General

Guideline Title

Melanoma: assessment and management.

Bibliographic Source(s)

National Collaborating Centre for Cancer. Melanoma: assessment and management. London (UK): National Institute for Health and Care Excellence (NICE); 2015 Jul 29. 59 p. (NICE guideline; no. 14).

Guideline Status

This is the current release of the guideline.

This guideline meets NGC’s 2013 (revised) inclusion criteria.

Recommendations

Major Recommendations

Note from the National Guideline Clearinghouse (NGC) : This guideline was developed by the National Collaborating Centre for Cancer (NCC-C) on behalf of the National Institute for Health and Care Excellence (NICE). See the “Availability of Companion Documents” field for the full version of this guidance.

The wording used in the recommendations in this guideline (for example, words such as ‘offer’ and ‘consider’) denotes the certainty with which the recommendation is made (the strength of the recommendation) and is defined at the end of the “Major Recommendations” field.

Communication and Support

To help people make decisions about their care, follow the recommendations on communication, information provision and support in NICE’s guideline on improving outcomes for people with skin tumours including melanoma, in particular the following 5 recommendations:

‘Improved, preferably nationally standardised, written information should be made available to all patients. Information should be appropriate to the patients’ needs at that point in their diagnosis and treatment, and should be repeated over time. The information given must be specific to the histopathological type of lesion, type of treatment, local services and any choice within them, and should cover both physical and psychosocial issues.’
‘Those who are directly involved in treating patients should receive specific training in communication and breaking bad news.’
‘Patients should be invited to bring a companion with them to consultations.’
‘Each local hospital skin cancer multidisciplinary team (LSMDT) and specialist skin cancer multidisciplinary team (SSMDT) should have at least one skin cancer clinical nurse specialist (CNS) who will play a leading role in supporting patients and carers. There should be equity of access to information and support regardless of where the care is delivered.’
‘All LSMDTs and SSMDTs should have access to psychological support services for skin cancer patients.’

Follow the recommendations on follow-up in NICE’s guideline on improving outcomes for people with skin tumours including melanoma, in particular the following 2 recommendations:

‘All patients should be given written instruction on how to obtain quick and easy access back to see a member of the LSMDT/SSMDT when necessary.’
‘All patients should be given both oral and written information about the different types of skin cancer and instruction about self-surveillance.’

Give people with melanoma and their families or carers advice about protecting against skin damage caused by exposure to the sun while avoiding vitamin D depletion.

Carry out a holistic needs assessment to identify the psychosocial needs of people with melanoma and their needs for support and education about the likelihood of recurrence, metastatic spread, new primary lesions and the risk of melanoma in their family members.

Follow the recommendations on communication and patient-centred care in NICE’s guideline on Patient experience in adult National Health Service (NHS) services .

Assessing Melanoma

Dermoscopy and Other Visualisation Techniques

See “Implementation: getting started” in the original guideline document for information about putting the recommendation below into practice.

Assess all pigmented skin lesions that are either referred for assessment or identified during follow-up in secondary or tertiary care, using dermoscopy carried out by healthcare professionals trained in this technique.

Do not routinely use confocal microscopy or computer-assisted diagnostic tools to assess pigmented skin lesions.

Photography

For a clinically atypical melanocytic lesion that does not need excision at first presentation in secondary or tertiary care:

Use baseline photography (preferably dermoscopic) and
Review the clinical appearance of the lesion, and compare it with the baseline photographic images, 3 months after first presentation to identify early signs of melanoma

Assessing and Managing Atypical Spitzoid Lesions

Discuss all suspected atypical spitzoid lesions at the specialist skin cancer multidisciplinary team meeting.

Make the diagnosis of a spitzoid lesion of uncertain malignant potential on the basis of the histology, clinical features and behaviour.

Manage a spitzoid lesion of uncertain malignant potential as melanoma.

Taking Tumour Samples for Genetic Testing

If targeted systemic therapy is a treatment option, offer genetic testing using:

A secondary melanoma tissue sample if there is adequate cellularity or
A primary melanoma tissue sample if a secondary sample is not available or is of inadequate cellularity

Genetic Testing in Early-stage Melanoma

Do not offer genetic testing of stage IA–IIB primary melanoma at presentation except as part of a clinical trial.

Consider genetic testing of stage IIC primary melanoma or the nodal deposits or in-transit metastases for people with stage III melanoma.

If insufficient tissue is available from nodal deposits or in-transit metastases, consider genetic testing of the primary tumour for people with stage III melanoma.

Managing Suboptimal Vitamin D Levels

See “Implementation: getting started” in the original guideline document for information about putting the recommendations below into practice.

Measure vitamin D levels at diagnosis in secondary care in all people with melanoma.

Give people whose vitamin D levels are thought to be suboptimal advice on vitamin D supplementation and monitoring in line with local policies and NICE’s guideline on Vitamin D .

Managing Concurrent Drug Treatment

Do not withhold or change drug treatment for other conditions, except immunosuppressants, on the basis of a diagnosis of melanoma.

Consider minimising or avoiding immunosuppressants for people with melanoma.

Staging Investigations

Sentinel Lymph Node Biopsy

Do not offer imaging or sentinel lymph node biopsy to people who have stage IA melanoma or those who have stage IB melanoma with a Breslow thickness of 1 mm or less.

Consider sentinel lymph node biopsy as a staging rather than a therapeutic procedure for people with stage IB–IIC melanoma with a Breslow thickness of more than 1 mm, and give them detailed verbal and written information about the possible advantages and disadvantages, using the table below. See “Implementation: getting started” in the original guideline document for information about putting this recommendation practice.

Possible Advantages of Sentinel Lymph Node Biopsy	Possible Disadvantages of Sentinel Lymph Node Biopsy
The operation helps to find out whether the cancer has spread to the lymph nodes. It is better than ultrasound scans at finding very small cancers in the lymph nodes.	The purpose of the operation is not to cure the cancer. There is no good evidence that people who have the operation live longer than people who do not have it.
The operation can help predict what might happen in the future. For example, in people with a primary melanoma that is between 1 and 4 mm thick: Around 1 out of 10 die within 10 years if the sentinel lymph node biopsy is negative Around 3 out of 10 die within 10 years if the sentinel lymph node biopsy is positive	The result needs to be interpreted with caution. Of every 100 people who have a negative sentinel lymph node biopsy, around 3 will subsequently develop a recurrence in the same group of lymph nodes.
People who have had the operation may be able to take part in clinical trials of new treatments for melanoma. These trials often cannot accept people who haven't had this operation.	A general anaesthetic is needed for the operation.
	The operation results in complications in between 4 and 10 out of every 100 people who have it.

Imaging

Offer computed tomography (CT) staging to people with stage IIC melanoma who have not had sentinel lymph node biopsy, and to people with stage III or suspected stage IV melanoma.

Include the brain as part of imaging for people with suspected stage IV melanoma.

Consider whole-body magnetic resonance imaging (MRI) for children and young people (from birth to 24 years) with stage III or suspected stage IV melanoma.

Managing Stages 0–II Melanoma

Excision

Consider a clinical margin of at least 0.5 cm when excising stage 0 melanoma.

If excision for stage 0 melanoma does not achieve an adequate histological margin, discuss further management with the multidisciplinary team.

Offer excision with a clinical margin of at least 1 cm to people with stage I melanoma.

Offer excision with a clinical margin of at least 2 cm to people with stage II melanoma.

Imiquimod for Stage 0 Melanoma

Consider topical imiquimod to treat stage 0 melanoma in adults if surgery to remove the entire lesion with a 0.5 cm clinical margin would lead to unacceptable disfigurement or morbidity. (At the time of publication [July 2015] topical imiquimod did not have a UK marketing authorisation for this indication. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council’s Prescribing guidance: prescribing unlicensed medicines for further information.)

Consider a repeat skin biopsy for histopathological assessment after treatment with topical imiquimod for stage 0 melanoma, to check whether it has been effective.

Managing Stage III Melanoma

Completion Lymphadenectomy

See “Implementation: getting started” in the original guideline document for information about putting the recommendation below into practice.

Consider completion lymphadenectomy for people whose sentinel lymph node biopsy shows micro-metastases and give them detailed verbal and written information about the possible advantages and disadvantages, using the table below.

Possible Advantages of Completion Lymphadenectomy	Possible Disadvantages of Completion Lymphadenectomy
Removing the rest of the lymph nodes before cancer develops in them reduces the chance of the cancer returning in the same part of the body.	Lymphoedema (long-term swelling) may develop, and is most likely if the operation is in the groin and least likely in the head and neck.
The operation is less complicated and safer than waiting until cancer develops in the remaining lymph nodes and then removing them.	In 4 out of 5 people, cancer will not develop in the remaining lymph nodes, so there is a chance that the operation will have been done unnecessarily.
People who have had the operation may be able to take part in clinical trials of new treatments to prevent future melanoma. These trials often cannot accept people who have not had this operation.	There is no evidence that people who have this operation live longer than people who do not have it.
	Having any operation can cause complications.

Lymph Node Dissection

Offer therapeutic lymph node dissection to people with palpable stage IIIB–IIIC melanoma or nodal disease detected by imaging.

Adjuvant Radiotherapy

Do not offer adjuvant radiotherapy to people with stage IIIA melanoma.

Do not offer adjuvant radiotherapy to people with stage IIIB or IIIC melanoma unless a reduction in the risk of local recurrence is estimated to outweigh the risk of significant adverse effects.

Palliative Treatment for In-Transit Metastases

Refer the care of all people with newly diagnosed or progressive in-transit metastases to the SSMDT.

If palliative treatment for in-transit metastases is needed, offer palliative surgery as a first option if surgery is feasible.

If palliative surgery is not feasible for people with in-transit metastases, consider the following options:

Systemic therapy (for more information see recommendations below)
Isolated limb infusion
Isolated limb perfusion
Radiotherapy
Electrochemotherapy in line with the NICE guideline on Electrochemotherapy for metastases in the skin from tumours of non-skin origin and melanoma
Carbon dioxide (CO 2 ) laser
A topical agent such as imiquimod (at the time of publication [July 2015] topical imiquimod did not have a UK marketing authorisation for this indication or for use in children and young people. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council’s Prescribing guidance: prescribing unlicensed medicines for further information.)

Palliative Treatment for Superficial Skin Metastases

Consider topical imiquimod to palliate superficial melanoma skin metastases.

Managing Stage IV Melanoma

Management of Oligometastatic Stage IV Melanoma

Refer the care of people who appear to have oligometastatic melanoma to the SSMDT for recommendations about staging and management.

Consider surgery or other ablative treatments (including stereotactic radiotherapy or radioembolisation) to prevent and control symptoms of oligometastatic stage IV melanoma in consultation with SSMDTs (such as an MDT for the brain or for bones).

Brain Metastases

Discuss the care of people with melanoma and brain metastases with the SSMDT.

Refer people with melanoma and brain metastases that might be suitable for surgery or stereotactic radiotherapy to the brain and other central nervous system tumours MDT for a recommendation about treatment.

Systemic Anticancer Treatment

Targeted Treatments

For adults, see the NGC summary of the NICE guideline Dabrafenib for treating unresectable or metastatic BRAF V600 mutation-positive melanoma . (Dabrafenib has a marketing authorisation in the UK in monotherapy for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation.)

For adults, ‘Vemurafenib is recommended as an option for treating BRAF V600 mutation-positive unresectable or metastatic melanoma only if the manufacturer provides vemurafenib with the discount agreed in the patient access scheme’. (This recommendation is from the NGC summary of the NICE guideline Vemurafenib for treating locally advanced or metastatic BRAF V600 mutation-positive malignant melanoma ). (Vemurafenib has a UK marketing authorisation for ‘the treatment of adult patients with BRAF V600 mutation-positive unresectable or metastatic melanoma’.)

Immunotherapy

For adults, see the NGC summaries of the NICE guidelines Ipilimumab for previously treated advanced (unresectable or metastatic) melanoma and Ipilimumab for previously untreated advanced (unresectable or metastatic) melanoma . (Ipilimumab has a UK marketing authorisation for ‘the treatment of advanced [unresectable or metastatic] melanoma in adults’.)

Cytotoxic Chemotherapy

Consider dacarbazine for people with stage IV metastatic melanoma if immunotherapy or targeted therapy are not suitable. (Although this use is common in UK clinical practice, at the time of publication [July 2015], dacarbazine did not have a UK marketing authorisation for this indication or for use in children and young people. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council’s Prescribing guidance: prescribing unlicensed medicines for further information.)

Do not routinely offer further cytotoxic chemotherapy for stage IV metastatic melanoma to people previously treated with dacarbazine except in the context of a clinical trial.

Follow-up After Treatment or Melanoma

Follow-up for All People Who Have Had Melanoma

Perform a full examination of the skin and regional lymph nodes at all follow-up appointments.

Consider personalised follow-up for people who are at increased risk of further primary melanomas (for example people with atypical mole syndrome, previous melanoma, or a history of melanoma in first-degree relatives or other relevant familial cancer syndromes).

Consider including the brain for people having imaging as part of follow-up after treatment for melanoma.

Consider imaging the brain if metastatic disease outside the central nervous system is suspected.

Consider CT rather than MRI of the brain for adults having imaging as part of follow-up or if metastatic disease is suspected.

Consider MRI rather than CT of the brain for children and young people (from birth–24 years) having imaging as part of follow-up or if metastatic disease is suspected.

Provide psychosocial support for the person with melanoma and their family or carers at all follow-up appointments.

All local follow-up policies should include reinforcing advice about self-examination (in line with recommendations under “Communication and Support”), and health promotion for people with melanoma and their families, including sun awareness, avoiding vitamin D depletion (in line with recommendations under “Communication and Support”), and NICE guidance on smoking cessation .

Continue to manage drug treatment for other conditions in line with recommendations under “Managing Concurrent Drug Treatment” after treatment for melanoma.

Follow-up After Stage 0 Melanoma

Discharge people who have had stage 0 melanoma after completion of treatment and provide advice in line with recommendations under “Follow-up For All People Who Have Had Melanoma.”

Follow-up After Stage IA Melanoma

For people who have had stage IA melanoma, consider follow-up 2 to 4 times during the first year after completion of treatment and discharging them at the end of that year.

Do not routinely offer screening investigations (including imaging and blood tests) as part of follow-up to people who have had stage IA melanoma.

Follow-up After Stages IB–IIB Melanoma or Stage IIC Melanoma (Fully Staged Using Sentinel Lymph Node Biopsy)

For people who have had stages IB–IIB melanoma or stage IIC melanoma with a negative sentinel lymph node biopsy, consider follow-up every 3 months for the first 3 years after completion of treatment, then every 6 months for the next 2 years, and discharging them at the end of 5 years.

Do not routinely offer screening investigations (including imaging and blood tests) as part of follow-up to people who have had stages IB–IIB melanoma or stage IIC melanoma with a negative sentinel lymph node biopsy.

Follow-up After Stage IIC Melanoma With No Sentinel Lymph Node Biopsy or Stage III Melanoma

For people who have had stage IIC melanoma with no sentinel lymph node biopsy, or stage III melanoma, consider follow-up every 3 months for the first 3 years after completion of treatment, then every 6 months for the next 2 years, and discharging them at the end of 5 years.

Consider surveillance imaging as part of follow-up for people who have had stage IIC melanoma with no sentinel lymph node biopsy or stage III melanoma and who would become eligible for systemic therapy as a result of early detection of metastatic disease if:

There is a clinical trial of the value of regular imaging or
The specialist skin cancer multidisciplinary team agrees to a local policy and specific funding for imaging 6-monthly for 3 years is identified

Take into account the possible advantages and disadvantages of surveillance imaging and discuss these with the person, using the table below.

Possible Advantages of Surveillance Imaging (Having Regular Scans)	Possible Disadvantages of Surveillance Imaging (Having Regular Scans)
If the melanoma comes back (recurrent melanoma), it is more likely to be detected sooner. It is possible that this could lead to a better outcome by allowing treatment with drugs (such as immunotherapy drugs) to start earlier.	Although early drug treatment of recurrent melanoma might improve survival, there is currently no evidence showing this.
Some people find it reassuring to have regular scans.	Some people find that having regular scans increases their anxiety.
	Scans expose the body to radiation, which can increase the risk of cancer in the future.
	Scans of the brain and neck increase the risk of developing cataracts.
	Scans of the chest cause a very small increase in the risk of thyroid cancer.
	Scans may show abnormalities that are later found to be harmless, causing unnecessary investigations and anxiety.

Follow-up After Stage IV Melanoma

Offer personalised follow-up to people who have had stage IV melanoma.

Definitions

Strength of Recommendations

Some recommendations can be made with more certainty than others. The Guideline Development Group (GDG) makes a recommendation based on the trade-off between the benefits and harms of an intervention, taking into account the quality of the underpinning evidence. For some interventions, the GDG is confident that, given the information it has looked at, most patients would choose the intervention. The wording used in the recommendations in this guideline denotes the certainty with which the recommendation is made (the strength of the recommendation).

Interventions That Must (or Must Not) Be Used

The GDG usually uses ‘must’ or ‘must not’ only if there is a legal duty to apply the recommendation. Occasionally the GDG uses ‘must’ (or ‘must not’) if the consequences of not following the recommendation could be extremely serious or potentially life threatening.

Interventions That Should (or Should Not) Be Used – a ‘Strong’ Recommendation

The GDG uses ‘offer’ (and similar words such as ‘refer’ or ‘advise’) when confident that, for the vast majority of patients, an intervention will do more good than harm, and be cost effective. The GDG uses similar forms of words (for example, ‘Do not offer…’) when confident that an intervention will not be of benefit for most patients.

Interventions That Could Be Used

The GDG uses ‘consider’ when confident that an intervention will do more good than harm for most patients, and be cost effective, but other options may be similarly cost effective. The choice of intervention, and whether or not to have the intervention at all, is more likely to depend on the patient’s values and preferences than for a strong recommendation, and so the healthcare professional should spend more time considering and discussing the options with the patient.

Clinical Algorithm(s)

The following algorithms are provided in the full version of the guideline (see the “Availability of Companion Documents” field):

Diagnosing melanoma
Genetic testing
Staging
Management of stage 0-III melanoma
In-transit melanoma
Follow-up
Management of stage IV melanoma

In addition, a National Institute for Health and Care Excellence (NICE) pathway titled “Melanoma” is available from the NICE Web site.

Scope

Disease/Condition(s)

Melanoma

Note : Primary ocular melanoma or melanoma arising in mucosal sites are not covered.

Guideline Category

Evaluation
Management

Clinical Specialty

Dermatology
Family Practice
Oncology
Pediatrics

Intended Users

Physician Assistants
Physicians

Guideline Objective(s)

To offer best practice advice on the care of children, young people and adults with suspected or diagnosed melanoma

Target Population

Children, young people and adults with suspected or newly diagnosed cutaneous melanoma (including vulval and penile melanoma)

Interventions and Practices Considered

Communication and support
Assessing melanoma * Dermoscopy * Photography * Tumour samples for genetic testing
Managing suboptimal vitamin D levels
Staging investigations (sentinel lymph node biopsy)
Managing stage III melanoma * Completion lymphadenectomy * Adjuvant radiotherapy
Follow-up after treatment for melanoma * Personalized follow-up for people at increased risk * Surveillance imaging

Major Outcomes Considered

Survival rate (disease-specific survival, progression-free, overall)
Sensitivity, specificity
Time to recurrence
Site of recurrence
Proportion of people receiving active therapy at recurrence
Quality of life
Cost-effectiveness

Methodology

Methods Used to Collect/Select the Evidence

Searches of Electronic Databases

Description of Methods Used to Collect/Select the Evidence

Developing Clinical Evidence-based Questions

Background

Clinical guidelines should be aimed at changing 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 Guideline Development Group (GDG) formulated a clinical question. For clinical questions about interventions, the PICO framework was used. This structured approach divides each question into four components: P – the population (the population under study), I – the interventions (what is being done), C – the comparison (other main treatment options), O – the outcomes (the measures of how effective the interventions have been).

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 Web sites: National Health Service (NHS) Evidence, Cochrane Databases of Systematic Reviews (CDSR), Health Technology Assessment Database (HTA), NHS Economic Evaluations Database (NHS EED), Health Economic Evaluations Database (HEED), 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 1 in the full version of the guideline) 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 evidence review (see Appendix H in the full guideline appendices [see the “Availability of Companion Documents” field]).

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 “Incorporating Health Economic Evidence” in the full version of the guideline).

Search filters, such as those to identify systematic reviews (SRs) and randomised controlled trials (RCTs) were applied to the search strategies when necessary. 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 1946 onwards
Excerpta Medica (EMBASE) 1974 onwards
Web of Science (specifically Science Citation Index Expanded [SCI-EXPANDED] 1899 onwards and Social Sciences Citation Index [SSCI] 1956 onwards)

Subject specific databases used for certain topics:

Cumulative Index to Nursing and Allied Health Literature (CINAHL) 1937 onwards
PsycINFO 1806 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 to 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, September 2014 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.

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 melanoma. 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 2012):

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
The feasibility of building an economic model

A review of the economic literature was conducted at scoping. Where published economic evaluation studies were identified that addressed the economic issues for a clinical question, these are presented alongside the clinical evidence.

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

Medline
EMBASE
NHS EED
HTA
HEED

Number of Source Documents

Refer to the evidence review (see Appendix H in the full guideline appendices [see the “Availability of Companion Documents” field]) for detailed information on the total number of studies for each guideline topic, including the economic article selection.

Methods Used to Assess the Quality and Strength of the Evidence

Weighting According to a Rating Scheme (Scheme Given)

Rating Scheme for the Strength of the Evidence

Overall Quality of Outcome Evidence in Grading of Recommendations Assessment, Development and Evaluation (GRADE)

High	Further research is very unlikely to change confidence in the estimate of effect.
Moderate	Further research is likely to have an important impact on confidence in the estimate of effect and may change the estimate.
Low	Further research is very likely to have an important impact on confidence in the estimate of effect and is likely to change the estimate.
Very low	Any estimate of effect is very uncertain.

Methods Used to Analyze the Evidence

Meta-Analysis
Review of Published Meta-Analyses
Systematic Review with Evidence Tables

Description of the Methods Used to Analyze the Evidence

Review of Clinical Literature

Critical Appraisal and Evidence Grading

Following the literature search one researcher independently scanned the titles and abstracts of every article for each question, and full publications were obtained for any studies considered relevant or where there was insufficient information from the title and abstract to make a decision. When papers were obtained the researcher applied inclusion/exclusion criteria to select appropriate studies, which were then critically appraised. For each question, data were extracted and recorded in evidence tables and an accompanying evidence summary prepared for the Guideline Development Group (GDG). All evidence was considered carefully by the GDG for accuracy and completeness.

Grading of Recommendations Assessment, Development and Evaluation (GRADE)

For interventional questions, studies which matched the inclusion criteria were evaluated and presented using GRADE (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 (very low, low, moderate or high) as well as an estimate of the size of effect. A narrative summary (evidence statement) was also prepared.

Each outcome was examined for the quality elements defined in Table 2 in the full version of the guideline and subsequently graded using the quality levels listed in Table 3 in the full version of the guideline. The reasons for downgrading or upgrading specific outcomes were explained in footnotes.

All procedures were fully compliant with NICE methodology as detailed in the ‘NICE guidelines manual’ (see the “Availability of Companion Documents” field). In general, no formal contact was made with authors.

For non-interventional questions, for example the questions regarding diagnostic test accuracy, a narrative summary of the quality of the evidence was provided. The quality of individual diagnostic accuracy studies was assessed using the Quality Assessment of Studies of Diagnostic Accuracy (QUADAS)-2 tool.

Incorporating Health Economics Evidence

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 National Health Service (NHS) practice. Thus studies that only report costs, non-comparative studies of ‘cost of illness’ studies are generally excluded from the reviews (NICE, 2012).

Economic studies identified through a systematic search of the literature are appraised using a methodology checklist designed for economic evaluations (NICE 2012; see Appendix H in the full guideline appendices [see the “Availability of Companion Documents” field]). 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 of 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) (see Table 4 in the full guideline).

Methods Used to Formulate the Recommendations

Expert Consensus

Description of Methods Used to Formulate the Recommendations

The Guideline Development Process – Who Develops the Guideline?

Overview

The development of this guideline was based upon methods outlined in the ‘NICE guidelines manual’ (NICE 2012). A team of health professionals, lay representatives and technical experts known as the Guideline Development Group (GDG) (see Appendix F in the full guideline), 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
Identifying the health economic priorities
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
Consultation and validation

The Scope

The scope was drafted by the GDG Chair and Lead Clinician and staff at the NCC-C in accordance with processes established by NICE (NICE 2012). 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
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 strategies

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 Web site.

The scope was subject to a three week stakeholder consultation in accordance with NICE processes. The full scope is shown in Appendix E. During the consultation period, the scope was posted on the NICE website. Comments were invited from registered stakeholder organisations and NICE staff. The NCC-C and NICE reviewed the scope in light of comments received, and the revised scope was reviewed and signed off by NICE and posted on the NICE Web site.

The Guideline Development Group (GDG)

The melanoma GDG was recruited in line with the ‘NICE guidelines manual’ (NICE 2012). The first step was to appoint a Chair and a Lead Clinician. Advertisements were placed for both posts and shortlisted candidates were interviewed in person prior to 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 F in the full guideline appendices [see the “Availability of Companion Documents” field]). Individual GDG members were selected for telephone interview 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 F in the full guideline appendices).

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 explicitly in the accompanying Linking Evidence to Recommendations (LETR) statement (see below).

Wording of the Recommendations

The wording used in the recommendations in this guideline denotes the certainty with which the recommendations were made. Some recommendations were made with more certainty than others. Recommendations are based on the trade-off between the benefits and harms of an intervention, whilst taking into account the quality of the underpinning evidence.

For all recommendations, it is expected that a discussion will take place with the patients about the risks and benefits of the interventions, and their values and preferences. This discussion should help the patient reach a fully informed decision. Terms used within this guideline are:

‘Offer’ – For the vast majority of patients, an intervention will do more good than harm
‘Do not offer’ – The intervention will not be of benefit for most patients
‘Consider’ – The benefit is less certain, and an intervention will do more good than harm for most patients

The choice of intervention, and whether or not to have the intervention at all, is more likely to depend on the patient’s values and preferences than for an ‘offer’ recommendation, and so the healthcare professional should spend more time considering and discussing the options with the patient.

Children and Young People

For every clinical question in this guideline the population always included children and young people as specified in the scope (see Appendix E in the full guideline appendices [see the “Availability of Companion Documents” field]). For clarity, children are defined as ‘from birth to 15 years’ and young people ‘aged 16 to 24 years’. Where recommendations in this guideline refer to ‘people’ this will include children, young adults and adults. However where the evidence allows, specific recommendations have been made for children and young adults and an explanation for these has been provided in the accompanying LETR section.

LETR 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
The quality of the evidence
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.

Rating Scheme for the Strength of the Recommendations

Strength of Recommendations

Interventions That Must (or Must Not) Be Used

Interventions That Should (or Should Not) Be Used – a ‘Strong’ Recommendation

Interventions That Could Be Used

Cost Analysis

Relevant health economic evidence for recommendations can be found in the specific chapters of the full version of the original guideline document (see the “Availability of Companion Documents” field).

See Appendices A and B in the full guideline appendices (see the “Availability of Companion Documents” field) for details of the health economic analyses undertaken for this guideline update.

Method of Guideline Validation

External Peer Review
Internal Peer Review

Description of Method of Guideline Validation

The guideline was validated through two consultations.

The first draft of the guideline (the full guideline and National Institute for Health and Care Excellence [NICE] guideline) were consulted with stakeholders and comments were considered by the Guideline Development Group (GDG).
The final consultation draft of the full guideline, the NICE guideline and the Information for the Public were submitted to stakeholders for final comments.

The final draft was submitted to the Guideline Review Panel for review prior to publication.

Evidence Supporting the Recommendations

Type of Evidence Supporting the Recommendations

The type of evidence supporting the recommendations is not specifically stated.

Benefits/Harms of Implementing the Guideline Recommendations

Potential Benefits

Dermoscopy performed in secondary care by suitably trained specialists is both more sensitive and more specific in classifying skin lesions than clinical examination with the naked eye alone. It lessens the chance of missing a diagnosis of melanoma and reduces the number of unnecessary surgical procedures to remove benign lesions.
Measuring vitamin D levels at diagnosis allows healthcare professionals to identify people with melanoma whose vitamin D levels are low and who might benefit from supplementation in line with national policies, as well as people with high vitamin D levels who do not need supplementation and in whom supplementation might be harmful. Knowing a person’s vitamin D level will also improve the accuracy of the advice given to them about the risks and benefits of sunlight exposure.
Considering sentinel lymph node biopsy (SLNB) for people who have stage IB–IIC melanoma with a Breslow thickness of more than 1 mm, and discussing the possible advantages and disadvantages with them, will enable people with these melanomas to make an informed decision about whether or not to have this procedure. Those who choose to have SLNB may benefit from more accurate staging, giving a better indication of outcome (including survival and risk of relapse). SLNB is more sensitive than ultrasound, so lymphatic spread may be diagnosed earlier. In addition, people who have SLNB may be able to participate in clinical trials of new treatments. Similarly, discussing the possible advantages and disadvantages of completion lymphadenectomy with people who have a positive SLNB will enable them to make an informed decision about whether or not to have this procedure after SLNB. Completion lymphadenectomy can reduce the chance of the melanoma returning and may enable the person to participate in clinical trials of new treatments.

See the “Trade-off between benefits and harms” sections in the full version of the guideline (see the “Availability of Companion Documents” field) for details about benefits of specific interventions.

Potential Harms

False-negative and false-positive results of diagnostic tests
The Guideline Development Group (GDG) acknowledged that there is a risk of adverse side effects and needless investigation associated with the treatments recommended. Although the treatments recommended by the GDG carry a potential risk of toxic side effects and/or discomfort related to the mode of treatment delivery, the GDG considered that these would be short-term harms and were outweighed by the potential benefit of disease control.

See the “Trade-off between benefits and harms” sections in the full version of the guideline (see the “Availability of Companion Documents” field) for details about harms of specific interventions.

Qualifying Statements

This guidance represents the view of the National Institute for Health and Care Excellence (NICE), which was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer, and informed by the summaries of product characteristics of any drugs.
Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.
The guideline will assume that prescribers will use a medicine’s summary of product characteristics to inform decisions made with individual patients.
This guideline recommends some medicines for indications for which they do not have a UK marketing authorisation at the date of publication, if there is good evidence to support that use. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. The patient (or those with authority to give consent on their behalf) should provide informed consent, which should be documented. See the General Medical Council’s Prescribing guidance: prescribing unlicensed medicines for further information. Where recommendations have been made for the use of medicines outside their licensed indications (‘off-label use’), these medicines are marked with a footnote in the recommendations.
See the “Person-centred care” section in the original guideline document for information about individual needs and preferences and transition of care.
See the original guideline document for information on safeguarding children.

Implementation of the Guideline

Description of Implementation Strategy

Implementation tools and resources to help clinicians put the guideline into practice are also available (see also the “Availability of Companion Documents” field).

Key Priorities for Implementation

The following recommendations have been identified as priorities for implementation.

See “Implementation: getting started” in the original guideline document for information about putting the recommendations on dermoscopy, managing suboptimal vitamin D levels, sentinel lymph node biopsy and completion lymphadenectomy into practice.

Communication and Support

To help people make decisions about their care, follow the recommendations on communication, information provision and support in the National Institute for Health and Care Excellence’s (NICE) guideline on improving outcomes for people with skin tumours including melanoma, in particular the following 5 recommendations:

‘Improved, preferably nationally standardised, written information should be made available to all patients. Information should be appropriate to the patients’ needs at that point in their diagnosis and treatment, and should be repeated over time. The information given must be specific to the histopathological type of lesion, type of treatment, local services and any choice within them, and should cover both physical and psychosocial issues.’
‘Those who are directly involved in treating patients should receive specific training in communication and breaking bad news.’
‘Patients should be invited to bring a companion with them to consultations.’
‘Each local hospital skin cancer multidisciplinary team (LSMDT) and specialist skin cancer multidisciplinary team (SSMDT) should have at least one skin cancer clinical nurse specialist (CNS) who will play a leading role in supporting patients and carers. There should be equity of access to information and support regardless of where the care is delivered.’
‘All LSMDTs and SSMDTs should have access to psychological support services for skin cancer patients.’

Assessing Melanoma

Dermoscopy and Other Visualisation Techniques

Photography

For a clinically atypical melanocytic lesion that does not need excision at first presentation in secondary or tertiary care:

Use baseline photography (preferably dermoscopic) and
Review the clinical appearance of the lesion, and compare it with the baseline photographic images, 3 months after first presentation to identify early signs of melanoma

Taking Tumour Samples for Genetic Testing

If targeted systemic therapy is a treatment option, offer genetic testing using:

A secondary melanoma tissue sample if there is adequate cellularity or
A primary melanoma tissue sample if a secondary sample is not available or is of inadequate cellularity

Managing Suboptimal Vitamin D Levels

Measure vitamin D levels at diagnosis in secondary care in all people with melanoma.

Staging Investigations

Sentinel Lymph Node Biopsy

Possible Advantages of Sentinel Lymph Node Biopsy	Possible Disadvantages of Sentinel Lymph Node Biopsy
The operation helps to find out whether the cancer has spread to the lymph nodes. It is better than ultrasound scans at finding very small cancers in the lymph nodes.	The purpose of the operation is not to cure the cancer. There is no good evidence that people who have the operation live longer than people who do not have it.
The operation can help predict what might happen in the future. For example, in people with a primary melanoma that is between 1 and 4 mm thick: * Around 1 out of 10 die within 10 years if the sentinel lymph node biopsy is negative * Around 3 out of 10 die within 10 years if the sentinel lymph node biopsy is positive	The result needs to be interpreted with caution. Of every 100 people who have a negative sentinel lymph node biopsy, around 3 will subsequently develop a recurrence in the same group of lymph nodes.
People who have had the operation may be able to take part in clinical trials of new treatments for melanoma. These trials often cannot accept people who haven't had this operation.	A general anaesthetic is needed for the operation.
	The operation results in complications in between 4 and 10 out of every 100 people who have it.

Managing Stage III Melanoma

Completion Lymphadenectomy

Possible Advantages of Completion Lymphadenectomy	Possible Disadvantages of Completion Lymphadenectomy
Removing the rest of the lymph nodes before cancer develops in them reduces the chance of the cancer returning in the same part of the body.	Lymphoedema (long-term swelling) may develop, and is most likely if the operation is in the groin and least likely in the head and neck.
The operation is less complicated and safer than waiting until cancer develops in the remaining lymph nodes and then removing them.	In 4 out of 5 people, cancer will not develop in the remaining lymph nodes, so there is a chance that the operation will have been done unnecessarily.
People who have had the operation may be able to take part in clinical trials of new treatments to prevent future melanoma. These trials often cannot accept people who have not had this operation.	There is no evidence that people who have this operation live longer than people who do not have it.
	Having any operation can cause complications.

Adjuvant Radiotherapy

Do not offer adjuvant radiotherapy to people with stage IIIB or IIIC melanoma unless a reduction in the risk of local recurrence is estimated to outweigh the risk of significant adverse effects.

Follow-up After Treatment for Melanoma

Follow-up For All People Who Have Had Melanoma

Follow-up After Stage IIC Melanoma With No Sentinel Lymph Node Biopsy or Stage III Melanoma

There is a clinical trial of the value of regular imaging or
The specialist skin cancer multidisciplinary team agrees to a local policy and specific funding for imaging 6-monthly for 3 years is identified

Take into account the possible advantages and disadvantages of surveillance imaging and discuss these with the person, using the table below.

Possible Advantages of Surveillance Imaging (Having Regular Scans)	Possible Disadvantages of Surveillance Imaging (Having Regular Scans)
If the melanoma comes back (recurrent melanoma), it is more likely to be detected sooner. It is possible that this could lead to a better outcome by allowing treatment with drugs (such as immunotherapy drugs) to start earlier.	Although early drug treatment of recurrent melanoma might improve survival, there is currently no evidence showing this.
Some people find it reassuring to have regular scans.	Some people find that having regular scans increases their anxiety.
	Scans expose the body to radiation, which can increase the risk of cancer in the future.
	Scans of the brain and neck increase the risk of developing cataracts.
	Scans of the chest cause a very small increase in the risk of thyroid cancer.
	Scans may show abnormalities that are later found to be harmless, causing unnecessary investigations and anxiety.

Stages of Melanoma

The stages of melanoma referred to in this guideline are from the American Joint Committee on Cancer’s Melanoma of the skin staging (7th edition).

Staging of primary melanoma can be carried out in 2 steps. The initial staging is based on the histopathological features reported by the pathologist looking at the microscopic sections of the tumour. The melanoma is staged as 0–IIC, based on factors such as the thickness of the tumour and the presence or absence of ulceration. In many hospitals in the UK, this first step is followed by the option of a second, which is a sampling of the lymph nodes most likely to contain secondary melanoma cells (sentinel lymph node biopsy). If a sentinel lymph node biopsy is performed and microscopic disease is detected, the melanoma becomes stage III. If no microscopic disease is detected then the initial stage is used.

Implementation Tools

Clinical Algorithm
Mobile Device Resources
Patient Resources
Resources

Institute of Medicine (IOM) National Healthcare Quality Report Categories

IOM Care Need

Living with Illness
Staying Healthy

IOM Domain

Effectiveness
Patient-centeredness

Identifying Information and Availability

Bibliographic Source(s)

National Collaborating Centre for Cancer. Melanoma: assessment and management. London (UK): National Institute for Health and Care Excellence (NICE); 2015 Jul 29. 59 p. (NICE guideline; no. 14).

Adaptation

Not applicable: The guideline was not adapted from another source.

Date Released

2015 Jul 29

Guideline Developer(s)

National Guideline Alliance - National Government Agency [Non-U.S.]

Source(s) of Funding

National Institute for Health and Care Excellence (NICE)

Guideline Committee

Guideline Development Group (GDG)

Composition of Group That Authored the Guideline

Guideline Development Group Members : Gill Godsell, Nurse Consultant (Skin Cancer), Nottingham NHS Treatment Centre; Laszlo Igali, Consultant Histopathologist, Norfolk and Norwich University Hospital NHS Foundation Trust; Richard Jackson, Patient and carer member; Charles Kelly, Consultant Clinical Oncologist, Northern Centre for Cancer Care, Freeman Hospital, Newcastle; Stephen Keohane, Consultant Dermatologist, Portsmouth Hospitals NHS Trust, Portsmouth Dermatology Centre; Fergus Macbeth ( Chair ), Clinical adviser, Wales Cancer Trials Unit, Cardiff University; Julia Newton-Bishop ( Clinical Lead ), Professor of Dermatology, University of Leeds; Christine Parkinson, Consultant in Medical Oncology, Addenbrooke’s Hospital, Cambridge; Barry Powell, Consultant Plastic Surgeon, St George’s Hospital, London; Saskia Reeken, Clinical Nurse Specialist, Skin Cancer and Dermatology, Kingston Hospital NHS Foundation Trust, Surrey; Rachael Robinson, GP, Stockwell Road Surgery, Knarlesborough, GPwSI Dermatology, Harrogate District Foundation Trust, GPwSI Durnford Dermatology, Middleton, Manchester; Simon Rodwell (from April 2013 until October 2013), Patient and carer member; John Rouse (from November 2013), Patient and carer member; Julia Schofifield, Principal Lecturer, University of Herefordshire, Consultant Dermatologist, United Lincolnshire Hospitals NHS Trust; Jonathan Smith, Consultant Radiologist, Leeds Teaching Hospital Trust; Sara Stoneham, Paediatric and Adolescent Oncology Consultant, University College Hospital, London; Martin Telfer, Consultant Maxillofacial Surgeon, York Teaching Hospital NHS Foundation Trust

Financial Disclosures/Conflicts of Interest

Members of the Guideline Development Group (GDG) made the declarations of interests listed in Section 4.4 in the original guideline document. All other members of the Group stated that they had no interests to declare. The conflicts of interest policy (2007) was followed until September 2014, when an updated policy was published.

Guideline Status

This is the current release of the guideline.

This guideline meets NGC’s 2013 (revised) inclusion criteria.

Guideline Availability

Available from the National Institute for Health and Care Excellence (NICE) Web site. Also available in ePub and eBook formats from the NICE Web site.

Availability of Companion Documents

The following are available:

Melanoma: assessment and management. Full guideline. London (UK): National Institute for Health and Care Excellence (NICE); 2015 Jul. 246 p. (NICE guideline; no. 14). Available from the National Institute for Health and Care Excellence (NICE) Web site.
Melanoma: assessment and management. Appendices A-G. London (UK): National Institute for Health and Care Excellence (NICE); 2015 Jul. 155 p. (NICE guideline; no. 14). Available from the NICE Web site.
Melanoma: assessment and management. Appendix H. London (UK): National Institute for Health and Care Excellence (NICE); 2015 Jul. 876 p. (NICE guideline; no. 14). Available from the NICE Web site.
Melanoma: assessment and management. Costing statement. London (UK): National Institute for Health and Care Excellence; 2015 Jul. 6 p. (NICE guideline; no. 14). Available from the NICE Web site.
Melanoma: assessment and management. Baseline assessment tool. London (UK): National Institute for Health and Care Excellence; 2015 Jul. (NICE guideline; no. 14). Available from the NICE Web site.
Melanoma: assessment and management. Podcast with Julia Newton-Bishop. Available from the NICE Web site.
Melanoma: assessment and management. Podcast with Barry Powell. Available from the NICE Web site.
The guidelines manual 2012. London (UK): National Institute for Health and Care Excellence (NICE); 2012 Nov. Available from the NICE Web site.

Patient Resources

The following is available:

Melanoma: assessment and management. Information for the public. London (UK): National Institute for Health and Care Excellence; 2015 Jul. (NICE guideline; no. 14). Available from the National Institute for Health and Care Excellence (NICE) Web site. Also available in ePub and eBook formats from the NICE Web site.

Please note: This patient information is intended to provide health professionals with information to share with their patients to help them better understand their health and their diagnosed disorders. By providing access to this patient information, it is not the intention of NGC to provide specific medical advice for particular patients. Rather we urge patients and their representatives to review this material and then to consult with a licensed health professional for evaluation of treatment options suitable for them as well as for diagnosis and answers to their personal medical questions. This patient information has been derived and prepared from a guideline for health care professionals included on NGC by the authors or publishers of that original guideline. The patient information is not reviewed by NGC to establish whether or not it accurately reflects the original guideline’s content.

NGC Status

This NGC summary was completed by ECRI Institute on December 7, 2015.

The National Institute for Health and Care Excellence (NICE) has granted the National Guideline Clearinghouse (NGC) permission to include summaries of their clinical guidelines with the intention of disseminating and facilitating the implementation of that guidance. NICE has not yet verified this content to confirm that it accurately reflects that original NICE guidance and therefore no guarantees are given by NICE in this regard. All NICE clinical guidelines are prepared in relation to the National Health Service in England and Wales. NICE has not been involved in the development or adaptation of NICE guidance for use in any other country. The full versions of all NICE guidance can be found at www.nice.org.uk.

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This NGC summary is based on the original guideline, which is subject to the guideline developer’s copyright restrictions.

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