colorectal
6 cancer module (29 items); EORTC QLQ-CR38: European Organisation for Research and Treatment of
7 Cancer Quality of Life Questionnaire colorectal cancer module (38 items); FACT-C: Functional Assess-
8 ment of Cancer Therapy questionnaire (colorectal cancer); FACT-G: Functional Assessment of Cancer
9 Therapy questionnaire (general); GRADE: Grading of Recommendations Assessment, Development
10 and Evaluation; HTA: Health Technology Assessment; M0: no distant metastasis; MCS: mental compo-
11 nent summary; MID: minimally important difference; N: nodal stage; NGA: National Guideline Alliance;
12 NHS: National health service; NICE: National Institute for Health and Care Excellence; PCS: physical
13 component summary; RCT: randomised controlled trial; RevMan5: Review Manager version 5; RoB: risk
14 of bias; ROBINS-I: Risk Of Bias In Non-randomised Studies - of Interventions; ROBIS: risk of bias in
15 systematic reviews; SD: standard deviation; SF-12: 12-Item Short Form Survey; SF-36: 36-Item Short
16 Form Survey; T: tumour stage
18
Colorectal cancer (update): evidence review for preoperative chemotherapy in non-
metastatic colon cancer FINAL (January 2020)FINAL
Preoperative chemotherapy in non-metastatic colon cancer
1 Appendix B – Literature search strategies
2 Literature search strategies for review question: Which people with non-meta-
3 static colon cancer would benefit from preoperative chemotherapy?
4 Databases: Embase/Medline
5 Last searched on: 31/10/2018
# 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.
19
Colorectal cancer (update): evidence review for preoperative chemotherapy in non-
metastatic colon cancer FINAL (January 2020)FINAL
Preoperative chemotherapy in non-metastatic colon cancer
# Search
44 or/31-43
45 13 not 44
46 limit 45 to (yr="2005 - current" and english language)
47 remove duplicates from 46
1 Database: Cochrane Library
2 Last searched on: 31/10/2018
# 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
3
20
Colorectal cancer (update): evidence review for preoperative chemotherapy in non-
metastatic colon cancer FINAL (January 2020)FINAL
Preoperative chemotherapy in non-metastatic colon cancer
1 Appendix C – Clinical evidence study selection
2 Clinical study selection for review question: Which people with non-metastatic
3 colon cancer would benefit from preoperative chemotherapy?
4 Figure 1: Study selection flow chart
5
Titles and abstracts
identified, N= 1064
Full copies retrieved Excluded, N= 1034
and assessed for eli- (not relevant population,
gibility, N= 30 design, intervention, com-
parison, outcomes, unable
to retrieve)
Publications included Publications excluded
in review, N= 2 from review, N= 28
(refer to excluded
studies list)
6
21
Colorectal cancer (update): evidence review for preoperative chemotherapy in non-
metastatic colon cancer FINAL (January 2020)FINAL
Preoperative chemotherapy in non-metastatic colon cancer
1 Appendix D – Clinical evidence tables
2 Clinical evidence tables for review question: Which people with non-metastatic colon cancer would benefit from preoperative
3 chemotherapy?
4 Table 4: Clinical evidence tables
Outcomes and Re-
Study details Participants Interventions Methods sults Comments
Full citation Agbamu Sample size Interventions Details Results Limitations
D, Day N, Walsh C, n= 150 "Chemotherapy was the Randomisation: "Eli- Grade ≥3 adverse Quality assessment
et al. (2012) Feasibil- Preoperative + postopera- standard UK modified de Gra- gible patients were events within 6 performed with the
ity of preoperative tive chemotherapy (CT), mont (OxMdG) regimen, con- randomly assigned, weeks, n/N Cochrane risk of bias
chemotherapy for lo- n=99 sisting of cycles of oxaliplatin in a 2:1 ratio, be- tool
cally advanced, oper- at 85 mg/m2 combined with l- tween preoperative Selection bias
Standard postoperative Preoperative + post-
able colon cancer: folinic acid 175 mg/m2 plus plus postoperative
chemotherapy alone, n=51 operative CT= 32/94 Random sequence
The pilot phase of a fluorouracil 400 mg/m2 by in- and postoperative
Postoperative CT= generation: low risk
randomised con- travenous bolus, followed by chemotherapy. Pa-
Characteristics 12/39 (computer generated
trolled trial. Lancet a 46 h infusion of 2400 tients were also ran- randomisation was
Oncology 13: 1152- Preoperative + postopera- mg/m2 through an indwelling domly assigned, in a used)
1160 tive CT, n=99 line, repeated at 2-weekly in- 1:1 ratio, to receive Grade ≥3 adverse
events within 12 Allocation conceal-
Age, years, median (IQR)= tervals. Capecitabine could panitumumab with
weeks, n/N: ment: unclear risk
Ref Id 745295 64 (59-68) not be substituted for fluor- the first 6 weeks of
(study was not
Sex, male, n=65 ouracil and folinic acid in this chemotherapy or not.
blinded)
Colonic obstruction, n=3 pilot study because of higher Patients were allo- Preoperative + post-
Country/ies where Performance bias
toxicity when combined with cated to a treatment operative CT= 14/81
the study was car- Radiological T-stage, n Blinding of partici-
panitumumab. Dose reduc- group by a telephone Postoperative CT=
ried out UK T3=69 pants and personnel:
tions and delays of up to 4 or web-based central 9/38
T4=30 weeks were allowed for re- randomisation ser- unclear risk (study
Study type Pilot RCT Radiological N-stage, n versible toxicity." vice at the University was not blinded)
of Birmingham Clini- Grade ≥3 adverse Detection bias
Nx=3 Preoperative + postoperative
cal Trials Unit. A events within 18
Aim of the study N0=23 CT= "Preoperative chemo- Blinding of outcome
therapy duration was only 6 computerised mini- weeks, n/N:
The aim of the study N1=44 assessment: low risk
was to assess patient weeks (three cycles of mised randomisation (study was not
selection and recruit- N2=29 OxMdG) to minimise the risk procedure was used Preoperative + post- blinded, but lack of
ment, safety, and tu- Extramural vascular inva- of progression of chemo- to ensure a good bal- operative CT= 18/75 blinding unlikely to
mour response to sion, n= 57/98 (one radiol- resistant tumours (15–20% of ance between groups Postoperative CT= affect outcome as-
ogy form had missing data) advanced metastatic colon for age, radiological 8/34 sessment)
T-stage, radiological
22
Colorectal cancer (update): evidence review for preoperative chemotherapy in non-metastatic colon cancer FINAL (January 2020)FINAL
Preoperative chemotherapy in non-metastatic colon cancer
Outcomes and Re-
Study details Participants Interventions Methods sults Comments
preoperative treat- Postoperative CT only, n=51 cancers progress during 12 nodal status, site of Attrition bias
ment as part of a fea- Age, years, median weeks of similar combination primary tumour, and Grade ≥3 adverse Incomplete outcome
sibility phase to the (IQR)=65 (56-69) chemotherapy). Surgery with defunctioning colos- events within 24 data: low risk (inten-
wider FOxTROT curative intent was under- tomy." weeks, n/N: tion-to-treat analysis
Sex, male, n=32
(Fluoropyrimidine Ox- taken at least 3 weeks after Allocation conceal- used)
aliplatin and Targeted Colonic obstruction, n=1 completing preoperative ther- ment: Allocation not Preoperative + post- Reporting bias
Receptor Pre-Opera- Radiological T-stage, n apy, to reduce perioperative concealed
tive Therapy) trial. T3=35 morbidity, followed by a fur- operative CT= 47/95 Selective reporting:
Blinding: Not blinded Postoperative CT= low risk (primary out-
T4=16 ther 18 weeks (nine cycles) of
Follow up: Not re- 20/39 come points were re-
Study dates May 15, Radiological N-stage, n OxMdG. CT scans were re-
ported ported)
2008 to September peated before surgery in the
Nx=1 Outcomes: Feasibil- Other bias
21, 2010 pre-operative group." Anastomotic leak,
N0=12 ity, safety, tolerance Other sources of
Postoperative CT only= "For n/N:
N1=22 of preoperative ther- bias: No other
the patients who were not as-
Source of funding N2=16 apy, and the accu- sources of bias
signed to receive preoperative Data extracted from
Cancer Research UK racy of radiological
Extramural vascular inva- chemotherapy, postoperative expert evidence pro-
staging. Other key
sion, n=31 chemotherapy duration was vided , refer to appen- Other information
outcomes were com-
Inclusion criteria 24 weeks (12 cycles) of dix M "The FOxTROT
pletion of planned
"18 years or older with lo- OxMdG. If allocated, pani- study aims to ran-
surgery, periopera-
cally advanced (T4 or T3 tumumab (6 mg/kg) was given domly assign at least
tive morbidity, timely Wound infection with
with extramural depth ≥5 by intravenous infusion at 2- 1050 patients to de-
completion of pre- or without intra-ab-
mm) adenocarcinoma of the weekly intervals during the tect a 25% propor-
operative KRAS test- dominal abscess, n/N:
colon, with staging deter- first 6 weeks of chemotherapy tional reduction
ing, and downstaging
mined preoperatively by ei- (preoperative or postopera- (roughly 8% absolute
of the resected tu-
ther spiral or multidetector tive)." Preoperative + post- difference) in recur-
mour as measured
computed tomography and operative CT= 13/99 rence at 2 years (eg,
by histopathological
for whom a 24-week course tumour diameter and Postoperative CT= 32% reduced to
of oxaliplatin and fluoropy- stage. 4/51 24%) with 80%
rimidine-based adjuvant Statistical analysis: power at pFINAL
Preoperative chemotherapy in non-metastatic colon cancer
Outcomes and Re-
Study details Participants Interventions Methods sults Comments
greater than 100×10⁹ plate- allocation, and us- Deep vein thrombosis, and any large differ-
lets per L; adequate renal bi- ing t tests to compare n/N: ences in other pri-
ochemistry with a glomerular continuous variables, mary outcomes."
filtration rate of greater than Mantel-Haenszel Preoperative + post-
Preoperative + post-
50 mL per minute as calcu- tests of association operative CT: "15
operative CT= 2/99
lated by the Wright or Cock- for ordinal variables." patients had no post-
roft formula or EDTA clear- Postoperative CT=
operative CT; five
ance of greater than 70 mL 0/51
patients (including
per minute; adequate three who had no
hepatobiliary function with Neutropenia, n/N: preoperative chemo-
bilirubin less than 25 μmol therapy) did not have
per L; and serum magne- Preoperative + post- postoperative chem-
sium levels within the normal operative CT= 1/99 otherapy because of
range at trial entry." low-risk pathology,
Postoperative CT=
0/51 five because of pre-
Exclusion criteria Not re- vious adverse events
ported (four because of tox-
Treatment-related icity of preoperative
mortality, n/N: CT, one because of
surgical morbidity),
Data extracted from three refused, one
expert evidence pro- had metastatic dis-
vided , refer to appen- ease, and one died
dix M in the postoperative
period. Additionally,
two had off-protocol
treatment (one pa-
tient had a different
chemotherapy regi-
men, and one was
treated with bevaci-
zumab)."
Postoperative CT
alone: "Of 51 pa-
tients allocated post-
operative CT, 94%
(48 of 51) had resec-
tional surgery with
24
Colorectal cancer (update): evidence review for preoperative chemotherapy in non-metastatic colon cancer FINAL (January 2020)FINAL
Preoperative chemotherapy in non-metastatic colon cancer
Outcomes and Re-
Study details Participants Interventions Methods sults Comments
one dying before-
hand and two who
were not resected
because of inopera-
ble peritoneal spread
detected at surgery.
78% (40 of 51)
started postoperative
chemotherapy with
11 not having post-
operative chemo-
therapy because of
low risk pathology
(seven) or dying be-
forehand (four). 95%
(38 of 40) of those
starting completed
the first 6 weeks and
72% (29 of 40) com-
pleted all 24 weeks
of CT. Toxicity
caused six patients
to discontinue chem-
otherapy." Thus, a
higher proportion of
patients started pre-
operative than post-
operative chemo-
therapy (96% [95 of
99] vs 78% [40 of
51]; p=0.001), and
CT completion rates
were also higher in
the preoperative
therapy group with
68% (67 of 99) of
those allocated pre
plus postoperative
25
Colorectal cancer (update): evidence review for preoperative chemotherapy in non-metastatic colon cancer FINAL (January 2020)FINAL
Preoperative chemotherapy in non-metastatic colon cancer
Outcomes and Re-
Study details Participants Interventions Methods sults Comments
CT completing 24
weeks of treatment
compared with 57%
(29 of 51) of postop-
erative CT patients
(p=0.19)."
Full citation Dehal Sample size Interventions Details Results Limitations
A, Vuong B, Graff- n= 27,575 Preoperative CT + surgery Data collection: Pa- 3-year overall sur- ROBINS-I checklist
Baker A, et al. (2017) Preoperative CT + surgery= Surgery + postoperative CT tient records were re- vival, hazard ratio for non-randomised
Neoadjuvant chemo- 921 trieved from the Na- (95% CI), p-value studies of interven-
Surgery: segmental resection,
therapy improves sur- tional Cancer Data (propensity score tions
Surgery + postoperative subtotal colectomy/hemicolec-
vival in patients with Base from 2006-2014 matched for age, gen- Pre-intervention
CT= 26,654 tomy, total colectomy, en bloc
clinical T4B colon using ICD-9-O coding der, race, insurance
resection Bias due to con-
cancer. Gastroenter- schema. status, comorbidity
Characteristics founding: High risk of
ology 152 (5 Supple- Follow up: 3 years score, hospital type, bias due to con-
ment 1), S1209 Preoperative CT + surgery, tumour histology,
Outcomes: 3-year founding ("There
n= 921 grade, N stage, tu-
overall survival, en were significant dif-
Ref Id 919057 Age, years, mean (SD)=58.4 bloc resection, resec- mour location, number ferences in patient
(12.1) tion margins of nodes examined, demographics, tu-
Sex, male, n=533 margin, and extent of mour features, and
Country/ies where Factors controlled
Histology, n surgery): treatment between
the study was car- for: "Characteristics
ried out USA Adenocarcinoma=786 with statistically sig- the two groups...and
Mucinous=121 nificant p values (p < T3 patients though propensity
0.001) as well as clin- Preoperative CT + score matching was
Study type Retro- Signet cell=14
ically relevant varia- surgery= 1.15 (0.92- used to minimize
spective cohort T stage, n bles obtained from 1.43), 0.24 confounding, there
study T3=479 univariate Cox pro- Surgery + postopera- remained a small
T4a=69 portional-hazards re- tive CT= reference number of un-
Aim of the study T4b=350 gression analysis matched patients")
The aim of the study were used to match Bias in selection of
was to assess the ef- N stage, n T4a patients
the two treatment participants into the
fect of neoadjuvant N0=450 Preoperative CT +
groups. This included study: Unclear risk of
chemotherapy for lo- N1=291 age, gender, race, in- surgery= 1.43 (0.85- bias ("The data does
cally advanced colon N2=106 surance status, 2.40), 0.18 not include the small
cancer on survival. Nx=74 comorbidity score, Surgery + postopera- groups of patients
Grade, n hospital type, histol- tive CT= reference who underwent sur-
Low=636 ogy, N stage, grade, gical resection but
26
Colorectal cancer (update): evidence review for preoperative chemotherapy in non-metastatic colon cancer FINAL (January 2020)FINAL
Preoperative chemotherapy in non-metastatic colon cancer
Outcomes and Re-
Study details Participants Interventions Methods sults Comments
Study dates 2006 to High=184 tumour location, T4b patients did not receive AC
2014 Unknown=101 nodes examined, Preoperative CT + due to morbidity and
margin, and extent of surgery= 0.77 (0.60- mortality nor patients
Nodes retrieved, n
surgery. The match- 0.98), 0.04 that had neoadjuvant
Source of funding 1-11=168 ing rate for T3, T4a, chemotherapy but
Not reported ≥12=745 Surgery + postopera-
and T4b was 80, 70, never had surgery
tive CT= reference
Unknown=8 and 78%, respec- due to disease pro-
Margin, n tively. The standard gression.")
mean difference be- Positive margins for At intervention
Negative=776
tween the two groups T4b patients, odds ra-
Positive=126 Bias in classification
after propensity score tio (CI), p-value (ad-
Unknown=19 of interventions: Low
matching was < 0.1, justed for age, gen-
risk of bias
Surgery + postoperative CT, indicating negligible der, race, insurance
n= 26,654 status, comorbidity Post-intervention
difference."
Age, years, mean (SD)=61.5 score, hospital type, Bias due to devia-
Statistical analysis:
tumour histology, tions from intended
Sex, male, n=13,270 "To examine the as-
grade, N stage, extent interventions: Low
Histology, n sociation between
of surgery, and tu- risk of bias
Adenocarcinoma=22,834 the two treatment
groups and 3-year mour location): Bias due to missing
Mucinous=3243 data: Unclear risk of
overall survival (OS),
Signet cell=577 univariate Cox pro- Preoperative CT + bias (Some data
T stage, n portional-hazards re- surgery= 0.95 (0.90- missing from patient
T3=19,999 gression analysis 0.98), p=0.04* characteristics)
T4a=3201 was performed, fol- Surgery + postopera- Bias in measurement
lowed by propensity tive CT= reference of outcomes: Low
T4b=2987
score matching to (* Note that calculated risk of bias
N stage, n
minimize the con- values appearing in Bias in selection of
N0=11,106 founding effects due the reported result:
the forest plot and
N1=8985 to nonrandomised corresponding table Low risk of bias
N2=5343 assignment within are different 0.95
Nx=1220 clinical tumour stages [0.91, 0.99] due to Other information
(T3, T4a, and T4b). rounding)
Grade, n None
Survival curves were
Low=18,843 also plotted using the
High=7086 Kaplan-Meier method
Unknown=725 and compared with
Nodes retrieved, n the log-rank test for
1-11=2844 each tumour stage
27
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