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The Diagnosis and Treatment of Lung Cancer (Update). Cardiff (UK): National Collaborating Centre for Cancer (UK); 2011 Apr. (NICE Clinical Guidelines, No. 121.)

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  • NICE's original guidance on diagnosis and treatment of lung cancer was published in February 2005; and subsequently updated in 2011. The guideline has undergone a further update for 2019. This document preserves evidence reviews and committee discussions for areas of the guideline that have not been updated in 2019. The PDF has been colour-coded as follows: Text without shading or a bar in the right hand margin indicates text from the original 2005 guideline that has not been amended by subsequent updates. Text with a bar in the right hand margin indicates text updated in 2011. Green shading indicates text from the 2011 update that has reviewed and added to or updated by the 2019 update. Grey shading indicates text from 2005 or 2011 that has been amended but not replaced by the 2019 update. Black shading indicates text from 2005 or 2011 that has been replaced by the 2019 update.

NICE's original guidance on diagnosis and treatment of lung cancer was published in February 2005; and subsequently updated in 2011. The guideline has undergone a further update for 2019. This document preserves evidence reviews and committee discussions for areas of the guideline that have not been updated in 2019. The PDF has been colour-coded as follows: Text without shading or a bar in the right hand margin indicates text from the original 2005 guideline that has not been amended by subsequent updates. Text with a bar in the right hand margin indicates text updated in 2011. Green shading indicates text from the 2011 update that has reviewed and added to or updated by the 2019 update. Grey shading indicates text from 2005 or 2011 that has been amended but not replaced by the 2019 update. Black shading indicates text from 2005 or 2011 that has been replaced by the 2019 update.

Cover of The Diagnosis and Treatment of Lung Cancer (Update)

The Diagnosis and Treatment of Lung Cancer (Update).

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4Diagnosis and staging

Clinical topic: How effective are diagnostic and staging investigations in patients with suspected/confirmed lung cancer?

Clinical topic: What clinical factors and information from sequential tests determine the choice of next test for diagnosis and/or staging?

4.1. Introduction

Accurately determining the diagnosis and stage of lung cancer is important to enable patients to be offered the best possible treatment but the process is often complex. The complexity is augmented by the need to consider the fitness of the patient which itself may influence both diagnostic and treatment decisions and may require a change to the diagnostic and staging pathway.

It is axiomatic that minimising the number of individual steps in the diagnosis and staging pathway and completing them quickly will reduce delays. Investigations that provide both diagnostic and staging information will reduce the number of steps required. The risks of tests need to be considered, and be proportionate to the potential benefits.

Where appropriate, pathways need to be flexible enough to allow management of patients to proceed with minimal diagnostic and staging information (e.g. where a patient would clearly not benefit from anything more than active supportive care or where a patient is suitable for surgical resection without a prior pathological diagnosis).

The informed preferences of the patient are of over-riding importance throughout (see Chapter 3, Communication).

The challenge is to design a pathway that is both accurate and flexible enough to allow patients to choose the most appropriate treatment for them without delay.

For this chapter, there were two clinical topics: the first concerning the effectiveness of diagnostic and staging investigations and the second concerning the most effective sequence of investigations.

4.1.1. TNM staging System

The 7th Edition of the UICC TNM classification of lung cancer has been implemented in the UK since January 2010. Almost all of the evidence reviewed for this guideline update used the 6th edition of the TNM staging and so areas where this may have a bearing on recommendations have been clearly indicated. The 7th classification recommends that TNM staging be applied to small cell lung cancer. However, the TNM system does not easily map to the ‘limited’ and ‘extensive’ stage classification that has been used historically in many clinical trials (see Chapter 7 and Appendix 2).

4.1.2. Pathological Assessment

Newer drug therapies for non-small cell lung cancer work best if they are targeted on the basis of histological sub-type and/or predictive markers. Tissue samples of sufficient size and quality are therefore required to enable pathologists to classify non-small cell lung cancer into squamous cell carcinoma or adenocarcinoma wherever possible. In addition, further tests, requiring additional tissue or cells, may also be needed to detect specific markers that predict whether targeted treatments are likely to be effective, for example epidermal growth factor receptor mutations. As more targeted therapies become available it is likely that further tests will need to be performed to detect the relevant predictive markers.

4.2. Effectiveness of Diagnostic and Staging Investigations

An updated review of all diagnostic tests was not undertaken where the place of the tests is not controversial. Therefore recommendations concerning these investigations (sputum cytology, CT scanning) have not been updated. It is worth noting however, that some pragmatic changes to practice have been made in some centres. For example, the extension of CT to include the lower neck may provide information about supraclavicular lymphadenopathy that may be easily biopsied to give pivotal diagnostic and staging information. The diagnosis and staging of pleural disease was also not reviewed as part of this update.

The place of diagnosis and staging investigations is determined by their accuracy in a given situation. In lung cancer, the initial clinical assessment and the information provided by the CT scan is able to classify patients into a limited number of groups that can suggest an appropriate preferred first test and sequence. The following subsequent investigations were considered further in this update.

Positron emission tomography (PET)
PET with computed tomography (PET-CT)
Magnetic resonance imaging (MRI)
Single photon emission computed tomography (SPECT)
Bronchoscopy ± biopsy
Transthoracic needle aspiration (TTNA)
Endoscopic ultrasound fine needle aspiration (EUS-FNA)
Endobronchial ultrasound trans-bronchial needle aspiration (EBUS-TBNA)
Non ultrasound-guided TBNA
Cutting needle biopsy
Mediastinoscopy
Video-assisted thoracic surgery (VATS)

4.2.1. PET-CT

PET- CT is now widely used to assess whether a primary lesion is likely to be malignant, to look for evidence of regional lymph node involvement and to detect distant metastases. However, PET-CT cannot provide a pathological diagnosis so there is often the dilemma about whether to obtain tissue, especially given the now well documented limitations of PET-CT.

In SCLC, occult metastases may be detected by PET-CT, however it is not clear in what way these findings should influence decisions about offering treatment with curative intent.

The role of PET-CT in assessing response to tumour or as a prognostic indicator was not within the scope of this guideline.

4.2.2. Other imaging modalities

MRI

MRI is generally superior to CT in its ability to resolve soft tissue anatomy, which was the basis of the 2005 recommendation to use MRI to clarify the extent of superior sulcus tumours, where necessary.

MRI is often used in other areas where clarification of anatomy is required, but this was not the subject of an evidence review.

The role of MRI as a primary staging procedure compared with CT was not examined in this update.

SPECT

SPECT imaging can be used in the same way as PET in diagnosis and staging of lung cancer but is not in widespread use.

Ultrasound

Ultrasound is a useful modality to guide needle aspiration or biopsy of cervical lymphadenopathy, peripheral tumours in contact with the pleura, distant metastases and sampling of pleural tissue or fluid.

4.2.3. Minimally invasive procedures

Fibreoptic bronchoscopy

Fibreoptic bronchoscopy is a safe and effective way to diagnose and stage many patients with lung cancer. As well as obtaining samples from endobronchial tumour it can be routinely combined with non-ultrasound guided transbronchial needle aspiration (non US-guided TBNA) to sample tumours beneath the mucosa and hilar and mediastinal lymphadenopathy detected by CT. There is debate about the place of non-US guided TBNA and especially where it fits with US guided TBNA.

Endobronchial Ultrasound (EBUS) and Endoscopic (oesophageal) Ultrasound (EUS)

EBUS and EUS offer real time ultrasound guided sampling. EBUS is able to access lymph node stations 2, 3P, 4, 7, 10 and 11. EUS is able to access lymph node stations 4L, 7, 8, 9, the left adrenal gland and the left lobe of the liver. Neither EBUS nor EUS are generally able to access the aorto-pulmonary window station 5 or para-aortic station 6. The role of EBUS and EUS is complex, especially where there are differing amounts of clinical information. How the results of a PET-CT influence effectiveness of these tests and how negative results provided by endosongraphic tests should be followed is debated.

Autofluorescence and narrow band imaging bronchoscopy have been shown to increase the diagnostic sensitivity of standard white light bronchoscopy. The impact of this technique on diagnosis of early stage endobronchial tumours is the subject of ongoing randomised trials.

Transthoracic needle biopsy

Transthoracic needle biopsy is used to obtain diagnostic samples from lesions that are not accessible via the bronchial tree and where there is no obvious lymph node involvement. This is usually where there are one or more peripheral lesions. CT is used to guide biopsy where lesions are in difficult to reach locations or where they are completely surrounded by aerated lung. Ultrasound is used where the lesion abuts the chest wall and is visible on ultrasound.

4.2.4. Mediastinoscopy and surgical diagnostic and staging techniques

Mediastinoscopy

Mediastinoscopy is a more invasive technique than EBUS or EUS, but provides much larger samples. There is currently debate about whether mediastinoscopy is warranted in patients who are suitable for treatment with curative intent who have had a negative EBUS or EUS. This is partly because such patients, even if found to have microscopic involvement of lymph nodes, may still benefit considerably from treatment with curative intent.

Anterior Mediastinotomy

Anterior (parasternal) mediastinotomy has developed primarily as a means of staging carcinoma of the lung located in the left upper lobe. It has also been advocated to establish the diagnosis of primary masses in the anterosuperior mediastinum, especially in the setting of superior vena caval obstruction when needle biopsy may be contraindicated.

Video-assisted thoracoscopic surgery (VATS)

Video-assisted thoracoscopic assessment may allow biopsies direct from the tumour mass and can often establish whether there is tumour invasion into the central mediastinal structures. Lymph node stations 7, 8 and 9 can be sampled. It may also be employed to establish the diagnosis in single pulmonary nodules, especially where the lesion is in a peripheral location.

4.2.5. Adequacy of diagnostic samples for pathological sub-typing and determination of predictive markers

There is concern that some minimally invasive diagnostic and staging techniques may yield insufficient material to allow adequate assessment of tumour sub-type and predictive markers. Considerations include the increasing number of predictive markers as well as advances in detection methods. These requirements may mean that a change to the approach to diagnosis and staging is required.

Recommendations

  • Sputum cytology is rarely indicated and should be reserved for the investigation of patients who have centrally placed nodules or masses and are unable to tolerate, or unwilling to undergo, bronchoscopy or other invasive tests. [2005]
  • Patients with known or suspected lung cancer should be offered a contrast-enhanced chest CT scan to further the diagnosis and stage the disease. The scan should also include the liver and adrenals1. [2005]
  • In the assessment of mediastinal and chest wall invasion:
    –

    CT alone may not be reliable

    –

    other techniques such as ultrasound should be considered where there is doubt

    –

    surgical assessment may be necessary if there are no contraindications to resection. [2005]

  • Ensure all patients potentially suitable for treatment with curative intent are offered PET-CT before treatment. [NEW 2011]
  • Every cancer network should have a system of rapid access to PET-CT scanning for eligible patients. [2005]
  • Magnetic resonance imaging (MRI) should not routinely be performed to assess the stage of the primary tumour (T-stage) in NSCLC. [2005]
  • MRI should be performed, where necessary to assess the extent of disease, for patients with superior sulcus tumours. [2005]
  • Offer EBUS-guided TBNA for biopsy of paratracheal and peri-bronchial intra-parenchymal lung lesions. [NEW 2011]
  • Every cancer network should have at least one centre with EBUS and/or EUS to ensure timely access. [NEW 2011]
  • The local test performance of non-ultrasound guided TBNA, EBUS and EUS-guided FNA should be the subject of audit. [NEW 2011]
  • Ensure adequate samples are taken without unacceptable risk to the patient to permit pathological diagnosis including tumour sub-typing and measurement of predictive markers. [NEW 2011]
1

This recommendation was outside the scope of the 2011 update but the GDG recognised that many centres include the lower neck when performing CT scans for the diagnosis of lung cancer. The GDG also recognised that contrast medium should only be given with caution to patients with known renal impairment.

Qualifying statement (efficacy of diagnostic and staging investigations)

Recommendations about efficacy of tests were based on a review of studies ranging from low to high quality including systematic reviews and prospective / retrospective case series. As stated, the evidence for CT and sputum cytology was not reviewed. A summary of the findings from the medium to high quality studies can be found in table 4.1. There have been several studies published on the performance of PET and some on the performance of PET-CT. However, the standard technology is now PET-CT so that the evidence provided about PET alone is not really applicable to current practice. Studies demonstrate considerable variation in sensitivities and specificities for some investigations, especially for imaging (PET-CT, SPECT, MRI and scintigraphy). Tests that involve tissue sampling generally show better performance, particularly specificity, and on the basis of this a recommendation was made about audit of local performance. The recommendation to use EBUS to sample paratracheal and peribronchial intra-parenchymal lesions was made on the basis of one diagnostic study and expert opinion.

Diagnostic samples, pathological sub-typing and predictive markers

There was no research evidence on which to inform this important topic so the GDG sought the opinion of three histopathologists who regularly process diagnostic samples and have considerable expertise in this area (please see acknowledgements). A questionnaire concerning the adequacy of samples, likely demands on the pathology service, ability of local services to provide the required expertise and developments in the field likely to be relevant was sent to each pathologist. The responses were used to develop a recommendation based on expert opinion. The questionnaire is re-produced in Appendix 3. Responses to the questionnaire can be found in the full evidence review which acciompanies this guideline.

4.3. Sequence of investigations

The sequence of investigations varies according to a variety of linked factors including the clinical and radiological information, patient fitness, intended treatment and patient preference. Added to this is the cost-effectiveness of the approach and the need to achieve a management decision without delay. In this section the preferred approach is developed given specific clinical and radiological information, assuming the overall aim is to allow a rapid diagnosis and stage sufficient to allow the patient to make clinically appropriate choices. For the purpose of developing management algorithms, fitness was not assumed to influence the choice of tests, when in reality if a patient's fitness means that definitive diagnosis and staging is not required, a modified approach will be adopted. The following section deals with the approach given broad categories defined according to clinical and radiological findings after initial CT.

4.3.1. Peripheral and central primary tumours

Peripheral primary tumours are those within the lung parenchyma and which may abut the pleura. Where they occur without other features of more advanced malignancy such as mediastinal lymphadenopathy, specific diagnostic techniques apply, in particular transthoracic needle biopsy or immediate resection.

Central primary tumours are those that are in close proximity to, or directly invading the mediastinum. There is usually endobronchial tumour, although there may also be submucosal disease or associated lymphadenopathy. Within this category is included gross mediastinal lymphadenopathy with obvious malignant features, contiguous with the main primary tumour.

4.3.2. Mediastinal lymph node assessment

Sampling of mediastinal lymph nodes (and other mediastinal masses) may yield enough diagnostic and staging information to allow the appropriate treatment to be offered to patients. However, the extent of mediastinal lymphadenopathy may influence the approach. The most effective sequence of investigation is subject of current debate.

4.3.3. Distant metastases (stage M1b)

The majority of patients with SCLC and around 40% of patients with NSCLC have distant metastases at presentation. Identification of distant metastases by clinical examination or radiological investigations may identify the most appropriate site for a biopsy. Asymptomatic metastases are present in around 10% of patients with NSCLC and with improvements in imaging (e.g. PET-CT) these are increasingly identified in the staging process.

Imaging of brain metastases

The brain is one of the most common metastatic sites in lung cancer and the issues of when to investigate patients and with what imaging modality are debated. Brain imaging is increasingly used prior to treatment with curative intent to exclude metastases. This applies especially to the asymptomatic individual with more advanced disease.

Other distant metastases

The adrenal glands are another common site for metastases in lung cancer, detected by CT or PET-CT and can present diagnostic difficulties.

Distant metastases in small cell lung cancer

This topic was not reviewed as part of the 2011 update. In early stage small cell lung cancer it is not known if metastases detected by PET-CT influence whether potentially curative multi-modality treatment is offered.

4.3.4. Pleural Disease

Where CT shows pleural effusion or pleural thickening, a different management path is followed. The evidence for this was not reviewed as part of this update but the British Thoracic Society2 has recently published guidance on the management of pleural disease.

Recommendations

  • Choose investigations that give the most information about diagnosis and staging with the least risk to the patient. Think carefully before performing a test that gives only diagnostic pathology when information on staging is also needed to guide treatment. [NEW 2011]
  • Chest CT should be performed before:
    –

    an intended fibreoptic bronchoscopy

    –

    any other biopsy procedure. [2005]

Peripheral primary tumour

  • Offer CT- or ultrasound-guided transthoracic needle biopsy to patients with peripheral lung lesions when treatment can be planned on the basis of this test. [NEW 2011]
  • Biopsy any enlarged mediastinal nodes (≥10 mm maximum short axis on CT) or other lesions in preference to the primary lesion if determination of stage affects treatment.3[NEW 2011]

Central primary tumour

  • Offer fibreoptic bronchoscopy to patients with central lesions on CT where nodal staging does not influence treatment. Enlarged lymph nodes (≥10 mm maximum short axis on CT) may be simultaneously sampled with TBNA (non-ultrasound guided) if required for diagnosis. [NEW 2011]

Mediastinal lymph node assessment

  • Offer PET-CT as the preferred first test after CT showing a low probability of mediastinal malignancy (lymph nodes < 10 mm maximum short axis on CT) for patients who are potentially suitable for treatment with curative intent. [NEW 2011]
  • Offer PET-CT, or EBUS-guided TBNA, or EUS-guided FNA, or non-ultrasound-guided TBNA as the first test for patients with an intermediate probability of mediastinal malignancy (lymph nodes between 10 and 20 mm maximum short axis on CT) who are potentially suitable for treatment with curative intent. [NEW 2011]
  • Offer neck ultrasound with sampling of visible lymph nodes, or non-ultrasound-guided TBNA to patients with a high probability of mediastinal malignancy (lymph nodes > 20 mm maximum short axis on CT). If neck ultrasound is negative, follow with non-ultrasound-guided TBNA, EBUS-guided TBNA or EUS-guided FNA. If non-ultrasound-guided TBNA is negative follow with EBUS-guided TBNA or EUS-guided FNA. [NEW 2011]
  • Offer neck ultrasound with biopsy of visible lymph nodes to patients that have neck nodes detected by initial CT. If negative, follow with non- ultrasound guided TBNA or EBUS-guided TBNA or EUS-guided FNA. [NEW 2011]
  • Evaluate PET-CT positive mediastinal nodes by mediastinal sampling (except where there is definite distant metastatic disease or a high probability that N2/N3 disease is metastatic [for example, if there is a chain of lymph nodes with high 18F-deoxyglucose uptake]). [NEW 2011]
  • Consider combined EBUS and EUS for initial staging of the mediastinum as an alternative to surgical staging. [NEW 2011]
  • Confirm negative results obtained by non-ultrasound-guided TBNA using EBUS-guided TBNA, EUS-guided FNA or surgical staging. [NEW 2011]
  • Confirm negative results obtained by EBUS-guided TBNA and/or EUS-guided FNA using surgical staging if clinical suspicion of mediastinal malignancy is high. [NEW 2011]
Stage M1b
  • Confirm the presence of isolated distant metastases/synchronous tumours by biopsy or further imaging (for example, MRI or PET-CT) in patients being considered for treatment with curative intent. [NEW 2011]
  • Consider MRI or CT of the head in patients selected for treatment with curative intent, especially in stage III disease. [NEW 2011]
  • Offer patients with features suggestive of intracranial pathology, CT of the head followed by MRI if normal, or MRI as an initial test. [NEW 2011]
  • An X-ray should be performed in the first instance for patients with localised signs or symptoms of bone metastasis. If the results are negative or inconclusive, either a bone scan or an MRI scan should be offered. [2005]
  • Avoid bone scintigraphy when PET-CT has not shown bone metastases. [NEW 2011]
Footnotes
3

Many patients with lung cancer will not be fit for treatment with curative intent. This needs to be taken into account when choosing diagnostic and staging investigations.

4.3.5. Management Algorithms

The recommendations are summarised in diagrammatic form in management algorithms 1 and 2. The algorithms are flexible to allow for variation in local test accuracy, fitness and patient preference.

Research Recommendation

Consider research into the outcome of treatment of small cell lung cancer with low volume metastases detected by PET-CT. [NEW 2011]

Consider research into the use of MRI and PET-CT in routine brain imaging prior to treatment with curative intent. Include stratification by stage and other prior imaging modalities. [NEW 2011]

Qualifying Statement (Sequence of Investigations)

The evidence reviewed for the accuracy of diagnosis and staging investigations also served to inform about the best sequence of tests, but there was no evidence of sufficient quality that specifically compared different sequences. Expert opinion was used to make recommendations based on consideration of the clinical scenario, accuracy of the test and safety. The results of the health economic model were also used to make recommendations for mediastinal sampling.

Peripheral lesions

The recommendation to use transthoracic needle aspiration or biopsy was made on the basis of the accuracy of the test but as this comes at a cost of more frequent complications (pneumothorax requiring intervention 3-5%, death 0.1%), alternative approaches were considered. The recommendation to only use this test when treatment planning depended on the result was made partly from expert opinion but also from the evidence for the accuracy of other tests. There was insufficient evidence to make recommendations about newer techniques such as radial endobronchial ultrasound, electromagnetic navigation, fluoroscopy and ultra-thin bronchoscopy. These are time-consuming, have lower sensitivities than transthoracic needle aspiration and are not widely used in the UK.

Central lesions

Recommendations were based on the evidence for accuracy of bronchoscopy and expert opinion.

Mediastinal sampling

Although evidence was available about the accuracy of non-US guided TBNA, EBUS-TBNA, EUS-FNA and surgical sampling techniques, there were no studies that provided adequate evidence to suggest the most effective sequence of tests according to the pre-test probability of mediastinal malignancy. Specifically, studies did not analyse test accuracy by lymph node size. The GDG defined three categories according to appearance on CT scan: i) no enlarged lymph nodes (all <10 mm short axis and hence a peripheral lesion only on CT); ii) one or two discreet lymph nodes 10 to 20 mm short axis; and iii) lymph nodes >20 mm. These categories correspond to low (15%), intermediate (50%) and high (>85%) probabilities of mediastinal malignancy respectively. A fourth category, where the CT scan shows multiple and bulky lymph nodes that display obvious malignant features, such as invasion of mediastinal structures may not require specific further investigation unless they are the only source of diagnostic material. It is recognised that these categories are simplified, for example, it is known that a higher tumour stage in the TNM classification is associated with a greater prevalence of nodal malignancy.

The health economic model showed that for low probability (nodal short axis diameter <10mm) the test that dominated was PET-CT alone, for intermediate probability (1 or more nodes 10-20mm), PET-CT followed by non-US guided TBNA and for high probability (nodes >20mm), Neck US then non-US guided TBNA then PET-CT. For all probabilities of malignancy, but for intermediate probability in particular, there were other sequences that were very close to the most cost effective and given the assumptions made in the model, expert opinion was employed to reflect this in the recommendations about the sequence of tests. It should also be noted that the test accuracy measured in studies may not reflect that in general use and so a degree of flexibility has been incorporated into the management algorithms. Thus for intermediate probability nodes US guided or non-US guided needle sampling is recommended to reflect the fact that US guided tests have greater accuracy yet are still well below the cost per QALY threshold of £20,000, compared the next best strategy. The GDG recognised that these categories were simplified and that they would not represent all patients. For example, it is known that a higher tumour stage in the TNM classification is associated with a greater prevalence of nodal malignancy.

Where mediastinal adenopathy has obvious malignant features such as invasion of mediastinal structures, the probability of malignancy is very high. Expert opinion was used to categorise these within the management pathway for central lesions.

A single randomised trial of endosonographic mediastinal staging (combined EBUS and EUS) versus surgical staging showed that when endosonography is combined with surgical staging, sensitivity for detection of mediastinal malignancy was significantly increased over that of surgical staging alone. In addition, it was found that the sensitivity of endosonographic staging alone was equivalent to that of surgical staging. These findings were used to make the recommendation that combined EBUS and EUS can be used for the initial sampling of mediastinal lymph nodes as an alternative to surgical staging. However, the GDG felt that surgical staging is still indicated where endosonographic assessment is negative if clinical suspicion of mediastinal nodal disease remains high and hence made a recommendation to that effect.

Ultrasound of the neck ± biopsy

No studies that met inclusion criteria were found on US of the neck ± biopsy. Recommendations were therefore based on knowledge of limited case series and expert opinion.

Distant metastases

Recommendations about the place of CT and MRI in symptomatic and asymptomatic individuals with cerebral metastases were made from smaller comparative studies that showed that MRI is superior to CT but that CT will detect identify cerebral metastases in the majority of affected patients.

Recommendations about the use of PET-CT prior to treatment with curative intent were in part based on evidence that showed that adrenal lesions are readily detected by PET-CT (sensitivity of 94 to 100% and specificity of 80 to 100%). Recommendations concerning detection of bone metastases were based on the evidence review for bone scintigraphy including SPECT and PET-CT. Compared with PET-CT, the sensitivity of scintigraphy is less, though specificity may be better. The evidence for the use of MRI and plain x-ray was not reviewed as part of the 2011 update.

Clinical evidence (sections 4.2 and 4.3)

The evidence for the effectiveness of different diagnostic and staging tests for patients with suspected or confirmed NSCLC consisted of ninety-seven studies that ranged in quality from low to high and examined the following diagnostic and staging tests: Bronchoscopy (including endobronchial and endoscopic ultrasound and transbronchial biopsy), needle biopsy of the lung (including percutaneous biopsy), radionuclide imaging (PET-CT, NeoSpect, PET), ultrasound-guided biopsy of cervival lymph nodes, other biopsies of metastatic sites (other than lung), pleural biopsy, thoracoscopy (including medical and pleuroscopy), surgical techniques (including VATS, mediastinoscopy/mediastinotomy, frozen section), observation, and MRI/CT of the brain. The ranges of sensitivities and specificities reported by the studies of moderate to high quality for the different diagnostic and staging tests are summarised in table 4.1.

Table 4.1. Sensitivities and specificities of various diagnostic and staging tests for suspected/confirmed lung cancer reported by the moderate-high quality studies.

Table 4.1

Sensitivities and specificities of various diagnostic and staging tests for suspected/confirmed lung cancer reported by the moderate-high quality studies.

Health economic evidence

In the 2005 NICE Lung cancer guideline (NICE 2005), the staging of non-small cell lung cancer was prioritised for independent economic modelling. Accurate diagnostic and staging information, particularly of mediastinal disease, helps the clinician decide which patients are suitable for treatment with curative intent; mediastinal lymph-node involvement reduces the chance of surgery being curative. Since 2005 a number of minimally invasive techniques have started to be used in some centres, and whilst PET-CT scanners are now routinely available, a question remains over where best to use them in the diagnostic and staging pathway.

An economic model was developed to assess the cost-effectiveness of PET-CT, TBNA, EBUS, mediastinoscopy and neck ultrasound in 26 clinically relevant sequences, from a UK NHS perspective see table 4.2. A detailed description of methods and results can be found in appendix 4. Separate analyses were run in three subgroups of patients with non-small cell lung cancer in which the prevalence of nodal and distant metastatic disease was low, intermediate or high. Not all staging strategies were considered by the GDG to be clinically relevant alternatives in each population subgroup; therefore the strategies considered in each analysis differ.

Table 4.2. Test sequences considered in each subgroup analysis.

Table 4.2

Test sequences considered in each subgroup analysis.

A decision tree approach was taken to model the staging alternatives with an embedded Markov process to model the longer term consequences resulting from treatment. For the purposes of the model, PET-CT only provides information on the presence of metastatic disease. If PET-CT is positive the patient is treated for distant metastasis. If PET-CT is negative the next test in the sequence is performed.

All other tests provide the clinician with information on the presence of nodal disease (defined as N2 or N3). If a test is positive the patient is treated for N2/3 M0 disease. Again, if a test is negative the next test is the sequence is performed.

The Markov model at the end of the decision tree branch is a simplified version of the natural progression of disease, accounting only for the possibility of death. Different stages of disease progression are not captured. Death can occur in the model as a result of a mediastinoscopy (in 0.5% of cases) or any other cause.

The decision about which treatment to offer patients on the basis of the staging test results was not evaluated in terms of cost-effectiveness (there are no embedded decision nodes in the decision tree). Instead the downstream consequences of the staging tests have been captured, as typified in current clinical practice or best practice as defined by relevant NICE guidance including recommendations within this guideline.

The model was populated with data from different sources considered to provide the best available evidence, as shown in table 4.3:

Table 4.3. Data sources used in to populate the model.

Table 4.3

Data sources used in to populate the model.

Data from the National Lung Cancer Audit was chosen over randomised controlled trial data since they capture the real treatment options offered to patients, given the stage of their disease, thus increasing the external validity of the model results.

Data on test accuracy was not reported for our three sub groups, so were dictated by expert opinion from the GDG. Gaps in data on test accuracy (in the three patient subgroups), quality of life and the cost of EBUS were acknowledged and assumptions were made by the GDG. Despite the rich source of data for survival estimates from National Lung Cancer Audit, we had no information about patients' survival from treatment given as the result of misleading test results (i.e. false positives or false negatives) so assumptions were made about the resulting survival outcomes in these patients.

In accordance with the perspective of this analysis, the only costs considered were those relevant to the UK NHS. Costs were estimated in 2008-9 prices (since this is the price year from the most recent edition of NHS Reference costs, published June 2010). Five categories of costs considered in the model; the cost of diagnostic tests, the cost of treatment, the cost of treating adverse events, the cost of follow-up and the cost of supportive and palliative care which was applied to all patients regardless of which (if any) anti-cancer treatment they initially received.

Deterministic sensitivity analysis was conducted on relevant parameters in order to identify variables which contribute most to the uncertainty surrounding the results of the model. The results of the cost-effectiveness analyses show that different sequences of staging tests are likely to be cost-effective in different subgroups of patients, see table 4.4 below.

Table 4.4. Summary of results.

Table 4.4

Summary of results.

These results may seem on the surface to be counter-intuitive. Those sequences of tests which lead to more accurate staging information do not lead to overall better outcomes for patients. However, test performance is only a surrogate endpoint – and the results of all three analyses are heavily dependent on assumptions made about downstream treatment decisions. Within the context of the model, strategies resulting in a higher number of false negatives allow a great proportion of patients with N2/3 disease to be offered surgery and other options for treatment with curative intent. Similarly if metastatic disease is missed, patients still achieve better outcomes with treatment for curative intent than with no anti-cancer treatment.

The sensitivity analysis performed showed the model was reasonably robust to small changes in the treatment options, the choice of radiotherapy schedules, the price of chemotherapy drugs, the price of diagnostic tests, the death rate from mediastinoscopy, changes in utility values as well as some assumptions about the choice of survival estimates for patients incorrectly staged. Other assumptions about utility values could not be tested without changing the model structure. Test accuracy data was not available for the three subgroups identified as relevant to the decision problem; as such we have relied on the expert opinion of the GDG.

Despite these acknowledged limitations, these three analyses provided the GDG with useful information in their deliberations when preparing recommendations on the best sequence in which to use tests to stage mediastinal disease in different subgroups of patients.

4.4. Organisational factors relevant to diagnosis and staging

Timing of treatment

In 1993, the Joint Council for Clinical Oncology (JCCO) issued targets for the time from first consultation to the start of radiotherapy or chemotherapy. Guidance on timing has also been issued by the Department of Health in the National Manual of Quality Measures for Cancer and the Welsh Assembly Government in the All Wales Minimum Standards for Lung Cancer. The 2005 guideline examined the evidence for the effect that delays in diagnosis or treatment might have on survival and quality of life and although the evidence was very limited, a number of recommendations were made. Since then the 62 and 31 day targets (for referral to treatment and diagnosis to treatment respectively) have been monitored nationally and some pressure has been placed on cancer centres and units to achieve them. The GDG considered that these targets had resulted in a marked improvement in the timeliness of care of lung cancer patients and every effort should be made to ensure compliance but without compromising the recommendations made in this guideline.

Rapid access clinics

The 2005 guideline reviewed the evidence in support of rapid access clinics in which patients are fast-tracked to respiratory physician-led clinics that either combine multiple investigations or are linked to early diagnostic and staging investigation appointments. The GDG noted that these clinics are now widespread and adopted the 2005 recommendation.

The Lung Cancer MDT

The central role of the MDT in ensuring that all patients are discussed by a full team of specialists is not disputed. A number of previous reports have affirmed this (the Calman- Hine report, Improving Outcomes in Lung Cancer (NHS Executive), NHS Cancer Plan, the Cancer Reform Strategy Clinical Oncology Information Network guidelines, British Thoracic Society recommendations on organising care for lung cancer patients and the American College of Chest Physicians). However, there remain concerns that some MDTs still do not have regular enough attendance by some specialists (especially thoracic surgeons) to ensure that all patients have a true multidisciplinary opinion. This is one reason put forward for the marked geographical differences in surgical resection and other treatment rate that have been shown by the National Lung Cancer Audit. The 2005 guideline included recommendations based on the expert opinion and formal consensus in the above reports.

Recommendations

  • Patients who have lung cancer suitable for radical treatment, or chemotherapy, or need radiotherapy or ablative treatment for relief of symptoms, should be treated without undue delay, according to the Welsh Assembly Government and Department of Health recommendations (within 31 days of the decision to treat and within 62 days of their urgent referral). [2005]

Multidisciplinary teams

  • All patients with a likely diagnosis of lung cancer should be referred to a member of a lung cancer MDT (usually a chest physician). [2005]
  • The care of all patients with a working diagnosis of lung cancer should be discussed at a lung cancer MDT meeting. [2005]

Rapid access lung clinics

  • Rapid access clinics4 should be provided where possible for the investigation of patients with suspected lung cancer, because they are associated with faster diagnosis and less patient anxiety. [2005]

Cancer clinical nurse specialists

  • All cancer units/centres should have one or more trained lung cancer clinical nurse specialists to see patients before and after diagnosis, to provide continuing support, and to facilitate communication between the secondary care team (including the MDT), the patient's GP, the community team and the patient. Their role includes helping patients to access advice and support whenever they need it. [2005]
Footnotes
4

These were previously known as early diagnosis clinics.

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Footnotes

2

British Thoracic Society Pleural Disease Guideline 2010 Thorax, Vol 65, Suppl 2

Copyright © 2011, National Collaborating Centre for Cancer.

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Bookshelf ID: NBK99038
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