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Guidelines on the radical management of patients with lung cancer

October 2010
Thorax 65 Suppl 3(Suppl 3):iii1-27

DOI:10.1136/thx.2010.145938

Source
PubMed

Authors:

David R Baldwin

National Health Service

Michael Beckles

Royal Free London NHS Foundation Trust

John Duffy

Doctors.net.uk

Show all 16 authorsHide

A joint initiative by the British Thoracic Society and the Society for Cardiothoracic Surgery in Great Britain and Ireland was undertaken to update the 2001 guidelines for the selection and assessment of patients with lung cancer who can potentially be managed by radical treatment.

nvestigation pathway for mediastinal diagnosis and staging. EBUS, endobronchial ultrasound; EUS, endoscopic ultrasound; FDG, [ 18 F]-2-fluoro-deoxy-D-glucose; MDT, multidisciplinary team; PET, positron emission tomography; TBNA, transbronchial needle aspiration.

…

Role of commonly used imaging modalities in the diagnosis and staging of patients suitable for radical treatment

…

Utility of commonly used imaging modalities

…

Risk assessment for post-treatment dyspnoea. FEV 1 , forced expiratory volume in 1 s; LVRS, lung volume reduction surgery; ppo, projected postoperative; TLCO, lung carbon monoxide transfer factor.

…

Active cardiac conditions

…

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Guidelines on the radical management of patients

with lung cancer

Eric Lim,

David Baldwin,

Michael Beckles,

John Duffy,

James Entwisle,

Corinne Faivre-Finn,

Keith Kerr,

Alistair Macﬁe,

Jim McGuigan,

Simon Padley,

Sanjay Popat,

Nicholas Screaton,

Michael Snee,

David Waller,

Chris Warburton,

Thida Win,

British Thoracic Society and the Society for

Cardiothoracic Surgery in Great Britain and Ireland

ABSTRACT

A joint initiative by the British Thoracic Society and the

Society for Cardiothoracic Surgery in Great Britain and

Ireland was undertaken to update the 2001 guidelines for

the selection and assessment of patients with lung cancer

who can potentially be managed by radical treatment.

SYNOPSIS OF RECOMMENDATIONS

The recommendations of the Guideline Develop-

ment Committee (GDC) are listed below and can

be cross-referenced in the main document. The

list includes recommendations for research denoted

by the abbreviation RR. The recommendations

should be read in conjunction with ﬁgure 1 (medi-

astinal diagnosis and staging), ﬁgure 2 (tripartite

risk assessment) and ﬁgure 3 (risk assessment for

postoperative dyspnoea).

SECTION 1: SELECTION OF PATIENTS FOR

RADICAL TREATMENT

1.1 Diagnosis and staging

1.1.1 Imaging

1. View all available historical images at the onset

of the diagnostic pathway and review them prior to

treatment. [C]

2. Ensure contemporaneous imaging is available at

the time of radical treatment. [C]

3. Ensure a CTscan that is <4 weeks old is available

at the time of radical treatment of borderline

lesions. [D]

4. Arrange a CT scan of the chest, lower neck and

upper abdomen with intravenous contrast medium

administration early in the diagnostic pathway for

all patients with suspected lung cancer potentially

suitable for radical treatment. [C]

5. Avoid relying on a CT scan of the chest as the

sole investigation to stage the mediastinal lymph

nodes. [B]

6. Ensure positron emission tomography (PET)-CT

scanning is available for all patients being considered

for radical treatment. [B]

7. Offer radical treatment without further medias-

tinal lymph node sampling if there is no signiﬁcant

uptake in normal sized mediastinal lymph nodes on

PET-CT scanning. [C]

8. Evaluate PET positive mediastinal nodes by

further mediastinal sampling. [C]

9. Conﬁrm the presence of isolated distant

metastases/synchronous tumours by biopsy or

further imaging in patients being considered for

radical treatment. [C]

10. Consider MRI or CT scanning of the head in

patients selected for radical treatment, especially in

stage III disease. [C]

11. Evaluate patients with features suggestive of

intracranial pathology by an initial CT scan of the

head followed by MRI if normal or MRI as an

initial test. [C]

12. Biopsy adrenal lesions that show abnormal

uptake on PET-CT scanning before radical treat-

ment. [D]

13. RR The role of PET-CT scanning in patients

with small cell lung cancer considered suitable for

radical treatment should be evaluated in clinical

trials.

1.1.2 Endoscopic procedures for diagnosis and staging

14. When obtaining diagnostic and staging samples,

consider the adequacy of these in the context of

selection of patients for targeted therapy. [D]

15. Ensure biopsy samples are taken in adequate

numbers and size where there is negligible additional

risk to the patient. [D]

16. Use transbronchial needle aspiration (TBNA)

and endobronchial ultrasound/endoscopic ultra-

sound (EBUS/EUS)-guided TBNA as an initial

diagnostic and staging procedure according to

ﬁndings on CT or PET-CT scans. [C]

17. Consider EBUS/EUS-guided TBNA to stage the

mediastinum. [C]

18. Conﬁrm negative results obtained by TBNA

and EBUS/EUS-guided TBNA by mediastinoscopy

and lymph node biopsy where clinically appro-

priate. [C]

19. RR The use of narrow band and autoﬂuor-

escence imaging should be investigated in clinical

trials.

1.1.3 7th Edition of TNM for lung tumours

20. The 7th edition of the TNM classiﬁcation of

lung cancer should be used for staging patients

with lung cancer. [B]

21. The IASLC international nodal map should be

used in the assessment and staging of lymph node

disease. [C]

1.2 Management of speciﬁc disease subsets

1.2.1 T3 disease

22. Offer patients with T3N0e1M0 disease radical

treatment. [D]

<Appendix 2 is published

online only. To view this ﬁle,

please visit the journal online

(http://thorax.bmj.com).

Royal Brompton Hospital,

London, UK

Nottingham University

Hospitals, Nottingham, UK

Royal Free Hospital, London,

University Hospitals of

Leicester NHS Trust, Glenﬁeld

Hospital, Leicester, UK

Christie Hospital, Manchester,

Grampian University Hospitals

NHS Trust, Aberdeen, UK

Golden Jubilee National

Hospital, Clydebank, UK

Royal Victoria Hospital, Belfast,

Chelsea and Westminster

Hospital, London, UK

Royal Marsden Hospital,

London, UK

Papworth Hospital NHS Trust,

Papworth Hospital, Papworth

Everard, Cambridge, UK

Leeds Teaching Hospitals

Trust, Leeds, UK

Glenﬁeld Hospital, Leicester,

Leicester, UK

Aintree Chest Centre,

University Hospital Aintree,

Liverpool, UK

Lister Hospital, Stevenage,

Hertfordshire, UK

Correspondence to

Eric Lim, Imperial College and

the Academic Division of

Thoracic Surgery, Royal

Brompton Hospital, Sydney

Street, London SW3 6NP, UK;

e.lim@rbht.nhs.uk

Received 28 June 2010

Accepted 29 June 2010

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1.2.2 T4 disease

23. Consider selected patients with T4N0e1M0 disease for

radical multimodality treatment. [D]

24. RR Consider clinical trials of radical treatment for T4

disease.

1.2.3 N2 disease

25. Consider radical radiotherapy or chemoradiotherapy in

patients with T1e4N2 (bulky or ﬁxed) M0 disease. [B]

26. Consider surgery as part of multimodality management in

patients with T1e3N2 (non-ﬁxed, non-bulky, single zone) M0

disease. [B]

27. RR Consider further randomised trials of surgery added to

multimodality management in patients with multi-zone N2

disease to establish if any subgroups of patients might beneﬁt

more from the addition of surgery.

1.2.4 N3 disease

N3 disease describes any metastatic involvement of contralateral

mediastinal or hilar nodes or any scalene or supraclavicular

nodes. Based on limited available evidence in support of radical

management, the standard treatment in this group of patients is

chemotherapy and/or radiotherapy. Feasibility studies have

recently reported favourable outcomes with induction regimens,

with impressive 5-year survival results ranging from 40% to

52%.

78[2],86[2],87[1]

Research recommendation

<Consider clinical trials of radical treatment for patients with

T1e4N3M0 disease.

1.2.5 M1 disease

M1a designation is assigned to the presence of distant metas-

tases by virtue of a separate tumour nodule in the contralateral

lung, tumour with pleural nodules or malignant pericardial or

pleural effusion. The results of surgery for multifocal lung cancer

are discussed in section 1.2.6. The management of patients with

positive cytology of pleural or pericardial effusion is palliative.

M1b designation is assigned to distant metastases, and

management of this subset is palliative. It is important to note

that the survival of patients with pathological stage IV disease is

higher than patients with IIIB disease in the seventh edition of

the TNM classiﬁcation of lung tumours.

5[N/A]

This phenomenon

may be explained by the selection of speciﬁc subgroups who

underwent surgical management.

Research recommendation

<Consider clinical trials of radical treatment for patients with

M1a and M1b disease.

1.2.6 Bronchioloalveolar carcinoma

Considerable interest has been generated in this tumour subtype

of adenocarcinoma, particularly after its redeﬁnition in

1999.

88[N/A]

Speciﬁcally, Noguchi et al reported 100% 5-year

survival

89[2+]

in patients with this tumour subtype, underpin-

ning the reclassiﬁcation of bronchioloalveolar carcinoma (BAC)

as essentially adenocarcinoma-in-situ. Since true BAC cannot be

conﬁdently diagnosed on anything other than a complete

resection, allowing full lesion examination to rule out invasion

in the tumour, a preoperative diagnosis of BAC is presumptive

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and based on appropriate radiology (pure localised ‘ground glass’

lesions) and, in some cases, consistent pathology. It is also worth

noting that, if limited small biopsy samples are available,

a mucinous BAC pattern adenocarcinoma carries a higher risk of

being multifocal/more advanced than non-mucinous BAC.

Numerous reports have been published, afﬁrming excellent

postoperative survival in patients, not only with pure true BAC

as currently deﬁned, but also in those with small peripheral

tumours

90[2+],91[3],92[3],93[3]

in which a BAC component was

prominent, and in resected multifocal BAC pattern disease.

94[3]

Based on these reports, opinions are emerging to suggest that

that this tumour subtype has a better than expected prognosis

by current staging classiﬁcation, and lesser (sublobar resections)

forms of management

95[3]

may be acceptable for multifocal

disease.

96[3]

It is important to recognise that good results are

not uniform

97[2e]

and are critically dependent on accurate

contemporaneous classiﬁcation and reporting.

93[3]

It must also

be realised that older reports on BAC will not refer to tumours as

currently deﬁned.

It is worth noting that a joint IASLC/ATS/ERS working

group has proposed a signiﬁcant change to the nomenclature

and classiﬁcation of adenocarcinoma. This proposal was driven

by the historical multiplicity of different meanings for the term

BAC which has caused considerable confusion. The recommen-

dations include dropping the term BAC, as currently deﬁned, in

favour of adenocarcinoma-in-situ, referring to the BAC pattern

of adenocarcinoma in all other instances as ‘lepidic growth’and

introducing a category of minimally invasive adenocarcinoma.

At the time of writing is seems highly likely that these proposals

will be incorporatedinto the next WHO Lung Cancer classiﬁcation.

Recommendations

<Offer suitable patients with single-site bronchioloalveolar

carcinoma anatomical lung resection. [C]

<Consider multiple wedge resections in suitable patients with

a limited number of sites of bronchioloalveolar carcinoma. [C]

1.2.7 Open and close thoracotomy

In the UK, open and close thoracotomy rates have been steadily

declining from more than 20% in the early 1980s to a national

average of approximately 6% in 2005.

98[N/A]

This has been

attributed to improvements in preoperative imaging and hence

case selection. While the declining proportion represents an

improvement, a reduction to 0% would imply extreme case

selection, and patients who may be technically surgically resect-

able would be denied the opportunity for surgery, especially where

there are difﬁculties in differentiating between T3 and T4 (section

1.1.1.2). The current national average is approximately 5%.

Recommendation

<Surgical units should have an open and close thoracotomy

rate of around 5%. [D]

SECTION 2: SURGERY

2.1 Assessment of the risks of surgery

In this section a tripartite risk assessment model is presented

that considers risks of operative mortality, risk of perioperative

myocardial events and risk of postoperative dyspnoea (ﬁgure 2).

Unlike previous guidelines, the recommendations facilitate the

calculation and assessment of individual outcomes that may be

discussed by the MDT and with the patient.

2.1.1 Risk assessment for operative mortality

The ability to estimate the risk of in-hospital death is one of the

most important considerations for surgeons and patients when

evaluating the option of surgery for lung cancer. In-hospital

death after lobectomy for cancer in the UK was reported as 2.6%

in 2003.

99[2+]

The 30-day mortality for lobectomy and pneu-

monectomy in England from the National Lung Cancer Audit is

2.3% and 5.8%. respectively.

An ideal model to estimate the risk of death would have

ahigh degree of discrimination within the applied population,

be simple to use and be reproducible. As the in-hospital

mortality rates are low, large numbers (multi-institutional or

multinational studies) would be required to develop these

models. Risk stratiﬁcation for death in thoracic surgery thus

remains relatively rudimentary. While there is a large body of

work on factors that inﬂuence death after thoracic surgery, most

either explore only individual variables (not a global risk model),

have composite outcomes (rather than death alone) or do not

contain sufﬁciently large numbers to produce a robust model.

Among the largest series are the European Society of Thoracic

Surgeons (ESTS) risk model that had 3426 patients with 66

deaths

100[2+]

and the Veterans Affairs model with 3516 patients

with 184 deaths.

101[2+]

Thoracoscore is currently the largest and most discriminating

model, and was developed by the French Society of Thoracic and

Cardiovascular Surgery on 15 183 patients with 338 deaths with

a corresponding c-index of 0.86 in the validation dataset.

102[2+]

Apart from internal validation, it has also been validated in

a North American cohort with a similar c-index of 0.84.

103[2+]

is a logistic regression-derived model with nine variables (age,

sex, American Society of Anesthesiologists (ASA) score, perfor-

mance status, dyspnoea score, priority of surgery, extent of

surgery, malignant diagnosis and a composite comorbidity score,

see appendix 5). The performance of Thoracoscore exceeds that

of the logistic EuroSCORE,

104[2++]

a widely used model in

cardiac surgery.

Although a number of studies report an association with

increasing age and risk of hospital death and complica-

tions,

102[2+]

age alone should not exclude a patient from surgery

as good outcomes have been reported with appropriate case

selection.

105[2]

A recent study has reported that elderly

patients, while being aware of their lower health status

preoperatively (they had poorer ECOG performance status and

Risk assessment for surgery

Post-operative

cardiac event

Peri-operative

death

Post-operative

dyspnoea

Address any potentially modifiable risk factors & reassess

ACC/AHA* risk

stratification

+/- cardiology review

*see text

Thoracoscore

Appendix 5

Dynamic lung volumes,

transfer factor

+/- split function testing

Does the patient accept the risk in each category +/- potential impact on lifestyle?

Exclude surgery from

multi-modality management

Offer surgery as part of multi-modality

management

Yes

Figure 2 Tripartite risk assessment. ACC, American College of

Cardiology; AHA, American Heart Association.

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ASA scores compared with the younger subjects), had no

signiﬁcant differences in their quality of life at 3 months after

surgery.

106[2+]

Recommendation

<Consider using a global risk score such as Thoracoscore to

estimate the risk of death when evaluating and consenting

patients with lung cancer for surgery. [C]

2.1.2. Risk assessment for cardiovascular morbidity

Clinical assessment and risk stratiﬁcation

Myocardial infarction is a major cause of mortality after

non-cardiac surgery. The risk of cardiac death or non-fatal

myocardial infarction associated with lung resection is generally

1e5% and is ranked as intermediate risk by the revised 2007

American College of Cardiology and the American Heart Asso-

ciation (ACC/AHA) guidelines on cardiovascular evaluation

before non-cardiac surgery.

107[N/A]

The current evidence base

that guides clinical management of the speciﬁc thoracic surgical

patient with coronary artery disease is limited.

The history (including assessment of functional status),

physical examination and resting ECG are prerequisites for

cardiac risk assessment as deﬁned by the ACC/AHA in

2007.

108[N/A]

All patients with an audible murmur or unex-

plained dyspnoea should also have an echocardiogram. The ﬁrst

step in cardiac risk assessment is to identify patients with an

active cardiac condition, as they all require evaluation by

a cardiologist and correction before surgery (table 3).

In patients who do not have an active cardiac condition, risk

assessment is performed using the revised cardiac index (table 4),

a validated model with receiver operator characteristic (ROC)

area under the curve (AUC) of 0.81.

109[2++]

Patients with #2 risk factors and good cardiac functional

capacity (able to climb a ﬂight of stairs without cardiac symp-

toms) can proceed to surgery without further investigations.

Patients with poor cardiac functional capacity or with $3 risk

factors should have further investigations to screen for reversible

cardiac ischaemia (eg, exercise stress testing, exercise thallium

scan) and, if necessary, cardiology review prior to surgery.

Recommendations

<Use the American College of Cardiology guidelines 2007 as

a basis for assessing perioperative cardiovascular risk. [C]

<Avoid lung resection within 30 days of myocardial infarction.

[B]

<Seek a cardiology review in patients with an active cardiac

condition or $3 risk factors or poor cardiac functional

capacity. [C]

<Offer surgery without further investigations to patients with

#2 risk factors and good cardiac functional capacity. [B]

Optimising medical therapy

Patients with coronary disease should have their medical

therapy and secondary prophylaxis optimised well in advance of

the surgery. Although the ACC/AHA 2007 recommendations

advocate the use of perioperative

blockers, the results from

a meta-analysis of 33 trials failed to demonstrate any signiﬁcant

reduction in mortality or heart failure.

110[1++]

The results indi-

cated a decrease in non-fatal myocardial infarction and

ischaemia at the expense of an increase in non-fatal strokes.

However, precipitous withdrawal of ongoing

blocker therapy

is not recommended as this may be hazardous.

111[3]

Further

studies are required to guide the management of patients with

coexisting coronary disease who are undergoing thoracic surgery.

Recommendations

<Begin optimisation of medical therapy and secondary

prophylaxis for coronary disease as early in the patient

pathway as possible. [C]

<Continue anti-ischaemic treatment in the perioperative

period including aspirin, statins and

blockade. [B]

Revascularisation

Thoracic surgery was found to be among the highest risk oper-

ation in patients identiﬁed with suspected coronary disease in

the non-randomised CASS registry but, for patients who had

undergone prior coronary bypass surgery, the risk of death and

myocardial infarction was observed to be reduced from 5.8% and

1.9% to 2.4% and 1.2%, respectively.

112[2]

Randomised studies

in vascular surgery

113[1],114[1]

have not suggested improved

outcomes in patients randomised to elective revascularisation

prior to surgery and, as no such trials exist in thoracic surgery,

it seems reasonable to extrapolate this indirect evidence in

patients who otherwise do not have conventional indications for

revascularisation.

115

Preoperative percutaneous coronary intervention (PCI) is

associated with a major risk of acute myocardial infarction and

stent thrombosis. Should this be required prior to thoracic

surgery, the use of balloon angioplasty alone or a bare metal

Table 3 Active cardiac conditions

Condition Examples

Unstable coronary

syndromes

Unstable or severe anginadCCS class III or IV*

Recent MIy

Decompensated heart

failure

NYHA functional class IV

Worsening heart failure

New onset heart failure

Signiﬁcant

arrhythmias

High-grade atrioventricular block

Mobitz II atrioventricular block

Third degree atrioventricular heart block

Symptomatic ventricular arrhythmias

Supraventricular arrhythmias including atrial ﬁbrillation with

uncontrolled ventricular rate: HR >100 beats/min at rest

Symptomatic bradycardia

Newly recognised ventricular tachycardia

Severe heart valve

disease

Severe aortic stenosis: mean pressure gradient

>40 mm Hg, aortic valve area <1.0 cm

or symptomatic

Symptomatic mitral stenosis: progressive dyspnoea on

exertion, exertional presyncope or heart failure

*May include ‘stable’ angina in patients who are unusually sedentary.

yThe American College of Cardiology National Database Library deﬁnes recent MI as

>7 days but #1 month within 30 days.

CCS, Canadian Cardiovascular Society grading for angina pectoris; HR, heart rate;

MI, myocardial infarction; NYHA, New York Heart Association.

Table 4 Revised cardiac risk index

Number

of factors

Risk of major

cardiac complication*

0 0.4%

11%

27%

$3 11%

Risk factors: high-risk type of surgery (includes all thoracic surgery),

ischaemic heart disease, history of congestive cardiac failure, history of

cerebrovascular disease, insulin therapy for diabetes, preoperative serum

creatinine >177 mmol/l.

*Cardiac complications deﬁned as myocardial infarction, pulmonary

oedema, ventricular ﬁbrillation or primary cardiac arrest, complete heart

block. The risks have been quoted from the validation cohort.

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stent should be considered to avoid dual antiplatelet therapy

(aspirin and clopidogrel) at the time of lung resection.

Recommendations

<Discuss management of patients with a coronary stent

with a cardiologist to determine perioperative antiplatelet

management. [C]

<Consider patients with chronic stable angina and conven-

tional ACC/AHA indications for treatment (coronary artery

bypass grafting and percutaneous coronary intervention) for

revascularisation prior to thoracic surgery. [C]

2.1.3 Assessment of lung function

Evaluation of lung function is an important aspect of preoper-

ative assessment to estimate the risk of operative mortality and

impact of lung resection on quality of life, especially in relation

to unacceptable post-resection dyspnoea (see section 2.2.1.1 for

estimation of predicted postoperative lung function in relation

to extent of resection).

A large number of studies have been published addressing the

contribution of lung function to operative mortality risk, most

citing an optimum cut-off of postoperative predicted forced

expiratory volume in 1 s (FEV

) of 40%.

116[2]

However, many

were conducted with sample sizes too small to provide any

precision to ascertain the independent impact of FEV

in-hospital mortality. Results from over 15 000 patients under-

going thoracic surgery in the French registry

102[2+]

suggested

FEV

as a surrogate for performance status rather than an

independent predictive factor for perioperative death (see section

2.1.1). This section focuses primarily on the utility of lung

function as a predictor of postoperative dyspnoea.

Dynamic lung volumes and transfer factor

Both FEV

and carbon monoxide transfer factor (TLCO) have been

previously identiﬁed as important predictors of postoperative

morbidity and death.

117[2+],118[2+]

Recent data revealed poor

correlation (coefﬁcient 0.38) between FEV

and TLCO,reﬂecting

the fact that they measure very different aspects of lung func-

tion.

119[2+]

It has been suggested that lung function tests alone

overestimate the decrease in functional capacity after lung resec-

tion.

120[2+]

Studies now suggest that transfer factor is an impor-

tant predictor of postoperative morbidity despite normal

spirometry.

121[2+]

In light of this evidence, spirometry alone

cannot be considered sufﬁcient unless within normal limits in

patients who also have good exercise tolerance. The GDC there-

fore chose to recommend the measurement of TLCO in all patients.

Previous guidelines advocated a stepwise approach in assess-

ment of lung function prior to resection.

1[N/A],122[N/A],123[N/A]

The 2001 BTS guidelines were based on recommendations on

a lower limit of postoperative predicted FEV

of 40%, but studies

have since reported poor correlation between postoperative

predicted FEV

and TLCO with composite quality of life

score.

124[2+]

These data led the GDC to question the 40% lower

limit. Currently there are few data that provide guidance on

a lower limit of lung function which predicts an acceptable

degree of postoperative dyspnoea and quality of life. A study of

253 consecutive patients using a lower cut-off point of post-

operative predicted FEV

and TLCO of 30% for the selection of

patients undergoing lung resection reported an acceptable

mortality rate of 4%, and observed that actual postoperative

FEV

and TLCO are higher than predicted postoperative values

achieved using the method of segment counting.

119[2+]

However, this study did not speciﬁcally address the risk of

unacceptable postoperative dyspnoea.

The risk of postoperative morbidity is a decision that has to be

tailored to the expectations and wishes of the patient; lowering

lung function thresholds allows more patients to undergo

surgery but increases the risk of unacceptable postoperative

dyspnoea and impaired quality of life. Any recommendations

must therefore reﬂect the degree of risk rather than a ﬁrm cut-off.

Recommendations

<Measure lung carbon monoxide transfer factor (TLCO) in all

patients regardless of spirometric values. [C]

<Offer surgical resection to patients with low risk of

postoperative dyspnoea. [C]

<Offer surgical resection to patients at moderate to high risk of

postoperative dyspnoea if they are aware of and accept the

risks of dyspnoea and associated complications. [D]

2.1.3.1 Split lung function testing

Different techniques have been used to predict postoperative lung

function including spirometry, quantitative ventilation and

perfusion scintigraphy. (

120[2+],125[3],126[2]

In practice there are

difﬁculties in interpreting the contribution of individual lobes to

overall ventilation or perfusion and lack of additional information

compared with segment counting alone for patients being

considered for lobectomy.

127[2],128[2],129[3],130[2]

There is also

considerable uncertainty about the accuracy of quantitative

perfusion to predict the postoperative FEV

in patients undergoing

pneumonectomy.

127[2],129[3],131[2],132[3],133[3],134[3],135[3],136[2+]

However, scintigraphy can be especially useful where an assess-

ment has suggested that any further loss of lung function would

be unacceptable if it is shown that no further (or minimal) lung

function would be lost by operating. This applies where there may

be compression of a pulmonary artery or marked emphysema in

the lobe containing cancer.

Either ventilation

136[2+]

or perfusion scintigraphy

129[3],133[3],134[3]

can be used to predict postoperative lung function; there is no

additional beneﬁt in performing both.

136[2+]

It is important to

bear in mind that scintigraphy results may underestimate

actual postoperative values.

127[2],131[2],134[3]

Although quantitative CT scanning has been reported to be

simpler and more accurate in the prediction of postoperative

FEV

in patients undergoing pulmonary resection,

137[2],138[2]

dynamic perfusion MRI currently has the best reported test

performance compared with qualitative CT and perfusion

SPECTand may be at least as accurate as quantitative CT.

139[2+]

Recommendations

<Consider using ventilation scintigraphy or perfusion scinti-

graphy to predict postoperative lung function if a ventilation

or perfusion mismatch is suspected. [C]

<Consider using quantitative CT or MRI to predict post-

operative lung function if the facility is available. [C]

2.1.3.2 Exercise testing

To assist the prediction of surgical outcome, a range of cardio-

pulmonary exercise tests has been used. These include assess-

ments of exercise capacity such as walk tests and stair climbing

and formal measurements of cardiopulmonary function such as

measurement of peak oxygen consumption (VO

max).

6 and 12 min walk tests. Good performance on the 6 min walk

test and stair climbing have been associated with improving

surgical outcomes

140[3]

and have been reported to be similar

predictors of mortality to formal exercise testing in patients

with chronic obstructive pulmonary disease (COPD)

141[2+]

and

pulmonary hypertension.

142[2+]

The distance walked in 12 min was reported to be a reliable

approximation to formal oxygen consumption (VO

) estimation

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in patients with COPD and more closely correlated than 6, 4 or

2 min walking tests.

143[2+]

However, the distance achieved on

the 12 min walk test has not been reported to be predictive of

complications after lung resection.

116[2],144[3]

Shuttle walk test. The shuttle walk test is the distance measured

by walking a 10 m distance usually between two cones at a pace

that is progressively increased. This test has good reproducibility

and correlates well with formal cardiopulmonary exercising

testing (VO

max).

145[2e],146[4]

Previous BTS recommendations

that the inability to walk 25 shuttles classiﬁes patients as high

risk has not been reproduced by prospective study.

147[2+]

Some

authors report that shuttle walk distance may be useful to

stratify low-risk groups (ability to walk >400 m) who would

not need further formal cardiopulmonary exercise testing.

148[2+]

Stair climbing. A number of authors have reported on the asso-

ciation between stair climbing and surgical

outcomes.

140[2],149[2],150[4]151[2],152[2+]

However, the data are

difﬁcult to interpret as there is a lack of standardisation of the

height of the stairs, the ceiling heights, different parameters used

in the assessment (eg, oxygen saturations, extent of lung

resection) and different outcomes.

Cardiopulmonary exercise testing. Formal cardiopulmonary exercise

testing can be performed using treadmill (walking) or cycling and the

most studied parameter is VO

max.

116[2],124[2+],153[2],154[2+],

155[2],156[2+],157[2],158[2],159[2],160[3],161[2],162[2],163[2],164[4],

165[2],166[3],167[2+],168[2]

Acompletereviewoftheprimaryevidence

was undertaken to deﬁnetheroleofcardiopulmonaryexercise

testing. Currently, there are no good data to inform on the discrim-

inating value of VO

max to predict the development of unacceptable

postoperative dyspnoea.

Meta-analysis has conﬁrmed the ﬁnding that lower levels of

max are associated with increasing ‘complications’after lung

resection.

169[2++]

However, numerous values have been used

to deﬁne ‘prohibitive risk’for lung surgery, and the studies

are difﬁcult to interpret owing to the widespread use of

composite endpoints. When scrutinised, individual endpoints

included lobar collapse, high levels of carbon dioxide tension

(PCO

), arrhythmia and readmission to ICU. It is doubtful that

many patients would consider the risk of developing these

complications as ‘prohibitive’for surgical resection.

With sample sizes ranging from 8 to 160 patients

169[2++]

and

an average death rate of 2.6% for lobectomy, the discriminating

cut-off points for VO

max to predict death is likely to be poor

and, without valid risk adjustment, it is not possible to estimate

an independent contribution of VO

max. The arbitrary use of

cut-off values for deﬁning patient groups with no adverse

outcome carries a large degree of imprecision; for example, the

95% binomial CI of no adverse outcomes in a typical sample of

30 patients would be 0e13.6%.

Perhaps the best conducted study was the Cancer and

Leukemia Group B (CALBG) Protocol 9238 in which 403

patients were classiﬁed into low, high and very high risk groups.

Of the 68 patients in the very high risk group (VO

max <15 ml/

kg/min), surgery was only undertaken at the ‘physician’s

discretion’with an operative mortality rate of 4% and no

difference in postoperative complication rate. A central message

from this study was that, in patients in the very high risk

subgroup who underwent lung resection, the median survival

was 36 months compared with 15.8 months for those in the

same risk group who did not undergo surgical resection

(p<0.001).

170[2+]

The evidence for cardiopulmonary exercise

testing providing a useful deﬁnition of ‘high risk’is therefore

limited and there are no data available to show how it can help

predict unacceptable levels of postoperative dyspnoea.

Recommendations

<Consider using shuttle walk testing as functional assessment

in patients with moderate to high risk of postoperative

dyspnoea using a distance walked of >400 m as a cut-off for

good function. [C]

<Consider cardiopulmonary exercise testing to measure peak

oxygen consumption as functional assessment in patients

with moderate to high risk of postoperative dyspnoea using

>15 ml/kg/min as a cut-off for good function. [D]

Research recommendation

<Further studies with speciﬁc outcomes are required to deﬁne

the role of exercise testing in the selection of patients for

surgery.

2.1.4 Postoperative quality of life/dyspnoea

Lung cancer is associated with the most disruption to quality of

life compared with other chronic diseases

171[3]

or cancers,

172[3]

and the reduction may persist for more than 5 years.

173[3]

The

physical domains of quality of life deteriorate early after lung

cancer surgery but improve to near baseline by

6 months.

174[3],175[2+],176[3],177[2+],178[2+],179[2]

Pneumonec-

tomy, however, is associated with both a poorer quality of

life

179[2],180[2+]

for a longer duration

178[2+],179[2],181[3]

compared with lobectomy or bilobectomy. When pneumonec-

tomy can be avoided but there is the potential for an increased

risk of recurrence, this should be explained to patients so that

they can make a choice.

Traditional parameters used to assess the postoperative

cardiorespiratory function do not correlate well with the quality

of life reported by patients.

178[2+]

Although it has been

suggested that quality of life after surgery may be related to

cardiopulmonary ﬁtness,

182[3]

pulmonary function assessment

alone is a poor predictor of patients’perceptions of physical

disruptions in day-to-day activities.

120[2+],181[3]

Currently, it is

thought that respiratory symptom burden rather than ventila-

tory impairment contributes to diminished quality of life.

183[3]

As discrepancies may exist between patients’perception about

their residual physical and emotional status and objective

functional measures, lung function tests and exercise tests

cannot be taken as sole surrogates for quality of life evaluation.

A quality of life instrument should always be used.

Other identiﬁed risks factors for poor postoperative quality of

life include preoperative dyspnoea and the administration of

postoperative chemotherapy.

184[2]

The inﬂuence of increasing

age is less clear, with some studies reporting that elderly patients

fail to make a complete recovery

185[3]

and others reporting no

difference compared with their younger counterparts.

106[2+]

risk assessment algorithm for postoperative dyspnoea is shown

in ﬁgure 3.

Recommendations

<Avoid pneumonectomy where possible by performing bron-

choangioplastic resection or non-anatomical resection. [C]

<Avoid taking pulmonary function and exercise tests as sole

surrogates for quality of life evaluation. [C]

<When estimating quality of life, use a validated instrument. [D]

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2.2 Surgical approach

2.2.1 Pulmonary resection

2.2.1.1 Estimating post-resection lung function

Postoperative lung function is estimated by the method of

segment counting.

The total number of segments is 19 (10

right, 9 left). The total number of obstructed segments as

measured by imaging (O) is subtracted from 19 to obtain the

number of functioning segments (T).

T¼19 O

R¼Tfunctioning segments to be resected

The number of segments to be resected is: right upper lobe¼3,

middle lobe¼2, right lower lobe¼5, left upper lobe¼5 (3 upper

division, 2 lingula) and left lower lobe¼4.

The predicted postoperative (ppo) lung function is then

estimated by:

ppoValue ¼

Preoperative value

T3R

While for the majority of patients the predicted postoperative

values are estimated for lobectomy and pneumonectomy, it is

important to recognise that the ability to perform segmental

and bronchoangioplastic resections allows fewer segments to be

resected and may allow surgery to be offered to patients who

would not tolerate a lobectomy. For example, lung parenchymal

sparing surgery can be considered for patients with a tumour in

the left upper lobe that extends into the apical segment of the

lower lobe by performing a left upper lobectomy and lower apical

segmentectomy (6 segments) as opposed to pneumonectomy

(9 segments).

Recommendations

<Employ segment counting to estimate postoperative lung func-

tion as part of risk assessment for postoperative dyspnoea. [D]

<Consider patients with moderate to high risk of postoperative

dyspnoea for lung parenchymal sparing surgery. [D]

2.2.1.2 Bronchoplastic and angioplastic resections

Bronchoplastic resection refers to the resections that include

the main bronchus or bronchus intermedius, usually with

a complete ring of airway with continuity restored by the

re-anastomosis of proximal and distal airway lumens. Angio-

plastic resections refer to resections that involve the main

pulmonary artery with continuity restored by end-to-end

anastomosis or reconstruction.

Bronchoplastic resection is usually used in the setting of

low-grade airway tumours such as typical carcinoid tumour

(bronchial sleeve resection) or to spare lung parenchymadfor

example, in the setting of lung cancer to avoid pneumonectomy

(sleeve lobectomy). Lower mortality and lower local recurrence

rates have been reported in a series comparing the outcomes of

sleeve lobectomy with pneumonectomy.

186[2]

Angioplastic

resections are usually employed in the setting of lung parenchymal

sparing surgery.

187[3],188[3]

While there may be technical advantages to lung parenchymal

sparing surgery, the use of this range of procedures is generally

uncommon and may be technically challenging.

Recommendation

<Consider bronchoangioplastic procedures in suitable patients

to preserve pulmonary function. [D]

2.2.1.3 Sublobar resections

Sublobar resections generally refer to wedge resections and

segmental resections. They are usually performed as an alter-

native to lobectomy in patients with peripheral tumours with

limited pulmonary reserve. Wedge resection entails the macro-

scopic clearance of the tumour with a surrounding margin of

normal lung tissue and does not follow anatomical boundaries,

whereas segmental resection involves the division of vessels and

bronchi to a distinct anatomical segment(s). Segmental resection

removes draining lymphatics and veins and might therefore

result in lower recurrence rates, although there is no evidence

for this. Segmental resection may not always be technically

feasible and is best suited to the left upper lobe (lingula, apico-

posterior and anterior segments) and the apical segment of

both lower lobes. Sublobar resections for patients with multiple

foci of bronchioloalveolar carcinoma have been discussed in

section 1.2.6.

In the only randomised trial comparing lobectomy with

sublobar resection in patients with T1N0 tumours, the authors

report similar overall survival but increased local recurrence at

3 years with limited resection.

189[1]

Thus, sublobar resection is

only an acceptable alternative to formal lobectomy in patients

with suboptimal respiratory function.

Recommendation

<Consider patients with limited pulmonary reserve for sublobar

resection as an acceptable alternative to lobectomy. [B]

Research recommendation

<Consider randomised trials of segmental resection versus

wedge resection.

2.2.1.4 Combined lung volume reduction surgery

Randomised trials of lung volume reduction surgery report

improved lung function after surgical resection in patients with

severe heterogeneous emphysema.

190[1++],191[1+],192[1+],193[1+]

Entry criteria in the largest clinical trial to date included patients

with a preoperative FEV

of only 20e40% predicted, and lung

Figure 3 Risk assessment for post-treatment dyspnoea. FEV

, forced

expiratory volume in 1 s; LVRS, lung volume reduction surgery; ppo,

projected postoperative; TLCO, lung carbon monoxide transfer factor.

iii14 Thorax 2010;65(Suppl III):iii1eiii27. doi:10.1136/thx.2010.145938

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function was shown to improve after surgical resection. There-

fore, if lung cancer is isolated to an area of severe heterogeneous

emphysema, it seems reasonable to use criteria currently used

for lung volume reduction surgery (preoperative FEV

or TLCO

>20% predicted) to select patients for lung resection.

194[1++]

Potential beneﬁt should be both improvement in symptoms due

to emphysema and curative resection.

Recommendation

<Consider patients with concomitant lung cancer within

severe heterogeneous emphysema for lung resection based on

lung volume reduction surgery criteria. [B]

2.2.2 Lymph node management

Intuitively, surgeons should be moving towards increasing the

accuracy of cancer staging by systematic nodal dissection.

However, there is considerable variation in practice, from no

lymph node sampling through lobe-speciﬁc sampling to

systematic nodal dissection. Postoperative morbidity is usually

cited against the use of routine systematic nodal dissection and,

in response to this, the results of the American ACOSOG Z30

trial conﬁrm that patients randomised to complete mediastinal

lymphadenectomy had little added morbidity compared with

those who underwent lymph node sampling.

195[1+]

Two trials

comparing systematic nodal dissection with lymph node

sampling reported better survival in patients randomised to

systematic nodal dissection.

196[1+],197[1+]

Currently, the International Union Against Cancer (UICC)

recommends that at least six lymph node stations should

be removed or sampled before the conﬁrmation of pN0

status.

61[N/A]

Three of these nodes/stations should be medias-

tinal (including the subcarinal station) and three should be from

N1 stations.

Recommendations

<Perform systematic nodal dissection in all patients under-

going resection for lung cancer. [A]

<Remove or sample a minimum of six lymph nodes or

stations. [D]

2.3 Chemotherapy

2.3.1 Preoperative chemotherapy

Preoperative (neoadjuvant/induction) chemotherapy offers the

opportunity to downstage the tumour prior to surgery, assess

the response to chemotherapy and thereby prognosis, and

potentially control micrometastatic disease at an earlier time

point including mitigation of any pro-oncogenic effects of

surgery.

198[4],199[3]

This paradigm has been adopted in other

cancers (breast, gastric, oesophageal and rectal) with consider-

able success. However, studies with non-small cell lung cancer

have been dogged by poor accrual, perhaps due to an inherent

belief that early surgery is required to prevent disease progression.

A number of studies of preoperative chemotherapy (versus

surgery alone) were closed early due to large survival beneﬁts

reported for patients randomised to preoperative chemo-

therapy.

200[1+],201[1]

Subsequent studies continued to demon-

strate a survival advantage for preoperative chemotherapy, albeit

not reaching statistical signiﬁcance, and were likely to have been

underpowered to detect even modest effects.

202[1++]

The largest trial comparing preoperative chemotherapy and

surgery versus surgery alone randomised 519 patients,

conﬁrming the feasibility of this approach with 75% of patients

completing the full course of chemotherapy, with a progression

rate of only 2%.

203[1+]

However, there was no difference in

survival between the two groups (HR 1.02, 95% CI 0.8 to 1.31,

p¼0.86) although 64% of patients in the chemotherapy arm had

stage I disease, probably less likely to beneﬁt from chemo-

therapy.

204[N/A],205[4]

Pooled results with all other preoperative

studies by meta-analysis obtained borderline signiﬁcance with

an overall reduction in HR of death by 12% (HR 0.88, 95% CI

0.76 to 1.01, p¼0.07),

202[1++]

which is similar to that of

postoperative chemotherapy.

204[N/A]

Given the relatively small number of studies of preoperative

chemotherapy compared with the evidence base for post-

operative chemotherapy, residual uncertainties about the overall

beneﬁts on pooled data and concern of progression on treatment,

routine clinical administration of preoperative chemotherapy is

not recommended.

Recommendation

<Patients with resectable lung cancer should not routinely be

offered preoperative chemotherapy. [B]

2.3.2 Postoperative chemotherapy

Data from ﬁve multicentre studies have established the survival

beneﬁt of postoperative (adjuvant) platinum-based chemo-

therapy in selected patients.

79[1++],206[1+],207[1],208[1+],209[1+]

Currently, the evidence in this section has been collated from

clinical trials that have used the 6th Edition of the TNM clas-

siﬁcation of lung cancer, so it is important to appreciate the

limitations with respect to the application of the recommen-

dation of patients by stage criteria. There is no evidence of

beneﬁt of postoperative chemotherapy in stage IA non-small cell

lung cancer in a western population.

204[N/A]

For stage IB non-small cell lung cancer, the evidence is

controversial. Kato et al report a survival beneﬁt in patients with

adenocarcinoma treated with Uracil-Tegafor, but it is thought

that that this may reﬂect a local epiphenomenon as this study

was based on a pharmacogenetically distinct (Japanese) popu-

lation.

206[1+]

The CALGB 9633 study was terminated early due

to interim analysis demonstrating signiﬁcant improvement in

overall and disease-free survival; however, more mature data

showed no ongoing beneﬁt to overall survival, although the

beneﬁts were maintained with disease-free survival except in

tumours of >4 cm where a survival beneﬁt was observed.

210[1+]

In the IB subgroups from larger trials, no beneﬁt was observed

on individual patient data meta-analysis.

84[1+]

Treatment should

be considered on an individual basis (eg, patients with tumours

>4 cm), noting the differences between the 6th and 7th edition

TNM staging systems. It should be noted that there are few data

to guide on the use of chemotherapy in patients who are found

to have 7th edition TNM T4 tumours by virtue of additional

tumour in a different ipsilateral lobe. Such patients should,

intuitively, receive postoperative chemotherapy, but the GDC

felt there was insufﬁcient evidence to make a recommendation.

For stage II and III non-small cell lung cancer, there is a strong

body of evidence supporting the use of postoperative adjuvant

chemotherapy with an HR of overall survival ranging from 0.74

to 0.89.

84[1+],211[1+],212[1++],213[1+],214[1+],215[1+]

Despite the role

of adjuvant chemotherapy in potentially curatively resected

non-small cell lung cancer, survival remains relatively poor and

efforts aimed at accruing patients into clinical trials of novel

therapeutics are warranted.

Selection of chemotherapy regimen

Current evidence supports the use of cisplatin-based chemo-

therapy, and the Lung Adjuvant Cisplatin Evaluation (LACE)

meta-analysis suggested that cisplatin and vinorelbine may be

the superior regimen.

84[1+]

In the current postoperative trials

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3e4 cycles of chemotherapy were used with scheduling based on

4- or 3-weekly cycles depending on the chosen regimen. The

JBR10 study reported that chemotherapy was poorly tolerated

with only 48% completing four cycles of treatment.

209[1+],216[1+]

Currently, the cisplatin-vinorelbine combination is the most

widely adopted postoperative schedule in the UK. In vinorelbine-

based studies,

209[1+],217[1++]

vinorelbine was given 4-weekly with

cisplatin. However, a 3-weekly day 1 and day 8 schedule (already

used in many parts of the UK for advanced disease) may be more

convenient, better tolerated and have similar efﬁcacy.

218[1+]

Although comorbidities increase with age, pooled data from

LACE indicate that elderly patients also beneﬁt from postoperative

chemotherapy, although the starting and total dose of cisplatin

may be signiﬁcantly lower than their younger counterparts.

84[1+]

Recommendations

<Offer postoperative chemotherapy to patients with TNM 7th

edition T1e3N1e2M0 non-small cell lung cancer. [A]

<Consider postoperative chemotherapy in patients with TNM

7th edition T2e3N0M0 non-small cell lung cancer with

tumours >4 cm diameter. [B]

<Use a cisplatin-based conjunction therapy regimen in post-

operative chemotherapy. [A]

Research recommendation

<Consider further trials of novel chemotherapeutic agents in

conjunction with surgical resection.

2.4 Postoperative radiotherapy

Effective adjuvant radiotherapy is routinely offered for breast

and rectal cancer improving both local control and survival. The

effectiveness of postoperative radiotherapy (PORT) remains

controversial in patients with non-small cell lung cancer.

The PORT Meta-analysis Trialists Group analysed individual

patient data from nine randomised trials (2128 patients) that

compared surgery followed by PORTwith surgery alone.

219[1++]

The authors reported a 21% relative increase in the risk of death

at 2 years with PORT, reducing the overall survival from 55% to

48% (mortality HR 1.21, 95% CI 1.08 to 1.34, p¼0.001).

Subgroup analyses suggested that PORT could be deleterious in

terms of overall survival, predominantly among patients with

stage I/II and pN0 or pN1 disease whereas, for those with N2

disease, there was no clear evidence of an adverse effect. It is

important to note that the radiotherapy used in these trials

would be regarded as suboptimal by current standards (no CT

scan-based radiotherapy planning, two-dimensional radio-

therapy, use of cobalt-60 equipment, use of spinal cord block, use

of controversial doses and fractionations).

The PORT meta-analysis was updated in 2005 adding the

Trodella study

220[1+]

which addressed the role of PORT

in patients with stage I disease.

221[1++]

The results continued

to show PORT to be detrimental overall, with an 18%

relative increase in the risk of death at 2 years. The updated

meta-analysis conﬁrmed that there was no clear evidence of

a detriment in patients with stage III disease treated with PORT.

Two studies not included in the original or updated PORT

meta-analysis showed no treatment-related mortality, a reduc-

tion in local recurrence but no difference in survival.

222[1+],223[3]

The results from a non-randomised subanalysis of the Adjuvant

Navelbine International Trialist Association (ANITA) trial

79[1++]

and from a Surveillance Epidemiology and End Results (SEER)

retrospective study

224[2e]

suggest the beneﬁt of PORT in

stage IIIA disease.

It should be noted that the role of PORT in the context of medi-

astinal dissection as opposed to mediastinal sampling is not known.

In summary, there is no indication for PORT based on nodal

status in completely resected disease. However, this is an area of

active research and patients should be offered participation in

randomised trials wherever possible.

The role of PORT in patients with a positive resection margin

(R1 resection) is unknown as there are no randomised trials

examining the role of radiotherapy in this group of

patients.

225[3],226[4]

PORT is often given in routine practice if

pathological examination shows tumour at the resection margin

on the basis of retrospective series showing a reduction in the

local recurrence rates following PORT

227[4],228[3],229[3],230[3]231[4]

or an excess of local recurrence rates without PORT.

232[3]

However, some retrospective series have shown high local

recurrence rates despite the use of PORT.

230[3],233[4]

It should also

be noted that a retrospective study showed an adverse impact of

radiotherapy on survival in patients irradiated for positive

margins.

227[4]

Microscopic residual disease includes bronchial and extra-

bronchial residual disease. Furthermore, bronchial residual

disease can be divided into mucosal (subdivided into inﬁltrative

carcinoma or carcinoma-in-situ) and peribronchial (outside the

cartilage) microscopic residual disease. Poorer survival has been

reported in patients with peribronchial disease.

234[3]

However, it

should be noted that the majority of patients with submucosal

and peribronchial disease have N2 or N3 lymph node meta-

stasis.

227[4],233[4]

A literature review on this topic suggested that

patients with stage I and II disease and positive margins are

more likely to beneﬁt from PORT than patients with stage III

disease.

225[3]

Indeed, survival of patients with stage I and II non-

small cell lung cancer and an R1 resection of the bronchial

resection margin is signiﬁcantly worse compared with the stage-

corrected survival after radical surgery.

235[4]

In the former,

survival is limited due to local recurrence.

232[3],236[3],237[3]

The

negative effect of microscopic residual disease at the bronchial

resection margin in stage III non-small cell lung cancer is less

pronounced. These patients probably die due to disseminated

disease before local recurrence occurs.

237[3]

Similarly, patients

with submucosal and peribronchial disease are unlikely to

beneﬁt from PORT. It is not possible based on the current

literature to recommend PORT for all patients with residual

microscopic disease at the bronchial resection margin, particu-

larly for stage III non-small cell lung cancer. The potential

beneﬁt of this treatment in terms of reduction of the risk of local

recurrence rate has to be weighed carefully against the risk of

morbidity and mortality related to PORT.

After surgical resection of lung cancer, when delivering PORT

it is crucial to keep the dose to the normal lung tissue to

a minimum.

238[4]

Ideally, the volume at risk should be delineated

on the radiotherapy planning scan by a clinical oncologist

specialised in thoracic malignancies with the input of the

thoracic surgeon who performed the operation. The optimal

dose/fractionation for PORT is not known, but modern studies

suggest that a dose in the range of 50e55 Gy using conventional

fractionation should be used.

220[1+],239[4]

There are few randomised data investigating the beneﬁtof

PORT and its optimal sequencing in the context of adjuvant

chemotherapy. In adjuvant chemotherapy trials allowing the use

of PORT, the radiotherapy was delivered after completion of

adjuvant chemotherapy and did not seem to offset the beneﬁcial

effect of adjuvant chemotherapy.

79[1++],208[1+],207[1+]

Recommendations

<Postoperative radiotherapy (PORT) is not indicated after R0

complete resection. [A]

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<Consider PORT for patients with residual microscopic disease

at the resection margin where the beneﬁt of reduction in local

recurrence outweighs the risk of mortality and morbidity

related to PORT. [C]

<Use CT-planned three-dimensional conformal radiotherapy

for patients receiving PORT. [B]

<Consider PORTafter completion of adjuvant chemotherapy. [B]

Research recommendation

<Randomised trials looking at the effect of PORT in pN2

non-small cell lung cancer are recommended.

SECTION 3: RADICAL RADIOTHERAPY

3.1 Assessment of the risks of radiotherapy

3.1.1 Risks of radical radiotherapy

When planning radical radiotherapy to the thorax it is crucial to

take into account the dose delivered to the normal lung tissue,

oesophagus, spinal cord and heart. In order to ensure the

maximum sparing of normal tissues, three-dimensional treat-

ment planning is mandatory.

238[4]

However, deﬁning limits of

dose tolerated by these tissues is complex as these limits vary

according to the total dose delivered, fractionation regimen and

use of concurrent chemotherapy.

240[4],241[4],242[3],243[3]

The risk of

developing radiotherapy-induced lung toxicity can be estimated

by calculating the dose-volume histogram of the lungs, including

and mean lung dose.

244[4],245[3]

3.1.2 Lung function assessment

The greatest limitation of thoracic radiotherapy is radiotherapy-

induced lung toxicity.

244[4],245[3],246[3],247[1]

It is generally

assumed that patients with pre-existing pulmonary disease

(particularly COPD) are at increased risk of radiation

morbidity,

248[3],249[3]

but the data relating premorbid physiology

to radiation toxicity are limited. Knowledge of the risks of

radiotherapy is usually used to guide the design of radiotherapy

treatment plans rather than to decide whether or not to

treat.

250[4]

However, in many chemoradiotherapy trials,

pulmonary function limits (similar to the limits used for surgical

patients) are set for exclusion of patients.

Safe lower limits of respiratory function (FEV

or TLCO)

for radical radiotherapy have not been established and

current evidence is insufﬁcient to determine safe lower

limits.

246[3],251[3],252[3],253[3],254[3],255[3],256[3],257[3],258[3]

Radio-

therapy planning parameters such as V

and mean lung dose are

effective tools for predicting radiation pneumonitis.

244[4],245[3]

Models based on a combination of radiotherapy planning

parameters, lung function tests and lung perfusion imaging may

have a higher predictive value than dosimetry alone and should

be addressed in further research. In the interim, it seems

appropriate to use risk criteria for postoperative dyspnoea when

deciding on radical radiotherapy. The clinical oncologist will

need to discuss the risks and beneﬁts with the patient.

Recommendations

<Perform three-dimensional treatment planning in patients

undergoing radical thoracic radiotherapy. [B]

<A clinical oncologist specialising in lung oncology should

determine suitability for radical radiotherapy, taking into

account performance status and comorbidities. [D]

Research recommendation

<Clinical trials of radical radiotherapy should include measures

of lung function, outcome and toxicity.

3.2 Radiotherapy and chemoradiotherapy regimens

3.2.1 Early stage disease

Usually patients with early disease are considered for radio-

therapy owing to the unacceptable risk of perioperative death,

surgical complications or postoperative dyspnoea. In stage I

non-small cell lung cancer, conventional radiotherapy is associ-

ated with long-term survival rates of 5e30% and local failure

rates of 40e70%.

259[3],

260[4],261[3],262[4],263[4],264[3],265[3],266[3]

Cochrane review of 2003 patients with stage I/IIA non-small cell

lung cancer from 26 non-randomised studies and 563 patients

from a randomised controlled trial concluded that ‘radical

radiotherapy appears to result in a better survival than might be

expected had treatment not been given’.

267[2+],268[1+]

However,

the optimal dose and treatment technique could not be deﬁned.

A clinical trial randomised 563 patients with stage IeIIIB

non-small cell lung cancer to either CHART (54 Gy in 36 frac-

tions over 12 days) or conventionally fractionated radiotherapy

(60 Gy in 30 fractions over 6 weeks) and reported an improve-

ment in 5-year survival in favour of CHART from 7% to

12%.

268[1+]

Subgroup analysis of 169 patients with stage I/IIA

disease also showed a similar beneﬁt in favour of CHART,

improving the 2-year survival from 24% to 37%. Dose escalation

studies investigating doses >60 Gy have not established the

optimal radiotherapy dose that achieves a balance between local

control and side effects.

269[2+],270[3],271[2+]

Hypofractionated radiotherapy regimens commonly used in

the UK such as 55 Gy in 20 fractions have not been compared

with conventional fractionation in patients with early stage

medically inoperable disease. The use of hypofractionated

stereotactic radiotherapy in patients with stage I and II disease is

associated with local control rates of 80e98% at 2e5 years with

overall survival of 52e83% at 2e5 years.

272[3],273[2+],274[2+],275[2+],

276[2+],277[2],278[2+],279[3]

The largest series to date reported 5-year

overall survival of 71% and local control rate of 84%.

276[2+]

variety of doses and fractionations have been used, ranging

from 30 Gy in two fractions to 75 Gy in 22 fractions.

272[3],273[2+],

274[2+],275[2+],276[2+],277[2],278[2+],279[3]

Treatment of tumours

adjacent to a primary or secondary bronchus should be avoided as

acute toxicity and symptomatic bronchial stenosis have been

reported.

280[3],281[3],282[3]

The optimal stereotactic radiotherapy

regimen has not yet been deﬁned, nor has stereotactic radio-

therapy been compared with standard radiotherapy or surgery in

randomised trials.

Recommendations

<Offer radical radiotherapy to patients with early stage

non-small cell lung cancer who have an unacceptable risk of

surgical complications. [B]

<Consider CHARTas a treatment option in patients with early

stage non-small cell lung cancer and unacceptable risk of

surgical complications. [A]

<Consider stereotactic body irradiation in patients with early

stage non-small cell lung cancer and unacceptable risk of

surgical complications. [C]

3.2.2 Locally advanced disease

3.2.2.1 Patients eligible for concurrent chemoradiotherapy

The literature supports the use of concurrent chemo-

radiotherapy in patients aged <75 years (patients aged

>75 years have not been included in clinical trials), performance

status 0e1, with reasonable lung function, without major

comorbidities, and for whom the radiotherapy plan produces

acceptable normal tissue doses.

283[1+],284[1+],285[1+]

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A body of evidence supports that, in patients with inoperable

stage III non-small cell lung cancer, survival is improved when

cisplatin-based chemotherapy is given at the same time as

radiotherapy (concurrent chemoradiotherapy).

286[1++]

A Cochrane review reported improved survival with cisplatin-

based concurrent chemoradiotherapy among patients with

inoperable stage III non-small cell lung cancer compared with

sequential treatment (RR 0.86, 95% CI 0.78 to 0.95, p¼0.003) at

the expense of increased radiation oesophagitis.

287[1++]

Improved

3-year survival in favour of concurrent chemoradiotherapy has

also been reported by individual patient data meta-analysis

with an absolute improvement of 6.6% from 18.2% with

sequential chemoradiotherapy to 24.8% with concurrent

chemoradiotherapy.

288[1]

There is currently no consensus on the optimal chemotherapy

regimen when combined with radiotherapy. There are data to

support the combination of cisplatin-based chemotherapy. A

number of regimens have been reported to show acceptable

outcome and toxicity proﬁles.

289[1],290[3],291[1+],292[1]

The choice of chemotherapy regimen with concurrent

thoracic radiotherapy should be considered based on individual

patient characteristics, toxicity proﬁle and local experience.

A meta-analysis of six concurrent chemoradiotherapy trials

reported that increasing radiation dose improved both local

control and overall survival; however, the optimal radiotherapy

regimen has not been deﬁned.

293[2+]

To date, no studies have demonstrated any beneﬁtof

induction chemotherapy prior to concurrent chemo-

radiotherapy.

289[1],290[3]

There have been initial reports that the

addition of consolidation docetaxel after concurrent treatment

was associated with median survival in excess of 20 months in

stage III non-small cell lung cancer,

247[1],284[1+]

but this was

subsequently refuted in a phase III randomised study.

294[1]

3.2.2.2 Patients not eligible for concurrent chemoradiotherapy

Sequential chemoradiotherapy with platinum-based chemo-

therapy is the standard of care in patients with locally advanced

non-small cell lung cancer not suitable for concurrent chemo-

radiotherapy. Three systematic reviews reported superior

survival for patients treated with chemotherapy and radiation

therapy compared with radiation therapy alone.

295[1++],296[1++],

297[1+]

The Non-Small Cell Lung Cancer Collaborative Group

reported on 22 trials (3033 patients) and showed a 13% reduc-

tion in risk of death, equivalent to an absolute beneﬁtof5%at

5 years, when cisplatin-based chemotherapy was combined with

radiation therapy compared with radiation therapy alone.

295[1++],

296[1++],297[1+]

The meta-analysis did not provide an answer to the

question of the optimal radiotherapy or chemotherapy regimen.

Recommendations

<Offer chemoradiotherapy to patients with locally advanced

non-small cell lung cancer and good performance status who

are unsuitable for surgery. [A]

<Offer selected patients with good performance status

concurrent chemoradiotherapy with a cisplatin-based chemo-

therapy combination. [A]

<Offer patients unsuitable for concurrent chemoradiotherapy

sequential chemoradiotherapy. [A]

3.2.2.3 Patients not eligible for chemotherapy

Patients who are not candidates for chemotherapy because of

signiﬁcant comorbidity (eg, cardiovascular disease, renal

impairment) or poor performance status should be offered

radical radiotherapy.

The CHART trial included 60% of patients with stage IIIeIV

disease who reported improved survival with hyperfractionated

accelerated radiotherapy compared with conventional radio-

therapy.

268[1+]

However, due to logistic reasons, the CHART

regimen is not used in the majority of UK centres.

There are currently no strong data supporting hyper-

fractionated radiotherapy over conventional radiotherapy. The

hypofractionated radiotherapy regimen used widely in the UK

consisting of 55 Gy in 20 fractions has not been compared with

conventional radiotherapy in patients with locally advanced

unresectable non-small cell lung cancer.

298[4]

A German trial compared 60 Gy/40 f/2.5 w (CHARTWEL) or

66 Gy/33 f/6.5 w in patients with stage IeIII non-small cell lung

cancer (84% stage III). No signiﬁcant difference in local control

and overall survival was reported between the CHARTWEL arm

and the conventional fractionation arm.

299[1+]

Recommendation

<Consider CHART as a treatment option for patients with

locally advanced non-small cell lung cancer. [A]

3.3 Other radical treatment

In early stage disease where patients have signiﬁcant comor-

bidities or poor lung function, other radical treatments should be

considered and discussed with patients as a valid alternative to

high risk of death or postoperative dyspnoea. The evidence base

for these approaches is very limited because it has been difﬁcult

ethically to justify randomised trials. This should no longer be

the case in high-risk patients and properly designed studies in

this area are strongly recommended.

Research recommendation

<Randomised controlled trials are recommended comparing

conventional radical treatment (surgery, radical radiotherapy)

with other radical treatments where there is evidence of

efﬁcacy in case series.

3.3.1 Radiofrequency ablation

Radiofrequency ablation (RFA) for primary lung tumours has

developed as a minimally invasive treatment for both radical

treatment and palliation. It is well tolerated and complication

rates are low. The treatment can be delivered in a single session,

usually requiring only a short admission. RFA is suitable for

small tumours, usually of 3 cm diameter or less, although larger

lesions may be considered suitable in certain circumstances. The

medium- and long-term follow-up data suggest survival ﬁgures

similar to other non-surgical treatment modalities with which it

may be combined.

Patients should be selected by the MDT and are usually

non-surgical candidates because of the site of the tumour or

more commonly because of comorbidity (especially limited

cardiorespiratory function). Occasionally patients may simply

refuse major surgical treatment or radiotherapy. FDG-PET

staging prior to choosing the appropriate treatment modality

should be mandatory.

No data have been published so far on the combination of RFA

with chemotherapy for early stage non-small cell lung cancer. In

studies with attempted RFA for radical management of early stage

non-small cell lung cancer, survival data are signiﬁcantly better

than for the patient population treated with a palliative intent.

Recently reported long-term survival rates after percutaneous

RFA of stage I non-small cell lung cancer were 78% at 1 year, 57%

at 2 years, 36% at 3 years, 27% at 4 years and 27% at 5 years.

300[3]

These ﬁgures are superior to the survival rates from external beam

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radiation, showing 2- and 5-year overall survival rates of 39% and

13%.

266[3]

These promising survival data only apply to T1N0 stage

I non-small cell lung cancer. Recent advances in the ﬁeld of

radiation therapy with hypofractionated high-dose proton

beam therapy show competitive survival results,

301[3]

as does

stereotactic radiosurgery.

302[3]

A combination of RFA and

conventional radiotherapy has already shown better local control

and survival rates than radiotherapy alone, with cumulative

survival rates of 50% and 39% at the end of 2 years and 5 years,

respectively.

303[3]

3.3.2 Radical brachytherapy

Radical brachytherapy uses high-dose radiotherapy delivered via

a catheter inserted at ﬂexible bronchoscopy. Case series have

shown that this technique is curative where disease is limited to

early mucosal or submucosal disease. Lesions up to 4 mm in

depth may be suitable and this technique offers a low morbidity

alternative to surgery. Lesions suitable for this treatment are

uncommon with current surveillance techniques. The results of

randomised trials of autoﬂuorescence bronchoscopy are awaited.

Recommendations

<Consider alternative radical treatment in early stage lung

cancer in patients at high risk of morbidity and mortality

with conventional radical treatment. [D]

<Consider radical brachytherapy in patients with early invasive

mucosal or submucosal non-small cell lung cancer. [D]

SECTION 4: SMALL CELL LUNG CANCER

4.1 Chemoradiotherapy

In general, patients with limited stage small cell lung cancer

should be treated with a combination chemotherapy and

radiotherapy.

304[1+],305[1+]

The standard chemotherapy regimen

is cisplatin and etoposide.

304[1+],306[1+],307[1+]

4.1.1 Patients eligible for concurrent chemoradiotherapy

The literature supports the use of concurrent chemo-

radiotherapy in patients aged <75 years (patients aged

>75years have not been included in clinical trials), performance

status 0e1, without major comorbidities and for whom the

radiotherapy plan produces acceptable normal tissue

doses.

308[2],309[1+],310[2+],311[1+]

Clinical trials have reported better survival in patients rand-

omised to concurrent chemoradiotherapy compared with

sequential chemoradiotherapy.

308[2],309[1+]

Based on data

obtained by meta-analysis, radiotherapy should start before the

third cycle of chemotherapy but it is currently unclear if thoracic

radiotherapy should commence with the ﬁrst or the second

cycle.

312[1+],313[1+]

Options for radical radiotherapy in the concurrent setting

include twice daily thoracic radiotherapy (45 Gy in 3 weeks

310[1+]

and 40 Gy once daily delivered in 3 weeks.

311[1+]

High doses of

radiation ($66 Gy) delivered once daily concurrently with CT are

currently under evaluation.

There are limited data supporting the use of conformal

radiotherapy without elective nodal irradiation to decrease acute

toxicity, an area that should be explored within the context of

randomised trials.

314[2++],315[2]

Patients with any response to

chemotherapy or stable disease should be given prophylactic

cranial irradiation.

316[1+]

4.1.2 Patients not eligible for concurrent chemoradiotherapy

Patients who are not suitable for concurrent chemoradiotherapy,

as outlined above, but eligible for platinum-based chemotherapy

should be treated with sequential chemoradiotherapy.

Patients who are not eligible for concurrent chemotherapy

should receive 4e6 cycles of platinum-etoposide chemotherapy

followed by radical thoracic radiotherapy.

304[1++],305[1+]

and

prophylactic cranial irradiation.

316[1+]

The current UK hypo-

fractionated regimen of 50e55 Gy in 20 fractions has not been

formally compared with conventional radiotherapy.

317[3]

Recommendations

<Offer selected patients with T1e4N0e3M0 limited stage small

cell lung cancer both chemotherapy and radiotherapy. [A]

<Offer patients with T1e4N0e3M0 limited stage small cell

lung cancer and good performance status concurrent chemo-

radiotherapy. [A]

<Recommended treatment options for concurrent chemo-

radiotherapy are twice daily thoracic radiotherapy (45 Gy in

3 weeks) with cisplatin and etoposide and 40 Gy once daily

delivered in 3 weeks. [A]

<Offer patients unsuitable for concurrent chemoradiotherapy

sequential chemoradiotherapy. [A]

<Offer prophylactic cranial irradiation to patients with

response to treatment and stable disease. [A]

4.2 Surgery

The role of surgery for the treatment of limited stage small cell

lung carcinoma has been considered inappropriate due to poor

overall survival. The only trial to evaluate the role of primary

surgery concluded no beneﬁt compared with radiotherapy.

318[1]

In this study, patients were recruited based on bronchial biopsies

and complete resection was only achieved in 48% of patients,

possibly reﬂecting the unavailability of CT scanning and non-use

of mediastinoscopy. The results were further limited; on inten-

tion-to-treat analysis, more than half of the patients in the

surgical arm underwent exploratory thoracotomy or no surgery.

In view of these limitations, and as it was conducted in an

era before the use of CT, the results of this trial cannot be

extrapolated into today’s practice.

The only trial to evaluate the role of surgery after response to

initial chemotherapy concluded no beneﬁt of adjuvant

surgery.

319[1+]

Patients who were diagnosed with small cell lung

cancer on bronchoscopy, where the origin of the tumour could

be identiﬁed preoperatively and who responded to initial

chemotherapy were randomised to surgery or no additional

treatment with an overall 2-year survival of 20% in both arms.

Following from these two trials published in 1972 and 1994,

evidence for the role of surgery has been limited to case series,

some reporting 5-year survival as high as 52%.

320[3],321[3]

The

selection criteria and estimated beneﬁt for surgery in current

clinical practice remains undeﬁned, and wide differences in

opinions currently exist with regard to appropriate surgical

selection. To address the role of surgery, patients should be

considered for entry into clinical trials when applicable.

Recommendations

<Consider patients with T1e3N0e1M0 small cell lung cancer

for surgery as part of multi-modality management. [D]

<Surgical management of patients with T1e3N2M0 small cell

lung cancer should only be considered in the context of

a clinical trial. [C]

SECTION 5: PROVISION OF TREATMENT OPTIONS

In this guideline, every effort has been made to ensure pragmatic

and feasible recommendations in the NHS. It is recognised that

delivery of radical treatment in the UK is below that in many

equivalent healthcare systems. This guideline supports

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advancement of effective radical treatment and has recom-

mended some treatments that may not be available in all

institutions. It is hoped that this will encourage the develop-

ment of services so that these treatments can be accessed by all

patients. The concept of a tripartite risk assessment with this

presented to patients to make an informed choice may present

some difﬁculties if the clinician is not willing to undertake the

risks of treatment or if complexity of the proposed management

cannot be provided locally. With the development of improved

services this situation is mitigated but, in the interim, clinicians

must be prepared to refer to colleagues who can provide these

services. Where radical treatments that push the boundaries are

the subject of research, this should be discussed with patients

and referrals made for entry into clinical trials.

Recommendation

<All available treatment options, including those that are the

subject of research, should be discussed with patients and

their carers and the risks and beneﬁts presented so that they

may make an informed choice. [D]

Acknowledgements The GDC is grateful to Lisa Stirk who created search

strategies and carried out the online literature searching that formed the evidence

base for this document.

Funding Committee meeting expenses were funded by the British Thoracic Society.

Competing interests JE, DW and TW are authors of some of the research evidence

used. SaP has received honoraria from Pierre-Fabre. The other authors have no

competing interests.

Contributors EL is Chair of the Guideline Development Committee, performed initial

literature review, wrote many sections of the document and edited the document; DB

set up and chaired the initial meetings, contributed to several sections, edited the

document, produced the quick reference guide and summary of recommendations;

MB attended meetings, commented on several sections of the document and

contributed the section relating to physiology; JD attended meetings and commented

on several sections of the document; JE attended meetings and contributed

predominantly to the radiology section; KK commented on the document and wrote

the section relating to pathological issues; CF-F attended meetings and contributed to

several sections of the document, especially radical radiotherapy; AM attended

meetings and contributed to several sections of the document, especially cardiac risk

assessment; JMcG attended meetings and commented on the document; SiP

contributed the section of radiofrequency ablation; SaP authored/co-authored several

sections and commented on the drafts; NS co-authored the imaging section and

commented on the drafts; MS attended meetings and contributed to several sections

of the document, especially radical radiotherapy; DW attended meetings, wrote

sections on N2 disease and surgery and commented on the ﬁnal draft; CW

contributed to the initial set-up of the group and contributed to the writing of several

sections; TW attended meetings and contributed to the risk assessment for surgery

sections.

Provenance and peer review The Guideline Development Group held regular

meetings over the period from December 2007 to January 2010. The draft guideline

was presented at the BTS Winter Meeting in December 2009 and circulated to

a number of stakeholders for consultation and review. The revised draft guideline was

submitted to the BTS Standards of Care Committee for review and published online for

a month (in March 2010) to allow for BTS member and public consultation. All the

feedback was reviewed and discussed by the Guideline Committee and incorporated

into the revised draft guideline.

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