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National Collaborating Centre for Cancer (UK). Colorectal Cancer: The Diagnosis and Management of Colorectal Cancer. Cardiff: National Collaborating Centre for Cancer (UK); 2011 Nov. (NICE Clinical Guidelines, No. 131.)

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Colorectal Cancer: The Diagnosis and Management of Colorectal Cancer.

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Methodology

Introduction

What is a Clinical Guideline?

Guidelines are recommendations for the care of individuals in specific clinical conditions or circumstances – from prevention and self-care through to primary and secondary care and on to more specialised services. NICE clinical guidelines are based on the best available evidence of clinical and cost effectiveness, and are produced to help healthcare professionals and patients make informed choices about appropriate healthcare. While guidelines assist the practice of healthcare professionals, they do not replace their knowledge and skills.

Clinical guidelines for the NHS in England, Wales and Northern Ireland are produced as a response to a request from the Department of Health (DH). They approve topics for guideline development. Before deciding whether to refer a particular topic to the National Institute for Health and Clinical Excellence (NICE) they consult with the relevant patient bodies, professional organisations and companies. Once a topic is referred, NICE then commissions one of four National Collaborating Centres (NCCs) to produce a guideline. The Collaborating Centres are independent of government and comprise partnerships between a variety of academic institutions, health profession bodies and patient groups. The National Collaborating Centre for Cancer (NCC-C) was referred the topic of the diagnosis and management of colorectal cancer in October 2007 as part of NICE’s sixteenth wave work programme. However, the guideline development process began officially in February 2009 when sufficient capacity became available at the NCC-C.

Who is the Guideline Intended For?

This guideline does not include recommendations covering every detail of the diagnosis and management of colorectal cancer. Instead this guideline has tried to focus on those areas of clinical practice (i) that are known to be controversial or uncertain; (ii) where there is identifiable practice variation; (iii) where there is a lack of high quality evidence; or (iv) where NICE guidelines are likely to have most impact. More detail on how this was achieved is presented later in the section on ‘Developing Clinical Evidence Based Questions’.

This guideline is relevant to all healthcare professionals who come into contact with patients with colorectal cancer or suspected of having colorectal cancer, as well as to the patients themselves and their carers. It is also expected that the guideline will be of value to those involved in clinical governance in both primary and secondary care to help ensure that arrangements are in place to deliver appropriate care for the population covered by this guideline.

The Remit of the Guideline

Guideline topics selected by the DH identify the main areas to be covered by the guideline in a specific remit. The following remit for this guideline was received as part of NICE’s sixteenth wave programme of work:

‘To prepare a clinical guideline on the diagnosis and management of patients with all stages of primary colorectal cancer. This excludes any population screening and surveillance of high-risk groups, including patients with a family history and patients with inflammatory bowel disease.’

Involvement of Stakeholders

Key to the development of all NICE guidance is the involvement of relevant professional and patient/carer organisations that register as stakeholders. Details of this process can be found on the NICE website or in the ‘NICE guidelines manual’ (NICE 2009). In brief, their contribution involves commenting on the draft scope, submitting relevant evidence and commenting on the draft version of the guideline during the end consultation period. A full list of all stakeholder organisations who registered for the diagnosis and management of colorectal cancer guideline can be found in Appendix 6.2.

The Process of Guideline Development – Who Develops the Guideline?

Overview

The development of this guideline was based upon methods outlined in the ‘NICE guidelines manual’ (NICE 2009). A team of health professionals, lay representatives and technical experts known as the Guideline Development Group (GDG) (see Appendix 6.1), with support from the NCC-C staff, undertook the development of this clinical guideline. The basic steps in the process of developing a guideline are listed and discussed below:

  • using the remit, define the scope which sets the inclusion/exclusion criteria of the guideline
  • forming the GDG
  • developing clinical questions
  • developing the review protocol
  • systematically searching for the evidence
  • critically appraising the evidence
  • incorporating health economic evidence
  • distilling and synthesising the evidence and writing recommendations
  • agreeing the recommendations
  • structuring and writing the guideline
  • updating the guideline.

The Scope

The remit was translated into a scope document by the Guideline Development Group (GDG) Chair and Lead Clinician and staff at the NCC-C in accordance with processes established by NICE (NICE 2009). The purpose of the scope was to:

  • set the boundaries of the development work and provide a clear framework to enable work to stay within the priorities agreed by NICE and the NCC-C and the remit set by the DH
  • inform professionals and the public about the expected content of the guideline.
  • provide an overview of the population and healthcare settings the guideline would include and exclude
  • specify the key clinical issues that will be covered by the guideline
  • inform the development of the clinical questions and search strategy

Before the guideline development process started, the draft scope was presented and discussed at a stakeholder workshop. The list of key clinical issues were discussed and revised before the formal consultation process. Further details of the discussion at the stakeholder workshop can be found on the NICE website (www.nice.org.uk).

The scope was subject to a four week stakeholder consultation in accordance with processes established by NICE in the ‘NICE guidelines manual’ (NICE 2009). The full scope is shown in Appendix 5. During the consultation period, the scope was posted on the NICE website (www.nice.org.uk). Comments were invited from registered stakeholder organisations and the NICE Guideline Review Panel (GRP). Further information about the GRP can also be found on the NICE website. The NCC-C and NICE reviewed the scope in light of comments received, and the revised scope was reviewed by the GRP, signed off by NICE and posted on the NICE website.

The Guideline Development Group (GDG)

The colorectal cancer GDG was recruited in line with the ‘NICE guidelines manual’ (NICE 2009). The first step was to appoint a Chair and a Lead Clinician. Advertisements were placed for both posts and candidates were interviewed before being offered the role. The NCC-C Director, GDG Chair and Lead Clinician identified a list of specialties that needed to be represented on the GDG. Details of the adverts were sent to the main stakeholder organisations, cancer networks and patient organisations/charities (see Appendix 6.2). Individual GDG members were selected by the NCC-C Director, GDG Chair and Lead Clinician, based on their application forms. The guideline development process was supported by staff from the NCC-C, who undertook the clinical and health economics literature searches, reviewed and presented the evidence to the GDG, managed the process and contributed to drafting the guideline. At the start of the guideline development process all GDG members’ interests were recorded on a standard declaration form that covered consultancies, fee-paid work, share-holdings, fellowships and support from the healthcare industry. At all subsequent GDG meetings, members declared new, arising conflicts of interest which were always recorded (see Appendix 6.1).

Guideline Development Group Meetings

Twelve GDG meetings were held between 19 May April 2009 and 2 February 2011. During each GDG meeting (either held over one or two days) clinical questions and clinical and economic evidence were reviewed, assessed and recommendations formulated. At each meeting patient/carer and service-user concerns were routinely discussed as part of a standing agenda item.

NCC-C project managers divided the GDG workload by allocating specific clinical questions, relevant to their area of clinical practice, to small sub-groups of the GDG in order to simplify and speed up the guideline development process. These groups considered the evidence, as reviewed by the researcher, and synthesised it into draft recommendations before presenting it to the GDG as a whole. Each clinical question was led by a GDG member with expert knowledge of the clinical area (usually one of the healthcare professionals). The GDG subgroups often helped refine the clinical questions and the clinical definitions of treatments. They also assisted the NCC-C team in drafting the section of the guideline relevant to their specific topic.

Patient/Carer Members

Individuals with direct experience of colorectal cancer gave an important user focus to the GDG and the guideline development process. The GDG included three patient/carer members. They contributed as full GDG members to writing the clinical questions, helping to ensure that the evidence addressed their views and preferences, highlighting sensitive issues and terminology relevant to the guideline and bringing service-user research to the attention of the GDG.

Developing Clinical Evidence-Based Questions

Background

Clinical guidelines should be aimed at improving clinical practice and should avoid ending up as ‘evidence-based textbooks’ or making recommendations on topics where there is already agreed clinical practice. Therefore the list of key clinical issues listed in the scope were developed in areas that were known to be controversial or uncertain, where there was identifiable practice variation, or where NICE guidelines were likely to have most impact.

Method

From each of the key clinical issues identified in the scope the GDG formulated a clinical question. For clinical questions about interventions, the PICO framework was used. This structured approach divides each question into four components: the population (the population under study – P), the interventions (what is being done - I), the comparisons (other main treatment options – C) and the outcomes (the measures of how effective the interventions have been – O). Where appropriate, the clinical questions were refined once the evidence had been searched and, where necessary, sub-questions were generated.

The final list of clinical questions can be found in the scope (see Appendix 5).

Review of Clinical Literature

Scoping search

An initial scoping search for published guidelines, systematic reviews, economic evaluations and ongoing research was carried out on the following databases or websites: National Library for Health (NLH) Guidelines Finder (now NHS Evidence), National Guidelines Clearinghouse, Cochrane Database of Systematic Reviews (CDSR), Heath Technology Assessment Database (HTA), NHS Economic Evaluations Database (NHSEED), DH Data, Medline and Embase.

At the beginning of the development phase, initial scoping searches were carried out to identify any relevant guidelines (local, national or international) produced by other groups or institutions.

Developing the review protocol

For each clinical question, the information specialist and researcher (with input from other technical team and GDG members) prepared a review protocol. This protocol explains how the review was to be carried out (see Table A) in order to develop a plan of how to review the evidence, limit the introduction of bias and for the purposes of reproducibility. All review protocols can be found in the full evidence review.

Table A. Components of the review protocol.

Table A

Components of the review protocol.

Searching for the evidence

In order to answer each question the NCC-C information specialist developed a search strategy to identify relevant published evidence for both clinical and cost effectiveness. Key words and terms for the search were agreed in collaboration with the GDG. When required, the health economist searched for supplementary papers to inform detailed health economic work (see section on ‘Incorporating Health Economic Evidence’).

Search filters, such as those to identify systematic reviews (SRs) and randomised controlled trials (RCTs) were applied to the search strategies when there was a wealth of these types of studies. No language restrictions were applied to the search; however, foreign language papers were not requested or reviewed (unless of particular importance to that question).

The following databases were included in the literature search:

  • The Cochrane Library
  • Medline and Premedline 1950 onwards
  • Excerpta Medica (Embase) 1980 onwards
  • Cumulative Index to Nursing and Allied Health Literature (Cinahl) 1982 onwards
  • Allied & Complementary Medicine (AMED) 1985 onwards
  • British Nursing Index (BNI) 1985 onwards
  • Psychinfo 1806 onwards
  • Web of Science [specifically Science Citation Index Expanded]
  • (SCI-EXPANDED) 1899 onwards and Social Sciences Citation Index (SSCI) 1956 onwards]
  • Biomed Central 1997 onwards

From this list the information specialist sifted and removed any irrelevant material based on the title or abstract before passing to the researcher. All the remaining articles were then stored in a Reference Manager electronic library.

Searches were updated and re-run 6–8 weeks before the stakeholder consultation, thereby ensuring that the latest relevant published evidence was included in the database. Any evidence published after this date was not included. For the purposes of updating this guideline, 25 February 2011 should be considered the starting point for searching for new evidence.

Further details of the search strategies, including the methodological filters used, are provided in the evidence review.

Critical Appraisal

From the literature search results database, one researcher scanned the titles and abstracts of every article for each question and full publications were ordered for any studies considered relevant or if there was insufficient information from the title and abstract to inform a decision. When the papers were obtained the researcher applied inclusion/exclusion criteria to select appropriate studies, which were then critically appraised. For each question, data on the type of population, intervention, comparator and outcomes (PICO) were extracted and recorded in evidence tables and an accompanying evidence summary prepared for the GDG (see evidence review). All evidence was considered carefully by the GDG for accuracy and completeness.

GRADE (Grading of Recommendations, Assessment, Development and Evaluation)

For interventional questions, studies which matched the inclusion criteria were evaluated and presented using a modification of GRADE (NICE 2009; http://gradeworkinggroup.org/). Where possible this included meta-analysis and synthesis of data into a GRADE ‘evidence profile’. The evidence profile shows, for each outcome, an overall assessment of both the quality of the evidence as a whole (low, moderate or high) as well as an estimate of the size of effect. A narrative summary (evidence statement) was also prepared.

Each topic outcome was examined for the quality elements defined in table B and subsequently graded using the quality levels listed in table C. The reasons for downgrading or upgrading specific outcomes were explained in footnotes.

Table B. Descriptions of quality elements of GRADE.

Table B

Descriptions of quality elements of GRADE.

Table C. Overall quality of outcome evidence in GRADE.

Table C

Overall quality of outcome evidence in GRADE.

All procedures were fully compliant with NICE methodology as detailed in the ‘NICE guidelines manual’ (NICE 2009). In general, no formal contact was made with authors; however, there were ad hoc occasions when this was required in order to clarify specific details.

Needs Assessment

As part of the guideline development process the NCC-C invited a specialist registrar, with the support of the GDG, to undertake a needs assessment (see Appendix 6.3). The needs assessment aims to describe the burden of disease and current service provision for patients with colorectal cancer in England and Wales, which informed the development of the guideline.

Assessment of the effectiveness of interventions is not included in the needs assessment, and was undertaken separately by researchers in the NCC-C as part of the guideline development process.

The information included in the needs assessment document was presented to the GDG. Most of the information was presented in the early stages of guideline development, and other information was included to meet the evolving information needs of the GDG during the course of guideline development.

Incorporating Health Economics Evidence

The aim of providing economic input into the development of the guideline was to inform the GDG of potential economic issues relating to the diagnosis and management of colorectal cancer. Health economics is about improving the health of the population through the efficient use of resources. In addition to assessing clinical effectiveness, it is important to investigate whether health services are being used in a cost effective manner in order to maximise health gain from available resources.

Prioritising topics for economic analysis

After the clinical questions had been defined, and with the help of the health economist, the GDG discussed and agreed which of the clinical questions were potential priorities for economic analysis. These economic priorities were chosen on the basis of the following criteria, in broad accordance with the NICE guidelines manual (NICE 2009):

  • The overall importance of the recommendation, which may be a function of the number of patients affected and the potential impact on costs and health outcomes per patient
  • The current extent of uncertainty over cost effectiveness, and the likelihood that economic analysis will reduce this uncertainty

In addition, for clinical questions in the guideline that related to updates of technology appraisals, an evaluation of cost effectiveness was required if significant new clinical evidence had become available or if costs had changed since the original technology appraisal was published.

For each topic that was considered a high priority for economic analysis, a review of the economic literature was conducted. Where published economic evaluation studies were identified that addressed the economic issues for a clinical question, these are presented alongside the clinical evidence wherever possible. For those clinical areas reviewed, the information specialists used a similar search strategy as used for the review of clinical evidence but with the inclusion of a health economics filter.

For systematic searches of published economic evidence, the following databases were included:

  • Medline
  • Embase
  • Cochrane
  • NHS Economic Evaluation Database (NHS EED)

Methods for reviewing and appraising economic evidence

The aim of reviewing and appraising the existing economic literature is to identify relevant economic evaluations that compare both costs and health consequences of alternative interventions and that are applicable to NHS practice. Thus studies that only report costs, non-comparative studies or ‘cost of illness’ studies are generally excluded from the reviews (NICE, 2009).

Economic studies identified through a systematic search of the literature are appraised using a methodology checklist designed for economic evaluations (NICE, 2009, Appendix H). This checklist is not intended to judge the quality of a study per se, but to determine whether an existing economic evaluation is useful to inform the decision-making of the GDG for a specific topic within the Guideline. There are two parts to the appraisal process; the first step is to assess applicability (i.e. the relevance of the study to the specific guideline topic and the NICE reference case) (Table D).

Table D. Applicability criteria.

Table D

Applicability criteria.

In the second step, only those studies deemed directly or partially applicable are further assessed for limitations (i.e. the methodological quality, Table E).

Table E. Methodological quality.

Table E

Methodological quality.

Where relevant, a summary of the main findings from the systematic search, review and appraisal of economic evidence is presented in an economic evidence profile alongside the GRADE table for clinical evidence.

For priority topics, if high-quality published economic evidence relevant to current NHS practice was identified through the search, the existing literature was reviewed and appraised as described above. However, it is often the case that published economic studies may not be directly relevant to the specific clinical question as defined in the guideline or may not be comprehensive or conclusive enough to inform UK practice. In such cases, consideration was given to undertaking a new economic analysis as part of this guideline.

Economic modelling

Once the need for a new economic analysis for high priority topics had been agreed by the GDG, the health economist investigated the feasibility of developing an economic model. Following this assessment, a decision was made to develop an integrated mixed treatment comparison and economic model to address the topic oxaliplatin and irinotecan-based chemotherapy in metastatic colorectal cancer. Full details of this analysis are presented in Appendix 2. In the development of the analysis, the following general principles were adhered to:

  • the GDG subgroup was consulted during the construction and interpretation of the analysis
  • the analysis was based on the best available clinical evidence from the systematic review
  • assumptions were reported fully and transparently
  • uncertainty was explored through sensitivity analysis
  • costs were calculated from a health services perspective
  • outcomes were reported in terms of quality-adjusted life years

Linking to NICE technology appraisals

There are several published technology appraisals (TA) which are relevant to this guideline (TA61, TA105, TA100, TA118, TA150, TA176 and TA212 - see www.nice.org.uk/TA/published). In line with NICE methodology, the recommendations from these TAs have either been reproduced verbatim in the colorectal cancer guideline or cross referenced.

Published TAs are periodically reviewed to determine if they need to be updated, particularly if any new evidence becomes available since the publication of the appraisal which means the original recommendations needed to be changed. In 2008, NICE consulted with stakeholders to assess whether TA93 should be updated within the guideline. The outcome was that TA93 should be updated within the colorectal cancer guideline.

Agreeing the Recommendations

For each clinical question the GDG were presented with a summary of the clinical evidence, and, where appropriate, economic evidence, derived from the studies reviewed and appraised. From this information the GDG were able to derive the guideline recommendations. The link between the evidence and the view of the GDG in making each recommendation is made explicit in the accompanying LETR statement.

LETR (Linking Evidence to Recommendations) statements

As clinical guidelines were previously formatted, there was limited scope for expressing how and why a GDG made a particular recommendation from the evidence of clinical and cost effectiveness. To make this process more transparent to the reader, NICE have introduced an explicit, easily understood and consistent way of expressing the reasons for making each recommendation. This is known as the ‘LETR statement’ and will usually cover the following key points:

  • the relative value placed on the outcomes considered
  • the strength of evidence about benefits and harms for the intervention being considered
  • the costs and cost-effectiveness of an intervention (if formally assessed by the health economics team)
  • the quality of the evidence (see GRADE)
  • the degree of consensus within the GDG
  • other considerations – for example equalities issues

Where evidence was weak or lacking the GDG agreed the final recommendations through informal consensus. Shortly before the consultation period, ten key priorities and five key research recommendations were selected by the GDG for implementation and the patient algorithms were agreed. To avoid giving the impression that higher grade recommendations are of higher priority for implementation, NICE no longer assigns grades to recommendations.

Consultation and Validation of the Guideline

The draft of the guideline was prepared by NCC-C staff in partnership with the GDG Chair and Lead Clinician. This was then discussed and agreed with the GDG and subsequently forwarded to NICE for consultation with stakeholders.

Registered stakeholders (see Appendix 6.2) had one opportunity to comment on the draft guideline which was posted on the NICE website between 29 March 2011 and 24 May 2011 in line with NICE methodology (NICE 2009). The Guideline Review Panel also reviewed the guideline and checked that stakeholder comments had been addressed.

The pre-publication check process

Following stakeholder consultation and subsequent revision, the draft guideline was then subject to a pre-publication check (NICE 2009). The pre-publication check provides registered stakeholders with the opportunity to raise any concerns about factual errors and inaccuracies that may exist in the revised guideline after consultation.

During the pre-publication check the full guideline was posted on the NICE website for 15 working days, together with the guideline consultation table that listed comments received during consultation from stakeholders and responses from the NCC-C and GDG.

All stakeholders were invited to report factual errors using a standard proforma. NICE, the NCC and the GDG Chair and Lead Clinician considered the reported errors and responded only to those related to factual errors. A list of all corrected errors and the revised guideline were submitted to NICE, and the revised guideline was then signed off by Guidance Executive. The list of reported errors from the pre-publication check and the responses from the NCC-C were subsequently published on the NICE website.

The final document was then submitted to NICE for publication on their website. The other versions of the guideline (see below) were also discussed and approved by the GDG and published at the same time.

Other Versions of the Guideline

This full version of the guideline is available to download free of charge from the NICE website (www.nice.org.uk) and the NCC-C website (www.wales.nhs.uk/nccc).

NICE also produces two other versions of the colorectal cancer guideline which are available from the NICE website:

  • the NICE guideline, which is a shorter version of this guideline, containing the key priorities, key research recommendations and all other recommendations
  • ‘Understanding NICE Guidance’ (‘UNG’), which describes the guideline using nontechnical language. It is written chiefly for people suspected of, or diagnosed with, colorectal cancer but may also be useful for family members, advocates or those who care for patients with colorectal cancer. For printed copies, phone NICE publications on 0845 003 7783 or email ku.gro.ecin@snoitacilbup The recommendations from this guideline have been incorporated into a NICE pathway, which is available from http://pathways.nice.org.uk/

Updating the Guideline

Literature searches were repeated for all of the clinical questions at the end of the GDG development process, allowing any relevant papers published before 25 February 2011 to be considered. Future guideline updates will consider evidence published after this cut-off date.

Three years after publication of the guideline, NICE will commission a review to determine whether the evidence base has progressed significantly to alter the guideline recommendations and warrant an early update.

Funding

The National Collaborating Centre for Cancer was commissioned by NICE to develop this guideline. Health economic analysis for this guideline was provided by the London School of Hygiene and Tropical Medicine and funded by the National Collaborating Centre for Cancer.

Disclaimer

The GDG assumes that healthcare professionals will use clinical judgment, knowledge and expertise when deciding whether it is appropriate to apply these guidelines. The recommendations cited here are a guide and may not be appropriate for use in all situations. The decision to adopt any of the recommendations cited here must be made by the practitioner in light of individual patient circumstances, the wishes of the patient and clinical expertise.

The NCC-C disclaims any responsibility for damages arising out of the use or non-use of these guidelines and the literature used in support of these guidelines.

References

  • Briggs A, Claxton K, Sculpher M. Decision Modelling for Health Economic Evaluation. Oxford: Oxford University Press; 2006.
  • National Institute for Health and Clinical Excellence. The guidelines manual. London: National Institute for Health and Clinical Excellence; 2009. Available from www​.nice.org.uk/guidelinesmanual.
Copyright © 2011, National Collaborating Centre for Cancer.
Bookshelf ID: NBK116627
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