The Diagnosis and Treatment of Lung Cancer The

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National Collaborating Centre
for Acute Care
The Diagnosis and
Treatment of Lung Cancer
The Diagnosis and Treatment of Lung Cancer
METHODS, EVIDENCE & GUIDANCE
FEBRUARY 2005
Commissioned by the National Institute for
Clinical Excellence
i
The Diagnosis and
Treatment of Lung Cancer
METHODS, EVIDENCE & GUIDANCE
ii
THE DIAGNOSIS AND TREATMENT OF LUNG C ANCER
iii
Published by the National Collaborating Centre for Acute Care at The Royal College of Surgeons of England, 35-43 Lincoln’s Inn
Fields, London, WC2A 3PE
First published 2005
© National Collaborating Centre for Acute Care 2005
Apart from any fair dealing for the purposes of research or private study, criticism or review, as permitted under the Copyright,
Designs and Patents Act, 1988, no part of this publication may be reproduced, stored or transmitted in any form or by any means,
without the prior written permission of the publisher or, in the case of reprographic reproduction, in accordance with the terms of
licences issued by the Copyright Licensing Agency in the UK. Enquiries concerning reproduction outside the terms stated here should
be sent to the publisher at the UK address printed on this page.
The use of registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that
such names are exempt from the relevant laws and regulations and therefore for general use.
The rights of National Collaborating Centre for Acute Care to be identified as Author of this work have been asserted by them in
accordance with the Copyright, Designs and Patents Act, 1988.
ISBN 0-9549760-0-2
Citing this document: National Collaborating Centre for Acute Care, February 2005. Diagnosis and treatment of lung cancer.
National Collaborating Centre for Acute Care, London. Available from www.rcseng.ac.uk
iv
LUNG C ANCER
Foreword
Contents
GUIDELINE DEVELOPMENT GROUP
MEMBERSHIP & ACKNOWLEDGEMENTS
Lung cancer remains the UK’s commonest cause of cancer death. It is now over 50 years since Sir Richard Doll’s seminal paper linked
tobacco smoking to lung cancer. Although tobacco consumption has fallen overall since then, with a resultant fall in the male
incidence of lung cancer, smoking has increased in women, having the effect of increased lung cancer in females. Tobacco control
remains the crucial factor in reducing future lung cancer rates.
It is clear to everyone involved in lung cancer care that the public concept of this disease is characterised by much negativity. There
is too much emphasis generally on the relatively poor outcomes of treatment, there is a lack of sympathy for the patients deemed to
have brought the disease on themselves through tobacco use, and there is an impression which is unwarranted, that some
professionals have a nihilistic attitude about the treatment of lung cancer patients. There are few patient advocates, and the disease
has a low public profile in respect of media coverage, general awareness and research funding.
However, in reviewing the research, and preparing this guideline, the Development Group were encouraged by many positive
developments such as the emergence of the lung cancer specialist nurse service, the creation of Lung Cancer Multi-Disciplinary
teams, and the improvement in the evidence base for treatment, especially chemotherapy. We would also wish to highlight
developments in technology, such as FDG-PET scanning in disease staging and the use of the CHART regimen for the delivery of
radical radiotherapy in suitable patients.
3.3
VIII
STAKEHOLDER INVOLVEMENT
X
ABBREVIATIONS
XII
4
GLOSSARY OF TERMS
1
The Development Group were charged to consider “the diagnosis and treatment of lung cancer”. This is a huge topic overall. To
consider every nuance of presentation and management in this guideline would have been a formidable and impossible task. We
have not set out to write a text book of lung cancer care. Rather, we have attempted to review the main outlines of lung cancer
presentation, diagnosis and treatment, with particular emphasis on areas where there has been new evidence, or, where it seems to
us, carefully evaluated guidance, which will improve patient care.
It has been a difficult decision for the group as to which aspects to include, which to omit and which to highlight. It has been particularly
difficult too to narrow down our original 94 recommendations to 10 key items, which we believe if implemented, will have the greatest
impact on patient outcomes. We hope however that the research review in this document and the conclusions we have drawn from it will
continue the improvements which are taking place in the care of patients with this common and important disease.
v
CONTENT S
INTRODUCTION
1
1.1
BACKGROUND
1
1.2
WHAT IS A GUIDELINE?
2
1.3
REMIT OF THE GUIDELINE
2
1.4
WHAT THE GUIDELINE COVERS
2
1.5
WHAT THE GUIDELINE DOES NOT COVER
3
1.6
COLLABORATION WITH THE SCOTTISH
INTERCOLLEGIATE GUIDELINE NETWORK
3
1.7
WHO DEVELOPED THE GUIDELINE?
3
1.8
SUMMARY OF THE RECOMMENDATIONS AND
THE ALGORITHM
2
Jesme Baird,
Chair, Guideline Development Group.
3
XIV
5
4
METHODOLOGY
21
2.1
GUIDELINE METHODOLOGY
21
2.2
REVIEW OF THE CLINICAL LITERATURE
21
2.3
HIERARCHY OF CLINICAL EVIDENCE
22
2.4
HEALTH ECONOMICS METHODS
24
2.5
FORMING AND GRADING THE RECOMMENDATIONS
25
6
PATIENT DELAY IN PRESENTATION TO
GENERAL PRACTITIONERS
27
3.4
KEY SYMPTOMS AND SIGNS
28
3.5
RECOMMENDATIONS
29
DIAGNOSIS
31
4.1
INTRODUCTION
31
4.2
TECHNIQUES INCLUDED IN THIS REVIEW
31
4.3
METHODOLOGY
31
4.4
IMAGING
32
4.5
TISSUE CONFIRMATION
34
4.6
ECONOMICS OF DIAGNOSIS OF LUNG CANCER
38
4.7
RECOMMENDATIONS
42
STAGING OF LUNG CANCER
43
5.1
INTRODUCTION
43
5.2
TECHNIQUES INCLUDED IN THIS REVIEW
43
5.3
METHODOLOGY
43
5.4
STAGING CLASSIFICATIONS
43
5.5
T-STAGE ASSESSMENT
44
5.6
N-STAGE ASSESSMENT
45
5.7
M-STAGE ASSESSMENT
49
5.8
STAGING OF SMALL CELL LUNG CANCER
52
5.9
ECONOMICS OF LUNG CANCER STAGING
53
5.10 RECOMMENDATIONS
58
SURGERY WITH CURATIVE INTENT
FOR PATIENTS WITH NON-SMALL
CELL LUNG CANCER
60
6.1
INTRODUCTION
60
6.2
TECHNIQUES INCLUDED IN THIS REVIEW
60
60
ACCESS TO SERVICES
27
3.1
INTRODUCTION
27
6.3
METHODOLOGY
3.2
METHODOLOGY
27
6.4
PREOPERATIVE SELECTION OF PATIENTS WITH
NON SMALL CELL LUNG CANCER FOR SURGERY
60
vi
LUNG C ANCER
6.5
RISK OF SURGERY
6.6
SURGERY FOR STAGE I
NON SMALL CELL LUNG CANCER
6.7
SURGERY FOR STAGE II
6.8
SURGERY FOR STAGE IIB-IIIA
NON SMALL CELL LUNG CANCER (N1 DISEASE)
NON SMALL CELL LUNG CANCER (T3 DISEASE)
6.9
60
61
6.12 RECOMMENDATIONS
83
83
8.4
PATIENT ELIGIBILITY
84
8.5
CHEMOTHERAPY + ACTIVE SUPPORTIVE
CARE (ASC) VERSUS ASC
67
68
84
SECOND GENERATION VERSUS
THIRD GENERATION REGIMENS
85
8.7
CARBOPLATIN VERSUS CISPLATIN
85
8.8
THIRD GENERATION CHEMOTHERAPY TREATMENT
85
8.9
DURATION OF THERAPY IN ADVANCED
70
6.11 ECONOMICS OF SURGERY FOR NON SMALL CELL
LUNG CANCER
THE DRUGS INCLUDED IN THIS REVIEW
METHODOLOGY
8.6
6.10 SURGERY FOR STAGE IIIB (N3 AND T4 DISEASE)
NON SMALL CELL LUNG CANCER
8.2
8.3
65
SURGERY FOR STAGE IIIA
NON SMALL CELL LUNG CANCER (N2 DISEASE)
NON SMALL CELL LUNG CANCER
86
8.10 DOSAGE OF CHEMOTHERAPY TREATMENT
87
71
8.11 SECOND-LINE CHEMOTHERAPY IN
72
NON SMALL CELL LUNG CANCER
10 ENDOBRONCHIAL TREATMENT AS
RADICAL TREATMENT FOR NON
SMALL CELL LUNG CANCER
10.1 INTRODUCTION
105
10.2 TECHNIQUES INCLUDED IN THIS REVIEW
105
10.3 METHODOLOGY
105
10.4 PHOTODYNAMIC THERAPY
105
10.5 BRACHYTHERAPY
106
10.6 ELECTROCAUTERY
106
10.7 CRYOTHERAPY
107
10.8 ND YAG L ASER ABLATION
107
RADICAL RADIOTHERAPY ALONE
FOR TREATMENT OF NON-SMALL
CELL LUNG CANCER
NON SMALL CELL LUNG CANCER
74
7.1
INTRODUCTION
74
7.2
TECHNIQUES INCLUDED IN THIS REVIEW
74
7.3
METHODOLOGY
75
7.4
7.5
7.6
8.13 CONCLUSIONS
94
8.14 RECOMMENDATIONS
94
COMBINATION TREATMENT FOR
NON SMALL CELL LUNG CANCER
95
ASSESSMENT OF PATIENTS FOR RADICAL RADIOTHERAPY 75
9.1
INTRODUCTION
95
RADICAL RADIOTHERAPY FOR STAGE I AND
9.2
TECHNIQUES INCLUDED IN THIS REVIEW
96
II MEDICALLY INOPERABLE NON SMALL CELL
9.3
METHODOLOGY
96
9.4
PREOPERATIVE CHEMOTHERAPY
96
9.5
POSTOPERATIVE CHEMOTHERAPY
97
9.6
PREOPERATIVE RADIOTHERAPY
98
9.7
POSTOPERATIVE RADIOTHERAPY
98
99
LUNG CANCER PATIENTS
75
TREATMENT OF STAGE IIIA AND IIIB NON
SMALL CELL LUNG CANCER PATIENTS
77
9
7.7
ECONOMICS OF RADICAL RADIOTHERAPY FOR
NON SMALL CELL LUNG CANCER
80
9.8
POSTOPERATIVE CHEMORADIOTHERAPY
7.8
CONCLUSION
81
9.9
PRIMARY CHEMORADIOTHERAPY FOR INOPERABLE
7.9
RECOMMENDATIONS
82
NON SMALL CELL LUNG CANCER
9.10 PANCOAST TUMOURS
8
87
9.11 ECONOMICS
CHEMOTHERAPY FOR NON SMALL
CELL LUNG CANCER
83
8.1
83
INTRODUCTION
FOR
OF
9.12 RECOMMENDATIONS
131
131
12.9 SUPERIOR VENA CAVA OBSTRUCTION
131
12.10 MANAGEMENT OF BRAIN METASTASES
132
12.11 SPINAL CORD COMPRESSION
133
12.12 HYPERCALCAEMIA, BONE PAIN AND
PATHOLOGICAL FRACTURES
134
12.13 OTHER SYMPTOMS: WEIGHT LOSS, LOSS OF APPETITE,
DIFFICULTY SWALLOWING, FATIGUE AND DEPRESSION
135
12.14 ECONOMICS OF PALLIATIVE INTERVENTIONS
136
12.15 RECOMMENDATIONS
138
10.10 RECOMMENDATIONS
107
107
11 TREATMENT OF SMALL CELL LUNG CANCER
11.1
INTRODUCTION
109
109
11.2 TREATMENT TECHNIQUES INCLUDED IN THIS REVIEW
109
11.3 METHODOLOGY
109
11.4 PATIENT ELIGIBILITY
109
11.5 CHEMOTHERAPY
110
11.6 RADIOTHERAPY
113
11.7 SURGERY FOR PATIENTS WITH SCLC
116
11.8 ECONOMICS OF THE TREATMENT OF SCLC
116
11.9 RECOMMENDATIONS
118
12 PALLIATIVE INTERVENTIONS AND
SUPPORTIVE AND PALLIATIVE CARE
13 SERVICE ORGANISATION
140
13.1 INTRODUCTION
140
13.2 ISSUES EXAMINED IN THIS REVIEW
140
13.3 METHODOLOGY
140
13.4 MULTI- DISCIPLINARY TEAMS (MDTS)
140
13.5 EARLY DIAGNOSIS CLINICS
141
13.6 SPECIALIST NURSE SUPPORT
141
13.7 TIMING OF TREATMENT
142
13.8 FOLLOW UP
143
13.9 THE PATIENT’S PERSPECTIVE
147
13.10 RECOMMENDATIONS
149
14 PRIORITY AREAS FOR AUDIT
150
15 BIBLIOGRAPHY
153
120
12.1 INTRODUCTION
120
Appendicies 1-8, including the evidence tables, are on the
99
12.2 TOOLS INCLUDED IN THIS REVIEW
122
attached CD-ROM.
101
12.3 METHODOLOGY
123
12.4 COMMUNICATION
123
102
12.5 MANAGEMENT OF DYSPNOEA (BREATHLESSNESS)
127
104
12.6 MANAGEMENT OF COUGH
130
COMBINATION TREATMENT
NON SMALL CELL LUNG CANCER
12.7 MANAGEMENT OF HOARSENESS
12.8 CHEST PAIN
10.9 ECONOMICS OF ENDOBRONCHIAL THERAPY FOR
NON SMALL CELL LUNG CANCER
87
105
8.12 ECONOMICS OF CHEMOTHERAPY FOR
7
vii
CONTENT S
viii
LUNG C ANCER
GUIDELINE DEVELOPMENT GROUP MEMBERSHIP AND ACKNOWLEDGMENT S
ix
Guideline Development Group
membership and acknowledgments
Guideline Development Group
NCC-AC staff on the Guideline Development Group
Dr Jesme Baird (Chair)
Director of Patient Care, The Roy Castle Lung Cancer Foundation; patient representative
Dr Jennifer Hill
Project Manager
Ms Caroline Belchamber*
Senior Oncology Physiotherapist, Poole Hospital, Dorset; Chartered Society of Physiotherapy
Mr Ian Hunt
Clinical Consultant
Dr David Bellamy
General Practitioner, Bournemouth, Dorset; Standing Committee of General Practitioners, Royal
College of Physicians, London
Ms Veena Mazarello Paes
Research Associate
Ms Guldem Okem
Health Economist
Ms Denise Blake
Lead Pharmacist, North London Cancer Network, and Chair British Oncology Pharmacy Association;
Royal Pharmaceutical Society of Great Britain
Ms Rachel Southon
Information Scientist
Ms Louise Thomas
Research Associate
Dr Colin Clelland
Consultant Pathologist, John Radcliffe Hospital, Oxford; Royal College of Pathologists
Mr David Wonderling
Health Economist
Dr Dennis Eraut
Consultant Chest Physician, Southend Hospital, Essex; British Thoracic Society
Dr Fergus Gleeson
Consultant Radiologist, Churchill Hospital, Oxford; Royal College of Radiologists
Dr Peter Harvey
Consultant Clinical Psychologist, St James’s University Hospital, Leeds; British Psychosocial Oncology Society
Ms Patricia Hunt
Palliative Care Nurse Specialist – Lung Cancer, Royal Marsden Hospital, London; Royal College of Nursing
Ms Barbara Leung
Clinical Nurse Specialist – Lung Cancer, Birmingham, Heartlands Hospital;
Royal College of Nursing
Ms Katherine Malholtra*
Superintendent Physiotherapist, Royal Marsden Hospital, London;
Chartered Society of Physiotherapy
Ms Theresa Mann‡
Formerly Cancer Support Service Specialist Nurse, CancerBACUP; patient representative
Ms Maureen McPake
Lecturer in Radiotherapy, Glasgow Caledonian University; Society of Radiographers
Ms Catriona Moore‡
Cancer Support Service Specialist Nurse, CancerBACUP; patient representative
Dr Martin Muers
Consultant Physician, The General Infirmary at Leeds; British Thoracic Society
Dr Mike O’Doherty
Senior Lecturer in Imaging Sciences, Guys, Kings and St Thomas’ School of Medicine, and Consultant
in Nuclear Medicine, Guy’s and St Thomas’ NHS Foundation Trust, London; British Nuclear Medicine Society
Dr Nick Rowell
Clinical Oncologist, Maidstone Hospital, Kent; Royal College of Radiologists, Faculty of Clinical
Oncology, and Cochrane Lung Cancer Group
Ms Denise Silvey
Clinical Nurse Specialist – Lung Cancer, Birmingham Heartlands Hospital; Royal College of Nursing
Dr Colin Sinclair
Consultant Anaesthetist, Cardiothoracic Surgery, Royal Infirmary of Edinburgh; Royal College of
Anaesthetists
Acknowledgements
The development of this guideline was greatly assisted by the following people:
>
From the NCC-AC: Jennifer Wood, Jacqueline Rainsbury, Carlos Sharpin, Gemma Kothari, Adrian Brown, James
Barnard, Christine Pennington, Sue Langham, Artyom Sedrakyan, James Lewsey, Funsho Akinluyi, Susan Murray, Arash
Rashidian, Jan van der Meulen, Peter B. Katz and Rifna Aktar.
>
The staff and lung cancer guideline development group at the Scottish Intercollegiate Guidelines Network (SIGN)
>
Jill Cooper – HOPE the College of Occupational Therapists Specialist Section for HIV/AIDS, Oncology, Palliative Care
and Education
>
Mick Peake- Royal College of the Physicians, for assistance with drafting the section on audit criteria.
Conflict of Interests
The Guideline Development Group were asked to declare any possible conflict of interest and none that could interfere with
their work on the guideline were declared. All documentation is held by the National Collaborating Centre for Acute Care.
Guideline Review Panel
The Guideline Review Panel is an independent panel that oversees the development of the guideline and takes
responsibility for monitoring its quality. The members of the Guideline Review Panel were as follows.
Mr Peter Tebbit
National Policy Adviser, National Council for Hospice and Specialist Palliative Care
Professor Tom Treasure
Consultant Thoracic Surgeon, Guy’s and St Thomas’ Hospital, London; Society of Cardiothoracic Surgeons
Dr Andrew Wilcock
Reader and Consultant in Palliative Medicine and Medical Oncology, Royal College of Physicians
Clinical Effectiveness Unit
Mr Peter Robb (Chair)
Consultant ENT Surgeon, Epsom and St Helier University Hospitals and
The Royal Surrey County NHS Trusts
Ms Judy Williams*
Senior Physiotherapist, Poole Hospital, Dorset; Chartered Society of Physiotherapy
Joyce Struthers
Patient representative, Bedford
Professor Penella Woll
Consultant Medical Oncologist, Weston Park Hospital, Sheffield; Royal College of Physicians
Dr Peter Duncan
Consultant in Anaesthetics and Intensive Care Medicine, Royal Preston Hospital, Preston
Anne Williams
Deputy Director of Clinical Governance, Kettering General Hospital NHS Trust
* Shared seat on Guideline Development Group
‡ Shared seat on Guideline Development Group
x
LUNG C ANCER
S TAKEHOLDER INVOLVEMENT
Guerbet Laboratories Ltd
Pierre Fabre Limited
Hammersmith Hospitals NHS Trust
Princess Alexandra Hospital NHS Trust
Healthcare Commission
Roche Products Limited
Help Adolescents with Cancer
Rotherham Primary Care Trust
Help the Hospices
Roy Castle Lung Cancer Foundation
Intercollegiate Lung Cancer Group
Royal Brompton and Harefield NHS Trust
Isle of Wight Healthcare NHS Trust
Royal College of Anaesthetists
Joint Committee on Palliative Medicine
Royal College of General Practitioners
Leeds North East PCT
Royal College of General Practitioners Wales
Leeds Teaching Hospitals NHS Trust
Royal College of Nursing – Lung cancer
Lifesyne
Royal College of Nursing (RCN)
Liverpool Reviews and Implementation Group
Royal College of Pathologists
Long Term Medical Conditions Alliance
Royal College of Physicians of London
Macmillan Cancer Relief
Royal College of Psychiatrists
Maidstone and Tunbridge Wells NHS Trust
Royal College of Radiologists
Marie Curie Cancer Care
Royal College of Surgeons of England
Medeus Pharma Ltd
Royal College of Surgeons of England / Thoracic Forum
Medical Research Council Clinical Trials Unit
Royal Pharmaceutical Society of Great Britain
Medicines and Healthcare Products Regulatory Agency
(MHRA)
Salford Primary Care Trust
British Thoracic Society
BUPA
Merck Pharmaceuticals
Scottish Intercollegiate Guidelines Network (SIGN)
Cancer Research UK
Mid Essex Hospitals NHS Trust
Sheffield Teaching Hospitals NHS Trust
Cancer Services Co-ordinating Group
Mid Staffordshire General Hospitals NHS Trust
Society and College of Radiographers
Cancer Voices
National Audit Office
Society of Cardiothoracic Surgeons
CancerBACUP
National Cancer Alliance
South & Central Huddersfield PCTs
Chartered Society of Physiotherapy
National Cancer Network Clinical Directors Group
Tameside and Glossop Acute Services NHS Trust
Chesterfield and North Derbyshire Royal Hospital
NHS Trust
National Cancer Research Institute (NCRI) Clinical Studies
Group
Teenage Cancer Trust, The
Clatterbridge Centre for Oncology NHS Trust
National Council for Disabled People, Black, Minority and
Ethnic Community (Equalities)
The Dudley Group of Hospitals NHS Trust
Stakeholder Involvement
The following stakeholders registered with NICE and were invited to comment on draft versions
of these guidelines:
Abbott Laboratories Limited (BASF/Knoll)
Action on Smoking and Health (ASH)
Afiya Trust, The
Aintree Hospitals NHS Trust
Airedale General Hospital
Amersham Health
Amgen UK Ltd
Anglesey Local Health Board
Association for Palliative Medicine of
Great Britain and Ireland
Association for Respiratory Technology & Physiology
Association of Hospice and Specialist Palliative Care Social
Workers
Association of the British Pharmaceuticals Industry (ABPI)
AstraZeneca UK Ltd
Aventis Pharma
Bard Limited
Bath and North East Somerset PCT
Baxter Oncology
Bayer PLC
Bedfordshire & Hertfordshire NHS Strategic Health Authority
Biolitec Pharma Ltd (formerly QuantaNova Limited)
Birmingham Heartlands & Solihull NHS Trust
Blaenau Gwent Local Health Board
Bolton Hospitals NHS Trust
Boston Scientific Limited
Brighton & Sussex University Hospitals Trust
Bristol-Myers Squibb Pharmaceuticals Ltd
British Association for Counselling and Psychotherapy
British Association for Parenteral & Enteral Nutrition (BAPEN)
British Association of Art Therapists
British Dietetic Association
British Geriatrics Society
British Lung Foundation
British National Formulary (BNF)
British Nuclear Medicine Society
British Psychological Society, The
British Psychosocial Oncology Society
College of Occupational Therapists
Countess of Chester Hospitals NHS Trust
xi
Sanofi-Synthelabo
Thames Valley Strategic Health Authority
The Medway NHS Trust
Craven Harrogate & Rural District PCT
National Council for Hospice and Specialist Palliative Care
Services
Department of Health
National Lung Cancer Forum for Nurses
Eisai Limited
National Patient Safety Agency
Elan Pharmaceuticals Ltd
National Public Health Service - Wales
Eli Lilly and Company Ltd
Newcastle Upon Tyne Hospitals NHS Trust
Faculty of Public Health
NHS Modernisation Agency, The
Gateshead Health NHS Trust
NHS Quality Improvement Scotland
GE Health Care
North Glamorgan NHS Trust – Merthyr Tydfil
General Medical Council
Novartis Pharmaceuticals UK Ltd
Welsh Assembly Government (formerly National Assembly for
Wales)
General Practice Airways Group Limited
Ortho Biotech
Wessex Cancer Trust
General Practice and Primary Care
Papworth Hospital NHS Trust
GlaxoSmithKline UK
Pfizer Limited
The National Association of Assistants in
Surgical Practice
The Royal Society of Medicine
The Royal West Sussex Trust
UK Pain Society
University College London Hospital NHS Trust
Velindre NHS Trust
Wareney PCT
xii
LUNG C ANCER
ABBREVIATIONS
Abbreviations
ASC
Active Supportive Care
BSC
Best Supportive Care
BTS
British Thoracic Society
CCOPGI
Cancer Care Ontario Practice Guidelines Initiative
CEA
Cost Effectiveness Analysis
CHART
Continuous Hyperfractionated Accelerated Radiotherapy
CI
Confidence Interval
CT
Computerised tomography
CWU
Conventional Work Up
CXR
Chest X-Ray
DEALE
Declining Exponential Approximation of Life Expectancy
DS
Diagnostic Studies
ED
Extensive disease
EUS
Endobronchial ultrasound
EUS-NA
Endoscopic ultrasound guided needle aspiration
FDG
18
FNA
Fine needle aspiration
FP
False positive
GDG
Guideline Development Group
GP
General Practitioner
GPP
Good Practice Point
HRQL
Health Related Quality of Life
HTA
Health Technology Assessment
HTBS
Health Technology Board for Scotland
ICER
Incremental Cost Effectiveness Ratio
IP
Inpatient
LD
Limited disease
LN
Lymph node
F-deoxyglucose
LY
Life-year
MDT
Multidisciplinary Team
MRC
Medical Research Council
MRI
Magnetic Resonance Imaging
MVP
mitomycin-vindecine-cisplatin
NCC-AC
National Collaborating Centre for Acute Care
ND-YAG
Neodymium-Yttrium Aluminum Garnet
NHS
National Health Service
NICE
National Institute for Clinical Excellence
NNH
Number needed to harm
NNT
Number needed to treat
NPV
Negative predictive value
NSCLC
Non-Small Cell Lung Cancer
OP
Outpatient
OR
Odds ratio
PCI
Prophylactic Cranial Irradiation
PDT
Photodynamic therapy
PET
Positron Emission Tomography
PPV
Positive predictive value
PS
Performance status
QALY
Quality adjusted life year
RCT
Randomised controlled trial
RT
Radiotherapy
SCLC
Small Cell Lung Cancer
SIGN
Scottish Intercollegiate Guidelines Network
SLN
Subcarinal Lymph Nodes
SPECT
Single Photon Emission Computerised Tomography
SPN
Solitary Pulmonary Nodules
SROC
Summary Receiver Operating Characteristic
SVCO
Superior vena cava obstruction
TTNA
Transthoracic needle aspiration
UK
United Kingdom
US
Ultrasound
VATS
Video assisted thoracoscopy
WHO
World Health Organisation
xiii
xiv
LUNG C ANCER
GLOSSARY OF TERMS
Glossary of Terms
Case report (or case study)
Detailed report on one patient (or case), usually covering the course of that person’s
disease and their response to treatment.
Case series
Description of several cases of a given disease, usually covering the course of the disease
and the response to treatment. There is no comparison (control) group of patients.
Cohort study
An observational study that takes a group (cohort) of patients and follows their progress
over time in order to measure outcomes such as disease or mortality rates and make
comparisons according to the treatments or interventions that patients received. Thus
within the study group, subgroups of patients are identified (from information collected
about patients) and these groups are compared with respect to outcome, e.g. comparing
mortality between one group that received a specific treatment and one group which did
not (or between two groups that received different levels of treatment). Cohorts can be
assembled in the present and followed into the future (a ‘concurrent’ or ‘prospective’
cohort study) or identified from past records and followed forward from that time up to
the present (a ‘historical’ or ‘retrospective’ cohort study). Because patients are not
randomly allocated to subgroups, these subgroups may be quite different in their
characteristics and some adjustment must be made when analysing the results to ensure
that the comparison between groups is as fair as possible.
Combined modality
Use of different treatments in combination (for example surgery, chemotherapy and
radiotherapy used together).
Co-morbidity
Co-existence of a disease or diseases in the people being studied in addition to the health
problem that is the subject of the study.
Confidence interval
A way of expressing certainty about the findings from a study or group of studies, using
statistical techniques. A confidence interval describes a range of possible effects (of a
treatment or intervention) that are consistent with the results of a study or group of
studies. A wide confidence interval indicates a lack of certainty or precision about the true
size of the clinical effect and is seen in studies with too few patients. Where confidence
intervals are narrow they indicate more precise estimates of effects and a larger sample of
patients studied. It is usual to interpret a ‘95%’ confidence interval as the range of effects
within which we are 95% confident that the true effect lies.
Confounder or confounding factor
Something that influences a study and can contribute to misleading findings if it is not
understood or appropriately dealt with. For example, if a group of people exercising
regularly and a group of people who do not exercise have an important age difference
then any difference found in outcomes about heart disease could well be due to one
group being older than the other rather than due to the exercising. Age is the
confounding factor here and the effect of exercising on heart disease cannot be assessed
without adjusting for age differences in some way.
Control group
A group of patients recruited into a study that receives no treatment, a treatment of
known effect, or a placebo (dummy treatment) - in order to provide a comparison for a
group receiving an experimental treatment, such as a new drug.
Amended from a glossary produced by the Patient Involvement Unit, NICE.
Absolute risk
Measures the probability of an event or outcome occurring (e.g. an adverse reaction to the
drug being tested) in the group of people under study. Studies that compare two or more
groups of patients may report results in terms of the Absolute Risk Reduction.
Absolute Risk Reduction (ARR)
The ARR is the difference in the risk of an event occurring between two groups of patients
in a study – for example if 6% of patients die after receiving a new experimental drug and
10% of patients die after having the old drug treatment then the ARR is 10% - 6% =
4%. Thus by using the new drug instead of the old drug 4% of patients can be prevented
from dying. Here the ARR measures the risk reduction associated with a new treatment.
See also Absolute risk.
Adjuvant chemotherapy
The use of chemotherapy after initial treatment by surgery and/or radiotherapy.
Adjuvant radiotherapy
The use of radiotherapy after treatment by surgery.
Benign
Non-cancerous. Does not metastasise and treatment or removal is curative.
Bias
Influences on a study that can lead to invalid conclusions about a treatment or
intervention. Bias in research can make a treatment look better or worse than it really is.
Bias can even make it look as if the treatment works when it actually doesn’t. Bias can
occur by chance or as a result of systematic errors in the design and execution of a study.
Bias can occur at different stages in the research process, e.g. in the collection, analysis,
interpretation, publication or review of research data.
Blinding or masking
The practice of keeping the investigators or subjects of a study ignorant of the group to
which a subject has been assigned. For example, a clinical trial in which the participating
patients or their doctors are unaware of whether they (the patients) are taking the
experimental drug or a placebo (dummy treatment). The purpose of ‘blinding’ or ‘masking’
is to protect against bias.
Case-control study
A study that starts with the identification of a group of individuals sharing the same
characteristics (e.g. people with a particular disease) and a suitable comparison (control)
group (e.g. people without the disease). All subjects are then assessed with respect to
things that happened to them in the past, e.g. things that might be related to getting the
disease under investigation. Such studies are also called retrospective as they look back in
time from the outcome to the possible causes.
xv
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LUNG C ANCER
Controlled clinical trial (CCT)
Cost benefit analysis
GLOSSARY OF TERMS
A study testing a specific drug or other treatment involving two (or more) groups of
patients with the same disease. One (the experimental group) receives the treatment that
is being tested, and the other (the comparison or control group) receives an alternative
treatment, a placebo (dummy treatment) or no treatment. The two groups are followed up
to compare differences in outcomes to see how effective the experimental treatment was.
A CCT where patients are randomly allocated to treatment and comparison groups is
called a randomised controlled trial.
A type of economic evaluation where both costs and benefits of health care treatment are
measured in the same monetary units. If benefits exceed costs, the evaluation would
recommend providing the treatment.
Cost-effectiveness
Value for money
Cost effectiveness analysis
A type of economic evaluation that compares the costs and benefits of different
treatments. In cost-effectiveness analysis benefits are measured in clinical outcome units,
for example, additional heart attack prevented, life years gained, etc. When a new
treatment is compared with current care, its additional costs divided by its additional
benefits is called the cost effectiveness ratio.
Cost utility analysis
Cross-sectional study
A special form of cost effectiveness analysis where benefit is measured in quality adjusted life
years. A treatment is assessed in terms of its ability to extend or improve the quality of life.
xvii
Evidence based clinical practice
Evidence based clinical practice involves making decisions about the care of individual
patients based on the best research evidence available rather than basing decisions on
personal opinions or common practice (which may not always be evidence based).
Evidence based clinical practice therefore involves integrating individual clinical expertise
and patient preferences with the best available evidence from research
Evidence table
A table summarising the results of a collection of studies which, taken together, represent the
evidence supporting a particular recommendation or series of recommendations in a guideline.
Exclusion criteria
See Selection criteria.
Focus group
A qualitative research technique. It is a method of group interview or discussion of
between 6–12 people focused around a particular issue or topic. The method explicitly
includes and uses the group interaction to generate data.
Gold standard
A method, procedure or measurement that is widely accepted as being the best available.
Good Performance Status
Performance Status 0/ 1 WHO/ Zubrod scale or 80-100 Karnofsky scale (see Appendix 2,
Figure 4)
Gray (Gy)
Unit of absorbed radiation dose
Health economics
The study of the allocation of scarce resources among alternative health care treatments.
Health economists are concerned with both increasing the average level of health in the
population and improving the distribution of health.
Heterogeneity
Or lack of homogeneity. The term is used in meta-analyses and systematic reviews when
the results or estimates of effects of treatment from separate studies seem to be very
different – in terms of the size of treatment effects or even to the extent that some
indicate beneficial and others suggest adverse treatment effects. Such results may occur as
a result of differences between studies in terms of the patient populations, outcome
measures, definition of variables or duration of follow-up.
Homogeneity
This means that the results of studies included in a systematic review or meta analysis are
similar and there is no evidence of heterogeneity. Results are usually regarded as homogeneous
when differences between studies could reasonably be expected to occur by chance.
The observation of a defined set of people at a single point in time or time period –
a snapshot. (This type of study contrasts with a longitudinal study which follows a set of
people over a period of time)
Decision analysis
A systematic way of reaching decisions, based on evidence from research. This evidence is
translated into probabilities, and then into diagrams or decision trees which direct the
clinician through a succession of possible scenarios, actions and outcomes.
Diagnostic study
A study to assess the effectiveness of a test or measurement in terms of its ability to
accurately detect or exclude a specific disease.
Double blind study
A study in which neither the subject (patient) nor the observer (investigator/clinician) is
aware of which treatment or intervention the subject is receiving. The purpose of blinding
is to protect against bias.
Inclusion criteria
See Selection criteria.
Economic evaluation
Economic evaluation is a comparative analysis of costs and consequences of each
alternative in order to provide an explicit criteria for making choices.
In situ
A cancer that is in the natural place, is non-invasive without invading neighbouring tissue
Elective
Name for clinical procedures that are regarded as advantageous to the patient but not urgent.
Intervention
Healthcare action intended to benefit the patient, e.g. drug treatment, surgical procedure,
psychological therapy, etc.
Evidence based
The process of systematically finding, appraising, and using research findings as the basis
for clinical decisions.
Life year
A measure of health outcome which shows the number of years of remaining life expectancy
Longitudinal study
A study of the same group of people at more than one point in time. (This type of study
contrasts with a cross sectional study which observes a defined set of people at a single
point in time)
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GLOSSARY OF TERMS
Lymph
Almost colourless fluid that baths body tissues and is carried by lymphatic vessels.
Contains cells that help fight infection and disease.
Lymph nodes or glands
Small bean-shaped organs located along the lymphatic system. Nodes filter bacteria or
cancer cells that might travel through the lymphatic system.
xix
Performance status
A measure of how well a patient is able to perform ordinary tasks and carry out daily
activities. (PS WHO score of 0=asymptomatic, 4=bedridden, or a Karnofsky score of
0=dead, 100=asymptomatic.
Pilot study
A small scale ‘test’ of the research instrument. For example, testing out (piloting) a new
questionnaire with people who are similar to the population of the study, in order to
highlight any problems or areas of concern, which can then be addressed before the full
scale study begins.
Malignant
Cancerous. Malignant tumours can invade and destroy surrounding tissue and have the
capacity to spread
Meta analysis
Results from a collection of independent studies (investigating the same treatment) are
pooled, using statistical techniques to synthesise their findings into a single estimate of a
treatment effect. Where studies are not compatible e.g. because of differences in the study
populations or in the outcomes measured, it may be inappropriate or even misleading to
statistically pool results in this way. See also Systematic review & Heterogeneity.
Placebo
Placebos are fake or inactive treatments received by participants allocated to the control
group in a clinical trial which are indistinguishable from the active treatments being given
in the experimental group. They are used so that participants are ignorant of their
treatment allocation in order to be able to quantify the effect of the experimental
treatment over and above any placebo effect due to receiving care or attention.
Metastasis
Spread of cancer from one part of the body to another.
Placebo effect
A beneficial (or adverse) effect produced by a placebo and not due to any property of the
placebo itself.
Negative lymph nodes
Lymph nodes showing no signs of cancer.
Positive lymph nodes
Lymph nodes that contain cancer cells.
Power
See Statistical power.
Neoadjuvant chemotherapy
Chemotherapy that is given before the treatment of a primary tumour with the aim of
improving the results and preventing the development of metastases.
Non-experimental study
A study based on subjects selected on the basis of their availability, with no attempt
having been made to avoid problems of bias.
Primary care
Healthcare delivered to patients outside hospitals. Primary care covers a range of services
provided by GPs, nurses and other health care professionals, dentists, pharmacists and opticians.
NSCLC
Non- small cell lung cancer
Primary tumour
Original site of the cancer.
Number Needed to Treat (NNT)
This measures the impact of a treatment or intervention. It states how many patients need
to be treated with the treatment in question in order to prevent an event which would
otherwise occur. E.g. if the NNT=4, then 4 patients would have to be treated to prevent
one bad outcome. The closer the NNT is to 1, the better the treatment is. Analogous to the
NNT is the Number Needed to Harm (NNH), which is the number of patients that would
need to receive a treatment to cause one additional adverse event. e.g. if the NNH=4,
then 4 patients would have to be treated for one bad outcome to occur.
Prognostic factor
Patient or disease characteristics, e.g. age or co-morbidity, which influence the course of
the disease under study. In a randomised trial to compare two treatments, chance
imbalances in variables (prognostic factors) that influence patient outcome are possible,
especially if the size of the study is fairly small. In terms of analysis these prognostic
factors become confounding factors.
Prospective study
A study in which people are entered into the research and then followed up over a period of time
with future events recorded as they happen. This contrasts with studies that are retrospective.
P value
If a study is done to compare two treatments then the P value is the probability of
obtaining the results of that study, or something more extreme, if there really was no
difference between treatments. (The assumption that there really is no difference between
treatments is called the ‘null hypothesis’.) Suppose the P-value was P=0.03. What this
means is that if there really was no difference between treatments then there would only
be a 3% chance of getting the kind of results obtained. Since this chance seems quite low
we should question the validity of the assumption that there really is no difference
between treatments. We would conclude that there probably is a difference between
treatments. By convention, where the value of P is below 0.05 (i.e. less than 5%) the result
is seen as statistically significant. Where the value of P is 0.001 or less, the result is seen
as highly significant. P values just tell us whether an effect can be regarded as statistically
significant or not. In no way do they relate to how big the effect might be, for which we
need the confidence interval.
Observational study
Odds ratio
In research about diseases or treatments, this refers to a study in which nature is allowed
to take its course. Changes or differences in one characteristic (e.g. whether or not people
received a specific treatment or intervention) are studied in relation to changes or
differences in other(s) (e.g. whether or not they died), without the intervention of the
investigator. There is a greater risk of selection bias than in experimental studies.
Odds are a way of representing probability, especially familiar for betting. In recent
years odds ratios have become widely used in reports of clinical studies. They provide
an estimate (usually with a confidence interval) for the effect of a treatment. Odds are
used to convey the idea of ‘risk’ and an odds ratio of 1 between two treatment groups
would imply that the risks of an adverse outcome were the same in each group. For
rare events the odds ratio and the relative risk (which uses actual risks and not odds)
will be very similar.
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Qualitative research
Quality adjusted life years (QALYS)
Quantitative research
GLOSSARY OF TERMS
Qualitative research is used to explore and understand people’s beliefs, experiences,
attitudes, behaviour and interactions. It generates non-numerical data, e.g. a patient’s
description of their pain rather than a measure of pain. In health care, qualitative
techniques have been commonly used in research documenting the experience of chronic
illness and in studies about the functioning of organisations. Qualitative research
techniques such as focus groups and in depth interviews have been used in one-off
projects commissioned by guideline development groups to find out more about the views
and experiences of patients and carers.
A measure of health outcome. QALYS are calculated by estimating the number of years of
life gained from a treatment and weighting each year with a quality of life score between
zero and one.
SCLC
Small Cell Lung Cancer
Scottish Intercollegiate
Guidelines Network (SIGN)
SIGN was established in 1993 to sponsor and support the development of evidence-based
clinical guidelines for the NHS in Scotland.
Secondary care
Care provided in hospitals.
Selection criteria
Explicit standards used by guideline development groups to decide which studies should
be included and excluded from consideration as potential sources of evidence.
Sensitivity
In diagnostic testing, it refers to the chance of having a positive test result given that you
have the disease. 100% sensitivity means that all those with the disease will test positive,
but this is not the same the other way around. A patient could have a positive test result
but not have the disease – this is called a ‘false positive’. The sensitivity of a test is also
related to its ‘negative predictive value’ (true negatives) – a test with a sensitivity of 100%
means that all those who get a negative test result do not have the disease. To fully judge
the accuracy of a test, its Specificity must also be considered.
Specificity
In diagnostic testing, it refers to the chance of having a negative test result given that you
do not have the disease. 100% specificity means that all those without the disease will test
negative, but this is not the same the other way around. A patient could have a negative test
result yet still have the disease – this is called a ‘false negative’. The specificity of a test is
also related to its ‘positive predictive value’ (true positives) – a test with a specificity of
100% means that all those who get a positive test result definitely have the disease. To fully
judge the accuracy of a test, its Sensitivity must also be considered.
Staging
Process of describing to what degree cancer has spread from its original site to another
part of the body. Staging involves clinical, surgical and pathology assessments.
Statistical power
The ability of a study to demonstrate an association or causal relationship between two
variables, given that an association exists. For example, 80% power in a clinical trial means that
the study has a 80% chance of ending up with a P value of less than 5% in a statistical test
(i.e. a statistically significant treatment effect) if there really was an important difference (e.g.
10% versus 5% mortality) between treatments. If the statistical power of a study is low, the
study results will be questionable (the study might have been too small to detect any
differences). By convention, 80% is an acceptable level of power. See also P value.
Research that generates numerical data or data that can be converted into numbers, for
example clinical trials or the national Census which counts people and households.
Random allocation or Randomisation A method that uses the play of chance to assign participants to comparison groups in a
research study, for example, by using a random numbers table or a computer-generated
random sequence. Random allocation implies that each individual (or each unit in the case
of cluster randomisation) being entered into a study has the same chance of receiving
each of the possible interventions.
Randomised controlled trial (RCT)
A study to test a specific drug or other treatment in which people are randomly assigned
to two (or more) groups: one (the experimental group) receiving the treatment that is
being tested, and the other (the comparison or control group) receiving an alternative
treatment, a placebo (dummy treatment) or no treatment. The two groups are followed up
to compare differences in outcomes to see how effective the experimental treatment was.
(Through randomisation, the groups should be similar in all aspects apart from the
treatment they receive during the study.)
xxi
Relative risk
A summary measure which represents the ratio of the risk of a given event or outcome
(e.g. an adverse reaction to the drug being tested) in one group of subjects compared to
another group. When the ‘risk’ of the event is the same in the two groups the relative risk
is 1. In a study comparing two treatments, a relative risk of 2 would indicate that patients
receiving one of the treatments had twice the risk of an undesirable outcome than those
receiving the other treatment. Relative risk is sometimes used as a synonym for risk ratio.
Retrospective study
A retrospective study deals with the present/ past and does not involve studying future
events. This contrasts with studies that are prospective.
Summary Receiver Operating
Characteristic curve (sROC)
Risk ratio
Ratio of the risk of an undesirable event or outcome occurring in a group of patients
receiving experimental treatment compared with a comparison (control) group. The term
relative risk is sometimes used as a synonym of risk ratio.
A statistical method to combine the results of multiple studies assessing the diagnostic
performance of a test. It takes into account the relationship between sensitivity and
specificity among the individual studies by plotting the true positive rate (sensitivity)
against the false positive rate (1-specificity)
Systematic review
A part of the study’s target population from which the subjects of the study will be
recruited. If subjects are drawn in an unbiased way from a particular population, the
results can be generalised from the sample to the population as a whole.
A review, in which evidence from scientific studies has been identified, appraised and
synthesised in a methodical way according to predetermined criteria. May or may not
include a meta-analysis.
TNM classification
TNM classification provides a system for staging the extent of cancer. T refers to the size
of the primary tumour. N refers to the involvement of the lymph nodes. M refers to the
presence of metastases or distant spread of the disease.
Sample
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INTRODUCTION
1
1 Introduction
1.1
Background
1.1.1
Epidemiology
Lung cancers are classified into two main categories:
small-cell lung cancers (SCLC), which account for
approximately 20% of cases, and non-small cell lung
cancers (NSCLC), which account for the other 80%.
Non-small cell lung cancer includes squamous cell
(35%), adenocarcinomas (27%) and large cell (10%)
carcinomas6. In practice however, not all patients
receive histological confirmation of the cell type of
their disease. Figures recorded by NYCRIS (North
Yorkshire Cancer Registry and Information Service),
from a registry-based population study conducted
during 1986-1994, showed that 55% were
confirmed as NSCLC, 11% as SCLC and 34% had no
histological confirmation of cell type7.
In 2002, lung cancer accounted for nearly 29,000
deaths in England and Wales. It is the most common
cause of cancer death for men, who account for 60%
of lung cancer cases. In women it is the second most
common cause of cancer death after breast cancer1.
Past trends of lung cancer incidence reflect the
changes in smoking habits over the last century2.
The age-standardised incidence rates show a long-term
decrease in cases among males but an increase in
cases among women. Under the age of 40 lung cancer
is rare, but incidence rises sharply with age and the
most common age group at diagnosis is 70-742.
Survival rates for lung cancer are very poor. In
England, for patients diagnosed between 1993 and
1995 and followed up to 2000, 21.4% of men and
21.8% of women with lung cancer were alive one
year after diagnosis and only 5.5% of both men
and women were alive after five years3. For Wales,
the latest figures on survival, for people diagnosed
between 1994 and 1998, showed 1-year relative
survival of 20.5% for both males and females and
five year relative survival figures of 6% for both
males and females4. These figures are around 5
percentage points lower than the European average
and 7-10 percentage points lower than the USA.
Five year survival rates vary between different
English health authorities, ranging from 2.2% to
8.9%, for patients diagnosed with lung cancer
between 1993 and 19955. Although 1-year survival
has improved by about five percentage points since
the early 1970s, there has been little improvement
in 5-year survival.
1.1.2
Risk Factors
Smoking is by far the greatest cause of lung cancer,
accounting for an estimated 85 to 90% of cases, but
the precise relationship with smoking is probably
complex6. The age-adjusted relative risk of developing
lung cancer, for people that smoke more than 20
cigarettes a day, is 20 times that compared with
lifelong non-smokers (or a 2000% increased risk), and
many studies have reported that women who smoke
are more likely to develop lung cancer than male
smokers6. Stopping smoking earlier is associated with
greater benefit8, stopping before middle age means
that an individual can avoid almost 90% of the risk9,
although the risk never drops to the level it was prior
to smoking. A number of studies, presented in a recent
review10, have shown the danger of environmental
tobacco smoke or passive smoking and have examined
its links with lung cancer. It has been estimated that in
the UK passive smoking could account for several
hundred cases of lung cancer each year11. A metaanalysis of 37 studies of non-smokers who lived with
smokers showed an increased risk of lung cancer of
24% (95% CI 13-36%)12.
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LUNG C ANCER
A number of other occupational and environmental
factors are risk factors for lung cancer. Asbestos is
the greatest occupational risk factor13. Other known
occupational carcinogens include arsenic, beryllium,
bis (chloromethyl) ether, cadmium, chromium, nickel,
polycyclic aromatic hydrocarbons, vinyl chloride and
radon. Radon is also an environmental carcinogen as
it is the decay product of naturally occurring
uranium in the earth and can accumulate in
buildings. Radon is estimated to account for around
2000 lung cancer deaths per year in the UK, or
about 6% of the total14. Other studies have
identified air pollution, poor nutrition, previous and
coexisting lung disease and genetic predisposition as
risk factors for lung cancer.
1.2
INTRODUCTION
1.3
> is relevant to multidisciplinary teams involved in
the diagnosis and care of patients with suspected
or diagnosed lung cancer. These teams may
include, for example, general physicians and
nurses, chest physicians, palliative care
physicians, clinical and medical oncologists,
thoracic surgeons, geriatricians, cellular
pathologists, radiologists, radiographers,
occupational therapists, specialist nurses,
physiotherapists, dietitians, pharmacists and
clinical psychologists.
The following remit was received from the
Department of Health and National Assembly for
Wales in July 2001 as part of NICE’s 6th wave
programme of work:
“To prepare clinical guidelines for the NHS in
England and Wales for the diagnosis and
treatment of lung cancer. This is to supplement
the existing service guidance published by the
Department of Health in 1998 and this
commission replaces the earlier commission to
update that guidance”.
1.5
The previous cancer service publications referred to,
in this remit, is the NHS Executive (1998) Guidance
on commissioning cancer services: improving
outcomes in lung cancer: the research evidence.
London: Department of Health15.
What is a guideline?
Guidelines are recommendations for the care of
individuals in specific clinical conditions or
circumstances – from prevention and self-care though
primary and secondary care to more specialised services.
Clinical guidelines are based on the best available
evidence, and are produced to help health care
professionals and patients make informed choices about
appropriate health care. While guidelines assist the
practice of healthcare professionals, they do not replace
their knowledge and skills.
Clinical guidelines for the NHS in England and Wales
are produced as a response to a request from the
Department of Health and the Welsh Assembly
Government. They select topics for guideline
development and before deciding whether to refer a
particular topic to the National Institute for Clinical
Excellence (NICE) they consult with the relevant patient
bodies, professional organisations and companies. Once
a topic is referred, NICE then commissions one of seven
National Collaborating Centres to produce a guideline.
The Collaborating Centres are independent of
government and comprise partnerships between a
variety of academic institutions, health profession
bodies and patient groups.
Remit of the Guideline
The NCC-AC was solely responsible for reviewing the
literature on diagnosis and the treatment of NSCLC,
while SIGN was solely responsible for the literature
on the treatment of SCLC, palliative care, follow up
and communication. Both the NCC-AC and SIGN
reviewed the literature (independently) on
background information, access to services, staging,
palliative interventions, and service organisation.
TABLE 1:
What the guideline does not cover
The guideline will not cover:
It was expected that this previous work should be
“updated to reflect recent evidence”, in the form of a
clinical guideline.
>
The care of patients with mesothelioma
>
The care of patients with lung metastases from
cancer arising from outside the lung
>
The prevention of lung cancer.
3
Division of work between
NCC-AC and SIGN
NCC-AC
SIGN
Background Information
Background Information
Access to Services
Access to Services
Diagnosis
Staging
Staging
Treatment of NSCLC
The recommendations in this guideline were arrived
at following careful consideration of the available
evidence.
1.4
What the guideline covers
This guideline:
>
>
>
is relevant for adults over the age of 18 years
who are suspected as having, or are diagnosed
with, lung cancer.
addresses diagnosis, staging and treatment.
Where there are issues specific to lung cancer, it
will also address palliative care, psychological
impact and day-to-day functioning.
offers guidance on care provided in primary care,
secondary care, outpatient and day treatment
services, tertiary care, specialist services and the
interface with the voluntary and social services
where relevant.
1.6
Collaboration with the Scottish
Intercollegiate Guideline Network
Treatment SCLC
In 2002, NICE received a referral from the
Department of Health and Welsh Assembly
Government to produce a guideline on the diagnosis
and management of lung cancer. This occurred at
approximately the same time that the Scottish
Intercollegiate Guideline Network (SIGN) was
preparing a similar guideline on lung cancer. In order
to avoid duplication of work, NICE and SIGN decided
to share the workload relating to searching and
reviewing the literature. NICE commissioned the
National Collaborating Centre for Acute Care to
develop this guideline and the Centre thus took on
the responsibility of working with SIGN.
Although the NCC-AC and SIGN shared certain
aspects of the search, retrieval and review of the
literature, they had autonomy in developing their
own clinical questions and final recommendations.
The areas of literature reviewed by the NCC-AC and
SIGN are outlined in Table 1.
Palliative Interventions
Palliative Interventions
Palliative Care
Follow Up
Communication
Service Organisation
Service Organisation
Each group summarised their respective literature
reviews in evidence tables and exchanged those related
to the topics that each had focused solely upon.
1.7
Who developed the guideline?
A multidisciplinary Guideline Development Group
(GDG) comprising professional group members and
consumer representatives of the main stakeholders
developed this guideline (see Guideline Development
Group Membership and acknowledgements).
4
LUNG C ANCER
INTRODUCTION
The National Institute for Clinical Excellence funds the
National Collaborating Centre for Acute Care and thus
supported the development of this guideline. The GDG
was convened by the National Collaborating Centre for
Acute Care (NCC-AC) and chaired by Dr. Jesme Baird. In
accordance with guidance from the National Institute for
Clinical Excellence (NICE)16, all GDG members’ interests
were recorded on a standard declaration form that
covered consultancies, fee-paid work, share-holdings,
fellowships and support from the healthcare industry.
The Group met on a monthly basis during
development of the guideline. Staff from the NCC-AC
provided methodological support and guidance for the
development process, undertook systematic searches,
retrieval and appraisal of the evidence and drafted the
guideline. The Glossary to the guideline contains
definitions of terms used by staff and the GDG.
1.8
Summary of the recommendations
and the algorithm
1.8.1
The Key Recommendations for
Implementation
The following recommendations have been selected
from the full list (see 1.8.2) as priorities for
implementation:
Palliative interventions and supportive
and palliative care
– dyspnoea
– weight loss
7.
– chest signs
– hoarseness
– finger clubbing
– features suggestive of metastasis from a
lung cancer (for example in brain, bone,
liver or skin)
Service organisation
– cervical/supraclavicular lymphadenopathy
8. The care of all patients with a working diagnosis
of lung cancer should be discussed at a lung
cancer multidisciplinary team (MDT) meeting.
3. If a chest X-ray or chest computed tomography
(CT) scan suggests lung cancer (including pleural
effusion and slowly resolving consolidation),
patients should be offered an urgent referral to a
member of the lung cancer multidisciplinary
team (MDT), usually a chest physician.
9. Early diagnosis clinics 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.
Staging
10. All cancer units/centres should have one or
more trained lung cancer 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.
4. Every cancer network should have a system of
rapid access to
18
F-deoxyglucose positron emission tomography
(FDG-PET) scanning for eligible patients.
Access to services
1.
All patients diagnosed with lung cancer should be
offered information, both verbal and written, on all
aspects of their diagnosis, treatment and care. This
information should be tailored to the individual
requirements of the patient, and audio and
videotaped formats should also be considered.
2. Urgent referral for a chest X-ray should be
offered when a patient presents with:
> haemoptysis, or
> any of the following unexplained or persistent
(that is, lasting more than 3 weeks) symptoms
or signs:
Radical radiotherapy alone for treatment of
non-small-cell lung cancer
5. Patients with stages I and II non-small-cell lung
cancer (NSCLC) who are medically inoperable
but suitable for radical radiotherapy should be
offered the continuous hyperfractionated
accelerated radiotherapy (CHART) regimen.
Chemotherapy for non-small-cell lung cancer
6. Chemotherapy should be offered to patients
with stages III and IV NSCLC and good
performance status (WHO 0, 1 or a Karnofsky
score of 80–100) to improve survival, disease
control and quality of life.
Non-drug interventions for breathlessness should
be delivered by a lung cancer multidisciplinary
group, co-ordinated by a professional with an
interest in breathlessness and expertise in the
techniques (for example, a nurse, physiotherapist
or occupational therapist). Although this support
may be provided in a breathlessness clinic, patients
should have access to it in all care settings.
5
1.8.2.1 Access to Services
All patients diagnosed with lung cancer should be
offered information, both verbal and written, on all
aspects of their diagnosis, treatment and care. This
information should be tailored to the individual
requirements of the patient, and audio and videotaped
formats should also be considered. [D(GPP)]
Treatment options and plans should be discussed
with the patient and decisions on treatment and care
should be made jointly with the patient. Treatment
plans must be tailored around the patient’s needs
and wishes to be involved, and his or her capacity to
make decisions. [D(GPP)]
The public needs to be better informed of the
symptoms and signs that are characteristic of lung
cancer, through co-ordinated campaigning to raise
awareness. [D(GPP)]
Urgent referral for a chest X-ray should be offered
when a patient presents with: [D]
>
haemoptysis, or
>
any of the following unexplained or persistent
(that is, lasting more than 3 weeks) symptoms or
signs:
– cough
– chest/shoulder pain
– dyspnoea
1.8.2
The Clinical Practice Recommendations
Recommendations are graded A, B, C, D or D(GPP)
according to the level of evidence on effectiveness
that the recommendation is based on. Studies of
diagnostic accuracy are graded A(DS), B(DS), C(DS)
or D(DS). Some recommendations are based on both
diagnostic and effectiveness evidence and therefore
receive two grades to reflect this. Please see Chapter
Two for grading information.
– weight loss
– chest signs
– hoarseness
– finger clubbing
– features suggestive of metastasis from a
lung cancer (for example in brain, bone,
liver or skin)
– cervical/supraclavicular lymphadenopathy
– cough
– chest/shoulder pain
6
LUNG C ANCER
If a chest X-ray or chest computerised tomography
(CT) scan suggests lung cancer (including pleural
effusion and slowly resolving consolidation), patients
should be offered an urgent referral to a member of
the lung cancer multidisciplinary team (MDT),
usually a chest physician. [D]
If the chest X-ray is normal but there is a high
suspicion of lung cancer, patients should be offered
urgent referral to a member of the lung cancer MDT,
usually the chest physician. [D]
Patients should be offered an urgent referral to a
member of the lung cancer MDT, usually the chest
physician, while awaiting the result of a chest X-ray,
if any of the following are present: [D]
>
>
>
persistent haemoptysis in smokers/ex-smokers
older than 40 years
signs of superior vena caval obstruction (swelling
of the face/neck with fixed elevation of jugular
venous pressure)
stridor
Emergency referral should be considered for
patients with superior vena cava obstruction
or stridor.
INTRODUCTION
Bronchoscopy should be performed on patients with
central lesions who are able and willing to undergo
the procedure. [B(DS)]
Every cancer network should have a system of rapid
access to FDG-PET scanning for eligible patients.
[D(GPP)]
metastasis. If the results are negative or inconclusive,
either a bone scan or an MRI scan should be
considered. [D(GPP)]
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. [B(DS)]
Patients who are staged as candidates for surgery on
CT should have an FDG-PET scan to look for involved
intrathoracic lymph nodes and distant metastases.
[A(DS)]
Small cell lung cancer
SCLC should be staged by a contrast-enhanced CT
scan of the patient’s chest, liver and adrenals and by
selected imaging of any symptomatic area. [D(GPP)]
Percutaneous transthoracic needle biopsy is
recommended for diagnosis of lung cancer in
patients with peripheral lesions. [B(DS)]
Surgical biopsy should be performed for diagnosis
where other less invasive methods of biopsy have not
been successful or are not possible. [B(DS)]
Where there is evidence of distant metastases,
biopsies should be taken from the metastatic site if
this can be achieved more easily than from the
primary site. [D(GPP)]
An 18F-deoxyglucose positron emission tomography
(FDG-PET) scan should be performed to investigate
solitary pulmonary nodules in cases where a biopsy
is not possible or has failed, depending on nodule
size, position and CT characterisation. [C; B(DS)]
1.8.2.3 Staging
1.8.2.2 Diagnosis
Where a chest X-ray has been requested in primary
or secondary care and is incidentally suggestive of
lung cancer, a second copy of the radiologist’s report
should be sent to a designated member of the lung
cancer MDT, usually the chest physician. The MDT
should have a mechanism in place to follow up these
reports to enable the patient’s GP to have a
management plan in place. [D(GPP)]
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 adrenals. [D(GPP)]
Chest CT should be performed before:
>
an intended fibreoptic bronchoscopy [A; C(DS)]
>
any other biopsy procedure. [D(GPP)]
7
Non-Small Cell Lung Cancer
In the assessment of mediastinal and chest wall invasion:
>
CT alone may not be reliable [B(DS)]
>
other techniques such as ultrasound should be
considered where there is doubt [D(GPP)]
>
surgical assessment may be necessary if there
are no contraindications to resection. [D(GPP)]
Magnetic resonance imaging (MRI) should not
routinely be performed to assess the stage of the
primary tumour (T-stage) in NSCLC. [C(DS)]
MRI should be performed, where necessary to assess
the extent of disease, for patients with superior
sulcus tumours. [B(DS)]
Patients who are otherwise surgical candidates and
have, on CT, limited (1–2 stations) N2/3 disease of
uncertain pathological significance should have an
FDG-PET scan. [D(GPP)]
Patients who are candidates for radical radiotherapy
on CT should have an FDG-PET scan. [B(DS)]
Patients who are staged as N0 or N1 and M0 (stages I
and II) by CT and FDG-PET and are suitable for surgery
should not have cytological/histological confirmation
of lymph nodes before surgical resection. [A]
Histological/cytological investigation should be
performed to confirm N2/3 disease where FDG-PET
is positive. This should be achieved by the most
appropriate method. Histological/cytological
confirmation is not required: [B(DS)]
>
where there is definite distant metastatic disease
>
where there is a high probability that the N2/N3
disease is metastatic (for example, if there is a
chain of high FDG uptake in lymph nodes).
When an FDG-PET scan for N2/N3 disease is
negative, biopsy is not required even if the patient’s
nodes are enlarged on CT. [B(DS)]
If FDG-PET is not available, suspected N2/3 disease,
as shown by CT scan (nodes with a short axis >
1cm), should be histologically sampled in patients
being considered for surgery or radical radiotherapy.
[D(GPP)]
An MRI or CT scan should be performed for patients
with clinical signs or symptoms of brain metastasis.
[D(GPP)]
An X-ray should be performed in the first instance
for patients with localised signs or symptoms of bone
1.8.2.4 Surgery with curative intent for patients
with NSCLC
Surgical resection is recommended for patients with
stage I or II NSCLC who have no medical
contraindications and adequate lung function. [D]
For patients with stage I or II NSCLC who can tolerate
lobar resection, lobectomy is the procedure of choice. [C]
Pending further research, patients with stage I or II
NSCLC who would not tolerate lobectomy because of
comorbid disease or pulmonary compromise should
be considered for limited resection or radical
radiotherapy. [D]
For all patients with stage I or II NSCLC undergoing
surgical resection – usually a lobectomy or a
pneumonectomy – clear surgical margins should be
the aim. [D(GPP)]
Sleeve lobectomy offers an acceptable alternative to
pneumonectomy for patients with stage I or II
NSCLC who have an anatomically appropriate
(central) tumour. This has the advantage of
conserving functioning lung. [C]
For patients with T3 NSCLC with chest wall
involvement who are undergoing surgery, complete
resection of the tumour should be the aim by either
extrapleural or en bloc chest wall resection. [C]
All patients undergoing surgical resection for lung
cancer should have systematic lymph node sampling
to provide accurate pathological staging. [D(GPP)]
In patients with stage IIIA (N2) NSCLC detected
through preoperative staging, surgery alone is
associated with a relatively poor prognosis.
Therefore, these patients should be evaluated by the
lung cancer MDT. [D(GPP)]
8
LUNG C ANCER
1.8.2.5 Radical radiotherapy alone for treatment
of NSCLC
Radical radiotherapy is indicated for patients with
stage I, II or III NSCLC who have good performance
status (WHO 0, 1) and whose disease can be
encompassed in a radiotherapy treatment volume
without undue risk of normal tissue damage. [D(GPP)]
All patients should undergo pulmonary function tests
(including lung volumes and transfer factor) before
having radical radiotherapy for NSCLC. [D(GPP)]
Patients who have poor lung function but are
otherwise suitable for radical radiotherapy should
still be offered radiotherapy, provided the volume of
irradiated lung is small. [D(GPP)]
Patients with stage I or II NSCLC who are medically
inoperable but suitable for radical radiotherapy
should be offered the CHART regimen. [A]
Patients with stages IIIA or IIIB NSCLC who are
eligible for radical radiotherapy and who cannot
tolerate or do not wish to have chemoradiotherapy
should be offered the CHART regimen. [A]
If CHART is not available, conventionally
fractionated radiotherapy to a dose of 64–66 Gy in
32–33 fractions over 61/2 weeks or 55 Gy in 20
fractions over 4 weeks should be offered. [D(GPP)]
1.8.2.6 Chemotherapy for NSCLC
Chemotherapy should be offered to patients with stage
III or IV NSCLC and good performance status (WHO 0,
1 or a Karnofsky score of 80–100), to improve survival,
disease control and quality of life. [A]
Chemotherapy for advanced NSCLC should be a
combination of a single third-generation drug
(docetaxel, gemcitabine, paclitaxel or vinorelbine)
plus a platinum drug. Either carboplatin or cisplatin
may be administered, taking account of their
toxicities, efficacy and convenience. [D(GPP)]
Patients who are unable to tolerate a platinum
combination may be offered single-agent
chemotherapy with a third-generation drug. [A]
INTRODUCTION
Docetaxel monotherapy should be considered if
second-line treatment is appropriate for patients with
locally advanced or metastatic NSCLC in whom relapse
has occurred after previous chemotherapy. [A]
dehydrogenase, liver function tests, serum sodium,
and stage. [D]
The development of this section included a review of
the following technology appraisal. “Doxetaxel,
paclitaxel, gemcitibine and vinorelbine for non-smallcell lung cancer. NICE Technology Appraisal No. 26
(2001)”. The appraisal is therefore now obsolete and
has been replaced by the guideline.
>
platinum-based chemotherapy [A]
>
multidrug regimens, because they are more
effective and have a lower toxicity than singleagent regimens. [A]
1.8.2.7 Combination treatment for NSCLC
Patients with stage I, II or IIIA NSCLC who are
suitable for resection should not be offered
preoperative chemotherapy unless it is part of a
clinical trial. [B]
Preoperative radiotherapy is not recommended for
patients with NSCLC who are able to have surgery. [A]
Postoperative radiotherapy is not recommended for
patients with NSCLC after complete resection. [A]
Postoperative radiotherapy should be considered
after incomplete resection of the primary tumour for
patients with NSCLC, with the aim of improving local
control. [D]
Adjuvant chemotherapy should be offered to NSCLC
patients who have had a complete resection, with
discussion of the risks and benefits. [A]
Patients who are pathologically staged as II and III
NSCLC following resection should not receive
postoperative chemoradiotherapy unless it is within
a clinical trial. [B]
Patients with stage III NSCLC who are not suitable
for surgery but are eligible for radical
radiotherapy should be offered sequential
chemoradiotherapy. [A]
1.8.2.8 Treatment of Small Cell Lung Cancer
Patients with SCLC should be offered an assessment
that includes evaluation of the major prognostic
factors: performance status, serum lactate
All patients with SCLC should be offered:
Four to six cycles of chemotherapy should be offered
to patients whose disease responds. Maintenance
treatment is not recommended. [A]
Patients with limited-stage SCLC should be offered
thoracic irradiation concurrently with the first or
second cycle of chemotherapy or following
completion of chemotherapy if there has been at
least a good partial response within the thorax. For
patients with extensive disease, thoracic irradiation
should be considered following chemotherapy if
there has been a complete response at distant sites
and at least a good partial response within the
thorax [A]
Patients undergoing consolidation thoracic
irradiation should receive a dose in the range of 40
Gy in 15 fractions over 3 weeks to 50 Gy in 25
fractions over 5 weeks. [D(GPP)]
Patients with limited disease and complete or good
partial response after primary treatment should be
offered prophylactic cranial irradiation. [A]
Second-line chemotherapy should be offered to
patients at relapse only if their disease responded to
first-line chemotherapy. The benefits are less than
those of first-line chemotherapy. [D(GPP)]
9
1.8.2.9 Palliative Interventions and Supportive and
Palliative care
This section focuses on palliative
interventions and supportive and palliative
care for patients with lung cancer and
therefore only evidence specific to lung
cancer was reviewed. An absence of evidence
does not imply that nothing can be done to
help, and supportive and palliative care
multidisciplinary teams- in particular
specialist palliative care teams- have an
important role in symptom control.
Supportive and palliative care of the patient should
be provided by general and specialist palliative care
providers in accordance with the NICE guidance
‘Improving supportive and palliative care for adults
with cancer’. [D(GPP)]
Patients who may benefit from specialist palliative
care services should be identified and referred
without delay. [D(GPP)]
External beam radiotherapy should be considered for
the relief of breathlessness, cough, haemoptysis or
chest pain. [A]
Opioids, such as codeine or morphine, should be
considered to reduce cough. [A]
Debulking bronchoscopic procedures should be
considered for the relief of distressing large-airway
obstruction or bleeding due to an endobronchial
tumour within a large airway. [D]
Patients with endobronchial symptoms that are not
palliated by other means may be considered for
endobronchial therapy. [D]
Patients with extrinsic compression may be
considered for treatment with stents. [D]
Non-drug interventions based on psychosocial support,
breathing control and coping strategies should be
considered for patients with breathlessness. [A]
Non-drug interventions for breathlessness should be
delivered by a multidisciplinary group, co-ordinated
by a professional with an interest in breathlessness
10
LUNG C ANCER
and expertise in the techniques (for example, a
nurse, physiotherapist or occupational therapist).
Although this support may be provided in a
breathlessness clinic, patients should have access to
it in all care settings. [D(GPP)]
Patients with troublesome hoarseness due to recurrent
laryngeal nerve palsy should be referred to an ear, nose
and throat specialist for advice. [D(GPP)]
Patients who present with superior vena cava
obstruction should be offered chemotherapy and
radiotherapy according to the stage of disease and
performance status. [A]
Stent insertion should be considered for the immediate
relief of severe symptoms of superior vena caval
obstruction or following failure of earlier treatment. [B]
Corticosteroids and radiotherapy should be
considered for symptomatic treatment of cerebral
metastases in lung cancer. [D]
Other symptoms, including weight loss, loss of appetite,
depression and difficulty swallowing, should be
managed by multidisciplinary groups that include
supportive and palliative care professionals. [D(GPP)]
Pleural aspiration or drainage should be performed
in an attempt to relieve the symptoms of a pleural
effusion. [B]
Patients who benefit symptomatically from aspiration
or drainage of fluid should be offered talc
pleurodesis for longer-term benefit. [B]
For patients with bone metastasis requiring
palliation and for whom standard analgesic
treatments are inadequate, single-fraction
radiotherapy should be administered. [B]
Spinal cord compression is a medical emergency and
immediate treatment (within 24 hours), with
corticosteroids, radiotherapy and surgery where
appropriate, is recommended. [D]
Patients with spinal cord compression should have
an early referral to an oncology physiotherapist and
an occupational therapist for assessment, treatment
and rehabilitation. [D(GPP)]
INTRODUCTION
complications. Thoracic imaging should be part of
the review. [D]
1.8.2.10 Service organisation
All patients with a likely diagnosis of lung cancer
should be referred to a member of a lung cancer
MDT (usually a chest physician). [D]
For patients who have had attempted curative
surgery for NSCLC, any routine follow-up should not
extend beyond 5 years. [D]
The care of all patients with a working diagnosis of
lung cancer should be discussed at a lung cancer
MDT meeting. [D]
Patients with lung cancer – in particular those with a
better prognosis – should be encouraged to stop
smoking. [D]
All cancer units/centres should have one or more
trained lung cancer 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. [D]
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). [D]
1.8.3
Research is needed to compare concurrent
chemoradiotherapy with alternative fractionation
schedules (such as 55 Gy in 20 fractions or
CHART) with sequential chemoradiotherapy for
patients with NSCLC. Outcomes measured
should include detailed recording of the impact
on quality of life and on toxicity.
>
The management of common symptoms such as
cachexia, anorexia fatigue and breathlessness
experienced by patients with lung cancer needs
further research. Specifically, research is required
into clinically meaningful outcome measures for
the treatment of the cachexia-anorexia
syndrome. For example, does the level of
physical activity as measured by an activity
meter relate to performance status, quality of life
and use of health and social care services?
Research Recommendations
The guideline development group made a number of
recommendations for research in areas where
research is lacking. They selected 5 of these that
were considered to be the highest priority. These are:
>
>
After completion of their treatment, patients with an
expectation of life of more than 3 months should have
access to protocol-controlled, nurse-led follow-up. [A]
Patients who have had attempted curative surgery
for NSCLC, or radical radiotherapy should be
followed up routinely by a member of the MDT for
up to 9 months to check for post-treatment
>
The opinions and experiences of lung cancer patients
and carers should be collected and used to improve
the delivery of lung cancer services. Patients should
receive feedback on any action taken as a result of
such surveys. [D(GPP)]
Patients who cannot be offered curative treatment, and
are candidates for palliative radiotherapy, may either be
observed until symptoms arise and then treated, or be
treated with palliative radiotherapy immediately. [A]
When patients finish their treatment a personal
follow-up plan should be discussed and agreed with
them after discussion with the professionals involved
in the patient’s care. GPs should be informed of the
plan. [D(GPP)]
better symptom control, quality of life and
survival for patients with advanced NSCLC of
performance status 2.
Patients who have had palliative radiotherapy or
chemotherapy should be followed up routinely at 1
month after completion of treatment. A chest X-ray
should be part of the review if clinically indicated. [D]
Early diagnosis clinics 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. [A]
11
>
Further research is needed into whether the use
of low-dose CT in early diagnosis of patients at
high risk of developing lung cancer has an effect
on the mortality of lung cancer. A randomised
trial should compare no intervention with lowdose CT performed at baseline and then
annually for 5 years.
Further research is needed into the symptoms
and signs associated with early- and late-stage
lung cancer and the factors associated with
delay in presentation. For patients diagnosed
with lung cancer, analysis should be undertaken
of the symptoms at presentation, the time
between onset of symptoms and presentation,
the stage at presentation and the reasons for
delay in presentation.
Further research is needed into whether
chemotherapy or active supportive care result in
The following research recommendations were
also made:
1.8.3.1 Staging
>
Further research is needed into the diagnostic
accuracy and efficacy of FDG-PET scanning in
follow-up of patients after radical treatment for
lung cancer to investigate possible recurrence of
the disease.
>
Further research is needed into the diagnostic
accuracy and efficacy of FDG-PET scanning in
staging patients with SCLC.
>
Further research is required to assess the
diagnostic accuracy and efficacy of FDG-PET in
the assessment of tumour response to
chemotherapy and radiotherapy.
1.8.3.2 Surgery for NSCLC
>
In stage I (IA and IB) NSCLC, further randomised
trials on the survival and morbidity after limited
resection in comparison to lobar resection for
small lung tumours (less than 2 cm) are needed.
12
LUNG C ANCER
>
>
In patients with clinical stage I (IA and IB)
NSCLC who are suitable for surgical resection,
further research on the survival and morbidity
after anatomical resection by thoracoscopic
techniques in comparison to open resection
is needed.
In patients with stage IIIA (N2) NSCLC detected
through preoperative staging, surgery alone is
associated with a relatively poor prognosis.
Research should be conducted in a
multidisciplinary setting into the survival and
morbidity after surgery alone in comparison with
multi-modality treatments.
INTRODUCTION
1.8.3.6 Endobronchial Therapy with curative intent
for NSCLC
>
>
Research should be conducted into whether
NSCLC patients with poor lung function have
better survival, morbidity and quality of life
when treated with radical radiotherapy alone
compared to no treatment or treatment with
chemotherapy or chemoradiotherapy .
•
Give all patients diagnosed with lung cancer verbal and written information on all aspects of their diagnosis, treatment
and care, in a form that is tailored to their needs. D (GPP)
•
Discuss treatment options and plans with the patient, and make decisions on treatment and care jointly with the patient.
Treatment plans should be tailored around the patient’s needs and wishes to be involved and his or her capacity to make
decisions. D (GPP)
•
Encourage patients with lung cancer – particularly those with a better prognosis – to stop smoking. D
Referral
•
– chest/shoulder pain
– weight loss
Further research is required to determine the
benefit of non-drug treatments for
breathlessness, compared to no treatment or
other drug based treatments, in terms of
symptom relief and performance status for
patients with lung cancer.
– chest signs
– hoarseness
– finger clubbing
– signs suggesting metastases (for example, in brain, bone, liver or skin)
– cervical/supraclavicular lymphadenopathy.
•
>
Further large-scale prospective trials should be
conducted into the effect on survival and quality
of life of postoperative radiotherapy compared to
surgery alone in the treatment of completely
resected stage III NSCLC patients.
Prospective randomised controlled trials should
be conducted into the effect on survival and
quality of life of treatment with preoperative
radiotherapy and chemotherapy in the treatment
of patients with Pancoast tumours compared to
surgery alone.
Offer urgent referral to lung cancer MDT (usually the chest physician) while waiting for chest X-ray results if any of the
following are present: D
– persistent haemoptysis in a smoker or ex-smoker older than 40 years
>
The effect of bisphosphonates in the relief of
pain and skeletal morbidity from bone
metastasis in lung cancer needs further research.
– signs of superior vena cava obstruction (swelling of the face and/or neck with fixed elevation of jugular venous
pressure – consider emergency referral)
– stridor (consider emergency referral).
1.8.3.5 Combination treatment for NSCLC
>
Offer urgent chest X-ray to patients presenting with haemoptysis, or any of the following if unexplained or present for
more than 3 weeks: D
– cough
1.8.3.8 Palliative Interventions and Supportive and
Palliative care
1.8.3.4 Chemotherapy for NSCLC
Further trials should invesigate the optimum
timing, combination, dosage and duration of
chemotherapy for patients with NSCLC who are
candidates for chemotherapy. These should
include assessment of quality of life and survival.
Information and support
– dyspnoea
>
>
Clinical trials should be conducted to determine
to benefit of prophylactic cranial irradiation
compared to no prophylactic treatment in terms of
survival and quality or life for patients with
extensive disease SCLC and a complete response
at distant metastatic sites and a complete or good
partial response within the thorax after treatment.
Algorithm
General Principles
1.8.3.7 Small Cell Lung Cancer
1.8.3.3 Radical Radiotherapy for NSCLC
>
Further randomised trials should be conducted
on the effect on survival and quality of life of
endobronchial techniques (photodynamic
therapy, brachytherapy, cryotherapy,
electrocautery, Nd-YAG laser ablation) used as
curative treatment in patients with early-stage
NSCLC not suitable for conventional treatment.
1.8.4
1.8.3.9 Service Organisation
>
>
For patients who have had attempted curative
treatment and have completed their initial follow
up, trials should examine the duration of followup and whether regular routine follow-up is
better than symptom-led follow-up in terms of
survival, symptom control and quality of life.
The impact of the time between first symptom
(or first detection if asymptomatic) and the
treatment of lung cancer on patients’ survival
and quality of life should be investigated.
13
Organisation of care – key features
•
Lung cancer as an incidental finding: a second copy of the chest X-ray report should be sent to a member of the MDT –
usually the chest physician. D (GPP)
•
MDTs: discuss care of all patients with a working diagnosis of lung cancer. D
•
Early diagnosis clinics: provided where possible, to speed up diagnosis and reduce patient anxiety. A
•
PET scanning: every cancer network should have a system of rapid access to FDG-PET scanning for eligible patients. D (GPP)
•
Lung cancer nurse specialists: each cancer unit/centre should have one or more trained nurse specialists to provide
continuing support to patients, and to facilitate communication between healthcare professionals. D
•
Timing of treatment: patients suitable for radical treatment or chemotherapy, or needing radiotherapy or ablative
treatment for symptom relief, 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). D
•
Patients’ views: use the opinions and experiences of patients and carers to improve the delivery of lung cancer services,
and give patients feedback on any action taken as a result. D (GPP)
14
LUNG C ANCER
Diagnosis of Lung Cancer
INTRODUCTION
Staging of non-small cell lung cancer
15
16
LUNG C ANCER
INTRODUCTION
Staging of small-cell lung cancer
Surgery (stages I to III)
Stages I and II
•
Surgical resection is recommended for patients with no
medical contraindications and adequate lung function. D
•
Lobectomy is the procedure of choice for patients who
can tolerate it. C
•
Consider limited resection or radical radiotherapy for
patients who would not tolerate lobectomy because of
comorbid disease or pulmonary compromise. D
•
Aim for clear surgical margins in all patients with stage
I or II NSCLC undergoing surgery – usually lobectomy
or pneumonectomy. D (GPP)
•
–
patients with stages IIIA or IIIB NSCLC who are eligible for
radical radiotherapy and who cannot tolerate or do not
wish to have chemoradiotherapy. A
•
If CHART is not available, offer conventionally
fractionated radiotherapy to a dose of 64–66 Gy in
32–33 fractions over 6 1 /2 weeks or 55 Gy in 20
fractions over 4 weeks. D (GPP)
Chemotherapy for patients with NSCLC
(stages III and IV)
•
Offer chemotherapy to patients with stage III or IV NSCLC
and good performance status (WHO 0, 1 or a Karnofsky
score of 80–100), to improve survival, disease control and
quality of life. A
•
Chemotherapy should be a combination of: D (GPP)
Sleeve lobectomy is an acceptable alternative to
pneumonectomy for patients with central tumour, and
conserves functioning lung. C
Stages II and III
•
•
Aim for complete resection for patients with T3 NSCLC
with chest wall involvement who are undergoing
surgery, by either extrapleural or en bloc chest wall
resection. C
The MDT should assess patients with stage IIIA (N2)
NSCLC because surgery alone is associated with a
relatively poor prognosis. D (GPP)
•
•
All patients having surgery
•
Perform systematic lymph node sampling to provide
accurate pathological staging. D (GPP)
– a single third-generation drug (docetaxel, gemcitabine,
paclitaxel or vinorelbine), plus
Treatment of small-cell lung cancer
– a platinum drug – carboplatin or cisplatin, taking
account of their toxicities, efficacy and convenience.
•
Single-agent chemotherapy with a third-generation drug
can be offered to patients who cannot tolerate a platinum
combination. A
Assessment includes evaluation of the major prognostic
factors: performance status, serum lactate dehydrogenase,
liver function tests, serum sodium, and stage. D
•
Offer all SCLC patients multidrug platinum-based
chemotherapy. A
•
If the disease responds, offer four to six cycles of
chemotherapy. Maintenance treatment is not
recommended. A
Consider docetaxel monotherapy if second-line treatment
is appropriate for patients with locally advanced or
metastatic NSCLC in whom relapse has occurred after
previous chemotherapy. A
Combination treatment
Radiotherapy alone (stages I to III)
•
All patients should undergo pulmonary function tests
(including lung volumes and transfer factor) before
having radical radiotherapy. D (GPP)
•
Patients who have poor lung function but are otherwise
suitable for radical radiotherapy should still be offered
radiotherapy, provided the volume of irradiated lung is
small. D (GPP)
•
•
– preoperative radiotherapy A
– postoperative radiotherapy after complete resection A
– postoperative chemoradiotherapy for patients whose
NSCLC is pathologically staged as II and III (except as
part of a clinical trial). B
•
Consider postoperative radiotherapy after incomplete
resection of the primary tumour, to improve local control. D
•
Offer adjuvant chemotherapy to patients who have had a
complete resection, with discussion of the risks and
benefits. A
•
Offer sequential chemoradiotherapy to patients with stage
III NSCLC who are not suitable for surgery but are eligible
for radical radiotherapy. A
Offer the CHART regimen to:
– patients with stage I or II NSCLC who are medically
inoperable but suitable for radical radiotherapy. A
The following treatments are not recommended:
– preoperative chemotherapy (except as part of a clinical
trial) B
Radical radiotherapy is indicated for patients with stage
I, II or III NSCLC who have good performance status
(WHO 0, 1) and whose disease can be encompassed in
a radiotherapy treatment volume without undue risk of
normal tissue damage. D (GPP)
•
17
•
Offer patients with limited-stage SCLC thoracic irradiation
concurrently with the first or second cycle of
chemotherapy or after completion of chemotherapy if
there has been at least a good partial response within the
thorax. For patients with extensive disease, consider
thoracic irradiation after chemotherapy if there has been
a complete response at distant sites and at least a good
partial response within the thorax. A
•
The dose for consolidation thoracic radiotherapy should
be between 40 Gy in 15 fractions over 3 weeks and 50
Gy in 25 fractions over 5 weeks. D (GPP)
•
Consider prophylactic cranial irradiation for patients with
limited disease and complete or good partial response
after primary treatment. A
•
At relapse, offer second-line chemotherapy only if the
disease responded to first-line chemotherapy. The benefits
are less than with first-line chemotherapy. D (GPP)
18
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Treatent of non-small-cell lung Cancer
INTRODUCTION
19
Surgery (Stages I to III)
• This section focuses on palliative interventions and supportive
and palliative care for patients with lung cancer and therefore
only evidence specific to lung cancer was reviewed. An
absence of evidence does not imply that nothing can be done
to help, and supportive and palliative care multidisciplinary
teams – in particular specialist palliative care teams – have an
important role in symptom control.
• Supportive and palliative care should be provided by
general and specialist palliative care providers in
accordance with the NICE Cancer Service Guidance
‘Improving supportive and palliative care for adults with
cancer’ (available from www.nice.org.uk/csgsp). D (GPP)
• Patients who cannot be offered curative treatment, and are
candidates for palliative radiotherapy, can be either observed
until symptoms arise and then treated or treated immediately. A
• Non-drug interventions for breathlessness should be delivered
by a multidisciplinary group, co-ordinated by a professional
with expertise in the techniques (such as a nurse,
physiotherapist or occupational therapist). Patients should have
access to this support in all care settings. D (GPP)
• Patients should be offered general supportive measures –
including drugs – for symptom control, in addition to the
specific interventions listed in the table below.
• Identify and refer without delay patients who may benefit
from specialist palliative care services. D (GPP)
Symptom
Management
Breathlessness
•
•
Cough
•
External beam radiotherapy.. A
Haemoptysis
•
External beam radiotherapy. A
Chest pain
•
External beam radiotherapy. A
Hoarseness
•
D (GPP)
Referral to ear, nose and throat specialist.D
Superior vena cava obstruction
•
Chemotherapy and radiotherapy, depending on stage of disease and performance
status. A
Stent insertion for immediate relief of severe symptoms or after failure of earlier
treatment. B
External beam radiotherapy. A
Non-drug interventions (psychosocial support, breathing control and coping
strategies). A
Intrinsic airway obstruction
• De-bulking bronchoscopic procedures.. D
• Endobronchial therapy (photodynamic therapy, brachytherapy) for endobronchial
symptoms not palliated by other means. D
Extrinsic airway compression
• Stents.. D
Pleural effusion
• Pleural aspiration/drainage for pleural effusion. B
• Talc pleurodesis if symptoms improve after aspiration/drainage of fluid. B
•
Symptoms from brain metastases
•
Corticosteroids and radiotherapy. D
Spinal cord compression
•
•
Corticosteroids, radiotherapy and surgery where appropriate, within 24 hours. D
D (GPP)
Early referral to oncology physiotherapist and occupational therapist.D
Symptoms from bone metastases
•
Single-fraction radiotherapy if standard analgesic treatments are inadequate. B
Other symptoms
•
Management by multidisciplinary groups including supportive and palliative care
professionals should address other symptoms, including weight loss, loss of
appetite, difficulty swallowing, and depression. D(GPP)
20
LUNG C ANCER
METHODOLOG Y
21
Follow-up
•
•
•
•
•
When patients finish their treatment, a personal
follow-up plan should be discussed and agreed with
them, after discussion with other professionals
involved in the patient’s care. The patient’s GP should
be informed of the plan. D (GPP)
After completion of treatment, patients with an
expectation of life greater than 3 months should be
offered the option of protocol-controlled nurse-led
follow-up. A
2 Methodology
2.1
The guideline was commissioned by NICE
and developed in accordance with the guideline
development process outlined in The Guideline
Development Process – Information for
National Collaborating Centres and Guideline
Development Groups16.
Patients who have had attempted curative surgery for
NSCLC or radical radiotherapy should be followed up
routinely by a member of the MDT for up to 9 months,
to check for post-treatment complications. The review
should include thoracic imaging. D
Routine follow-up should not extend beyond 5 years
after attempted curative surgery for NSCLC. D
Patients who have had palliative radiotherapy or
chemotherapy should be followed up routinely 1
month after completion of treatment. The review
should include a chest X-ray if clinically indicated. D
Guideline Methodology
2.2
Review of the clinical literature
The aim of the literature review was to identify and
synthesise relevant evidence within the published
literature, in order to answer specific clinical
questions. Searches were performed using generic
and specific filters, relevant medical subject heading
terms and free text terms. Only studies on patients
with lung cancer (or where the majority of patients
recruited were those with lung cancer) were
included, with one exception. When we considered
the treatment of pleural effusion, studies on patients
with mixed primary sites were included as specific
data was not available and the GDG agreed that the
site of the primary tumour would not determine
treatment in this case. Details of all literature
searches are available in appendix six. The scope and
the clinical questions can be found in appendix
seven and eight respectively.
Search filters to identify systematic reviews,
randomised controlled trials and observational
studies were adapted from the SIGN methodological
search filters
(http://www.sign.ac.uk/methodology/filters.html).
The lung cancer search strategy stem was devised in
collaboration with SIGN. It was then combined with
independently devised search strategies for each
section of the guideline. The following databases were
searched for all section:
>
The Cochrane Library (up to Issue 4, 2003)
>
Medline (OVID) 1966-2003 (week 52)
>
Embase (OVID) 1980-2003 (week 52)
The Cumulative Index to Nursing and Allied Health
Literature (CINAHL) and PsychInfo were also
searched for relevant clinical questions. Identification
of high quality systematic reviews determined the
date ranges searched for each clinical question. No
language restrictions were applied to the search but
identified foreign papers were not requested or
reviewed. The cut off date for the NCC-AC literature
search was 31st December 2003. In order to be
consistent and systematic we did not consider papers
after this date. This decision was made for pragmatic
reasons of work load and means that very current
data will be missed.
There was no systematic attempt to search for all the
‘grey literature’ (conferences, abstracts, theses and
unpublished literature). However, we searched ASCO
(http://www.asco.org) for interventional abstracts
to identify and verify published papers. We searched
for guidelines and reports from relevant websites,
including the following listed below. Bibliographies
of identified reports and guidelines were also
checked to identify relevant literature.
>
National Institute of Clinical Excellence (NICE)
(www.nice.org.uk)
>
National electronic Library for Health (NeLH)
(http://www.nelh.nhs.uk/)
22
LUNG C ANCER
>
>
>
National Institutes of Health Consensus
Development Program (consensus.nih.gov)
METHODOLOG Y
TABLE 2:
New Zealand Guidelines Development Group
(NZGG) (http://www.nzgg.org.nz/)
Scottish Intercollegiate Guideline Network
(SIGN) (www.sign.ac.uk)
2.3
US National Guideline Clearing House
(www.guidelines.gov)
>
Google (www.google.com)
1+
Ia
Systematic review (with homogeneity)* of level-1 studies**
High-quality meta-analyses,
systematic reviews of RCTs, or RCTs
with a very low risk of bias
Ib
Level-1 studies**
II
Level-2 studies***
Systematic reviews of level-2 studies
Well-conducted meta-analyses,
systematic reviews of RCTs, or RCTs
with a low risk of bias
III
Level-3 studies****
Systematic reviews of level-3 studies
IV
Evidence obtained from expert committee reports or opinions and/or clinical experience without
explicit critical experience, based on physiology, bench research, or first principles.
1-
Meta-analyses, systematic reviews of
RCTs, or RCTs with a high risk of bias
Hierarchy of clinical evidence
2++
High-quality systematic reviews of
case–control or cohort studies
High-quality case–control or cohort
studies with a very low risk of
confounding, bias, or chance and a
high probability that the relationship
is causal
2+
2-
for Evidence-based Medicine Levels of Evidence (2001)17 and the Centre for Reviews and
Dissemination Report Number 4 (2001)18
Type of Evidence
All retrieved articles have been methodologically
appraised using checklists developed by SIGN.
There are many different methods of ranking the
evidence and there has been considerable debate
about what system is best. A number of initiatives
are currently under way to find an international
consensus on the subject, but until a decision is
reached on the most appropriate system, for the
NICE guidelines the Institute advises the National
Collaborating Centres to use the system for evidence
shown in Table 2. This is the same system that the
Scottish Intercollegiate Guideline Network (SIGN)
used to evaluate the evidence in the areas they
reviewed. For more details on the methods used by
SIGN, please see their website (www.sign.ac.uk).
TABLE 3: Levels of evidence for studies of the accuracy of diagnostic tests. Adapted from The Oxford Centre
Levels of Evidence
Level of evidence Type of evidence
1++
>
Levels of evidence for intervention studies
(reproduced with permission of the
Scottish Intercollegiate Guidelines
Network)
*Homogeneity means there are no or minor variations in the directions and degrees of results between individual studies that
are included in the systematic review.
**Level-1 studies are studies:
>
That use a blind comparison of the test with a validated reference standard (gold standard)
>
In a sample of patients that reflects the population to whom the test would apply.
***Level-2 studies are studies that have only one of the following:
Well-conducted case–control or
cohort studies with a low risk of
confounding, bias, or chance and a
moderate probability that the
relationship is causal
>
Narrow population (the sample does not reflect the population to whom the test would apply)
>
Use a poor reference standard (defined as that where the ‘test’ is included in the ‘reference’, or where the
‘testing’ affects the ‘reference’)
>
The comparison between the test and reference is not blind
Case–control or cohort studies with a
high risk of confounding bias, or
chance and a significant risk that the
relationship is not causal
>
Case-control studies
****Level-3 studies are studies that have at least two or three of the features listed above.
3
Non-analytic studies (for example,
case reports, case series)
For each clinical question the highest level of evidence was sought. Where an appropriate systematic review, meta- analysis or
randomised controlled trial exist, we did not search for studies of a weaker design.
4
Expert opinion
Studies that were assessed to be of adequate quality were summarised in evidence tables. All the evidence tables can be found in
appendix one.
The ranking system described above covers studies of treatment
effectiveness and is less appropriate for studies reporting diagnostic
tests of accuracy. Since there is no validated ranking system for
diagnostic tests, NICE has developed a hierarchy for evidence of
this nature which takes into account factors likely to affect the
validity of these studies (Table 3). The NCC-AC was the first Centre
to pilot this hierarchy and it has yet to be systematically tested.
23
24
2.4
LUNG C ANCER
Health economics methods
It is important to investigate whether health services
are clinically effective and also cost-effective (that is,
value for money). If a particular diagnostic or
treatment strategy were found to yield little health
gain relative to the resources used, then it could be
advantageous to re-deploy resources to other
activities (either in lung cancer or beyond) that yield
greater health gain.
To assess the cost-effectiveness of each recommendation,
a comprehensive systematic review of the economic
literature relating to lung cancer was conducted. For
selected components of the guideline original costeffectiveness analyses were performed.The primary
criteria applied for an intervention to be considered costeffective were either:
a) the intervention dominated other relevant
strategies (that is it is both less costly in terms of
resource use and more clinically effective
compared with the other relevant alternative
strategies); or
b) the intervention cost less than £30,000 per
quality-adjusted life-year (QALY) gained compared
with the next best strategy (and compared with
best supportive care). However, between £20,000
and £30,000 per QALY, judgements about the
acceptability of the intervention as an effective use
of NHS resources will make more explicit reference
to such factors as the degree of uncertainty
surrounding the calculation of cost-effectiveness,
the innovative nature of the intervention and the
particular features of the condition and the
population receiving it.
2.4.1
Literature review for Health Economics
We obtained published economic evidence from a
systematic search of the following databases:
>
Medline (Ovid) (1966-2003)
>
Embase (1980-2003)
>
Health Economic Evaluations Database (HEED)
>
NHS Economic Evaluations Database (NHS EED)
METHODOLOG Y
For those clinical area’s we reviewed, the information
scientists used the same search strategy as for the
clinical questions, substituting an economics filter for
a study type filter. For those clinical area’s SIGN
reviewed, the information scientistics had to design a
filter specifically for the health economists.
inflation, therefore inflation to current prices was not
considered necessary.
>
>
>
Results were not reported specifically for lung
cancer patients (Although occasionally studies
were found and included, where most but not all
patients had lung cancer, e.g. in comparisons of
different types of thoracic surgery).
The study did not contain any original data on
cost or cost-effectiveness (i.e. it was a review or a
clinical paper).
The analysis was not incremental and was not
described adequately to allow incremental
analysis (so studies reporting only average costeffectiveness ratios were excluded unless they
provided data to allow the calculation of
incremental cost-effectiveness ratios).
For one topic – treatment of pleural effusion - it was
decided to include data not specific to lung cancer.
In this case, all studies were reviewed for malignant
pleural effusion, on the assumption that the site of
the primary tumour would not determine treatment.
For key papers where costs were in a currency other
than pounds sterling, US dollars or euros, the results
were converted to pounds sterling using the relevant
purchasing power parity for the study year. Most
studies were recent during a period of relatively low
2.4.2
Cost-effectiveness modelling
Specific topics were selected for original economic
analysis if there was a likelihood that the
recommendation made would substantially change
clinical practice in the NHS and have important
consequences for resource use.
The Guideline Development Group was presented with
summaries (text and evidence tables) of the best
available research evidence to answer the clinical
questions. Recommendations were based on, and
explicitly linked to, the evidence that supported them.
The evidence tables can be found in appendix one.
TABLE 4:
Grading of recommendations**
Grade
Evidence
A
> At least one meta-analysis, systematic review,
or RCT rated as 1++, and directly applicable to
the target population, or
> A systematic review of RCTs or a body of
evidence consisting principally of studies rated
as 1+, directly applicable to the target
population, and demonstrating overall
consistency of results
> Evidence drawn from a NICE technology
appraisal
B
> A body of evidence including studies rated as
2++, directly applicable to the target
population, and demonstrating overall
consistency of results, or
> Extrapolated evidence from studies rated as
1++ or 1+
C
> A body of evidence including studies rated as
2+, directly applicable to the target population
and demonstrating overall consistency of
results, or
> Extrapolated evidence from studies rated as 2++
D
> Evidence level 3 or 4, or
> Extrapolated evidence from studies rated as 2+,
or
> Formal consensus
In three cases there was not a relevant economic
evaluation in the published literature: CHART versus
conventional radical radiotherapy for NSCLC; FDGPET in the work-up to radical radiotherapy for NSCLC;
and platinum versus non-platinum drug regimens in
the treatment of SCLC.
In a fourth case, economic evaluations had been
previously published but had substantial limitations FDG-PET in the work-up to curative surgery for NSCLC.
Methods used depended on the question being
analysed, however, the following principles were
followed:
>
The GDG was consulted during the construction
and interpretation of each model.
>
Each model was based on the best evidence from
the systematic review.
>
Model assumptions were reported fully and
transparently.
>
The results were subject to thorough sensitivity
analysis and limitations discussed.
>
Costs were calculated from a health services
perspective.
Forming and grading the
recommendations
NICE guideline recommendations are graded
according to the strength of the supporting
evidence, which is assessed from the design of each
study (see Table 2 and Table 3). The grading system
currently used is presented in Table 4 and Table 5.
Each study was categorised as one of the following:
cost analysis, cost-effectiveness analysis or costutility analysis (i.e. cost-effectiveness analysis with
effectiveness measured in terms of QALYs). We did
not find any cost benefit analyses (studies that put a
monetary value on health gain). Studies labelled as
‘cost consequences analysis’ or ‘cost minimisation
analysis’ were simply categorised as cost analyses,
since the lack of an overall measure of health gain
prevents such studies being considered full
economic evaluations.
Each search strategy was designed to find any applied
study estimating the cost or cost-effectiveness of some
aspect of lung cancer. A health economist reviewed
abstracts and database reviews of papers. Relevant
references in the bibliographies of reviewed papers
were also identified and reviewed.
Given the diversity of economic studies, it was not
possible to determine a general exclusion criterion
based on study quality. Hence all studies were
included in the evidence tables (including abstracts)
and study quality and applicability are discussed in
the review. Papers were only excluded from the
evidence tables and review if:
2.5
25
D (GPP) A good practice point (GPP) is a recommendation
for best practice based on the experience of the
Guideline Development Group
26
LUNG C ANCER
ACCESS TO SERVICES
27
The Group worked on an informal consensus basis.
The recommendations were then graded according
to the level of evidence upon which they were based.
Recommendations based on studies assessing the
diagnostic accuracy of tests are also classified
according to the strength of the supporting
evidence. The classification system used for this
guideline is presented in
Table 5. It is currently being piloted and has not yet
been systematically tested by NICE. Some
recommendations in this guideline have two grades
because they are based on both diagnostic and
effectiveness evidence.
TABLE 5:
Classification of recommendations for
studies of the accuracy of diagnostic tests.
(DS = diagnostic studies)
Class
Level of Evidence (See Table 3)
A (DS)
Studies with levels of evidence Ia or Ib
B (DS
Studies with levels of evidence II
C (DS)
Studies with levels of evidence III
D (DS)
Studies with levels of evidence IV
The usefulness of a classification system based solely
on the level of evidence has been questioned
because it does not take into consideration the
importance of the recommendation in changing
practice and improving patient care. It is worth
noting that NICE is currently assessing the best way
of presenting recommendations for future guidelines.
3 Access to Services
3.1
Introduction
In this chapter we examine access to services. In
particular we examine the delay between patients
first experiencing symptoms and their presentation
at their general practitioner (GP), interventions that
may encourage patients to present sooner and the
key symptoms and signs for which a GP should make
a referral. This latter issue is particularly problematic
because the symptoms of lung cancer, such as
cough, are common among smokers and patients
with chronic obstructive pulmonary disease (COPD).
Information on the delays before treatment of lung
cancer and the effect of using rapid access clinics are
discussed in chapter 13 (Service organisation).
Although this chapter discusses presentation to and
referral by GPs it should be noted that many other
management pathways for lung cancer patients
exist. A regional randomised stratified analysis of the
management pathways of 400 patients, found 80
such pathways and that more than 50% of patients
did not present to hospital with a chest x-ray
suspicious of lung cancer19.
Patient communication and support are discussed
more fully in chapter 12 (Palliative Interventions and
Supportive and Palliative Care). It is, however,
important to stress that at diagnosis and throughout
treatment and care, patients are given information,
both verbal and written, on aspects of their disease
such as prognosis, treatment options and anticipated
benefits and side effects in a form that is tailored to
the needs of the individual patient. Good
communication between patients and professionals
must be encouraged and patients involved in the
decision making process on their personal treatment
and care plan.
3.2
Methodology
We conducted a systematic literature search and review
according to the methods described in chapter 2. The
search strategy is shown in appendix six.
3.3
Patient delay in presentation to general
practitioners
We found no research that specifically addressed the
effect of delay in presentation to GPs on the
outcome for patients with lung cancer. However, a
survey of lung cancer patients and carers in the UK
looked at the delay between patients first
experiencing symptoms of lung cancer and reporting
them to a GP20. The survey revealed that for patients
who reported visiting their GP because of chest
symptoms there was a wide variation in delay in
presentation between 3 weeks and 3 months (Level
3). One Swedish study of 134 patients noted similar
results (see Table 7) finding that the mean delay
from first symptom to presentation was 43 days
(median 21 days)21 (Level 3).
We searched for studies on the effectiveness of
interventions at encouraging patients to present to
healthcare services sooner with symptoms of lung
cancer. Better provision of information to the public
on how to recognise symptoms has been suggested
as a way of getting people with suspected cancer to
present to GPs sooner20,22. Campaigns such as ‘lung
cancer awareness month’ (The Roy Castle Lung
Cancer Foundation and Macmillan Cancer Relief)
have been run to address this and although
outcomes are difficult to assess and have not been
formally evaluated, an increase in callers to
telephone helplines was noted23. There is scope for
additional innovative and imaginative ways to
engage those at risk.
28
LUNG C ANCER
ACCESS TO SERVICES
The effect of delays in treatment on patient
outcomes and the effect of using rapid access clinics
or fast track systems are discussed in chapter 13 on
service organisation.
3.4
The Department of Health have issued referral
guidelines for suspected cancer in 200025 and we
found no recent evidence with which to update
these guidelines. The guideline development group
support these recommendations (Level 4). These
guidelines state that:
Key Symptoms and Signs
The symptoms and signs of lung cancer can be
difficult for the GP to distinguish from those of
other diseases. The main symptoms and signs at
presentation have been collected in case series
and are shown in Table 6 (Level 3). We identified
no evidence on whether any symptoms, or
combinations of symptoms, can be used to predict
the presence of lung cancer.
TABLE 6:
Range of frequency of initial symptoms
and signs of lung cancer (Source: Beckles
et al. 200324)
Symptoms and Signs
Range of frequency,%
Cough
8-75
Weight Loss
0-68
Dyspnoea
3-60
Chest Pain
20-49
Haemoptysis
6-35
Bone Pain
6-25
Clubbing
0-20
Fever
0-20
Weakness
0-10
Superior Vena Cava
Obstruction (SVCO)
0-4
Dysphagia
0-2
Wheezing and stridor
0-2
cancer, through co-ordinated campaigning to raise
awareness. [D(GPP)]
In a limited number of circumstances, patients
should be offered an urgent referral to a member
of the MDT, usually the chest physician while
awaiting the result of a chest x-ray, if any of the
following are present:
Urgent referral for a chest x-ray should be offered
when a patient presents with: [D]
>
>
haemoptysis, or
>
any of the following unexplained or persistent (that
is, lasting more than 3 weeks) symptoms or signs:
Urgent referral for a chest x-ray should be made
when a patient presents with:
>
>
Haemoptysis
Persistent haemoptysis in smokers/ex-smokers
over 40 years of age
Signs of superior vena caval obstruction
(swelling of the face/neck with fixed elevation
of jugular venous pressure)
– cough
Or unexplained or persistent (more than 3 weeks)
– chest/shoulder pain
>
>
Stridor
Cough
>
Chest/shoulder pain
>
Dyspnoea
>
Weight loss
>
Chest signs
>
Hoarseness
>
Finger clubbing
>
Features suggestive of metastasis from a lung
cancer (e.g. brain, bone, liver or skin)
>
Persistent cervical/supraclavicular
lymphadenopathy
The Department of Health Guidelines25 note that in
most cases where lung cancer is suspected it is
appropriate to arrange for an urgent chest x-ray
before urgent referral to a chest physician.
Chest x-ray (CXR) findings are abnormal in the vast
majority of symptomatic patients. However, a normal
CXR does not exclude a diagnosis of lung cancer25.
The guideline development group support the
Department of Health guidelines in stressing that
where the GP is suspicious of lung cancer a referral
should be offered even if the chest x-ray is normal.
If a chest x-ray or chest CT is suggestive or suspicious
of a lung cancer (including pleural effusion and slowly
resolving consolidation), patients should be offered
urgent referral to a chest physician who is a member of
the multidisciplinary lung cancer team.
29
– dyspnoea
Emergency referral should be considered for patients
with superior vena caval obstruction or stridor.
– weight loss
– chest signs
This has been adapted from the Department of
Health guidelines on referral25. No economic
evidence was found in this area.
– hoarseness
– finger clubbing
The Department of Health has commissioned NICE
to produce an update of the original GP referral
guidelines for suspected cancers, including lung
cancer, and these are due to be published in March
2005. NICE commissioned the National
Collaborating Centre for Primary Care to produce
evidence based guidelines on referral.
3.5
Recommendations
3.5.1
Clinical Practice Recommendations
All patients diagnosed with lung cancer should be
offered information, both verbal and written, on all
aspects of their diagnosis, treatment and care. This
information should be tailored to the individual
requirements of the patient, and audio and videotaped
formats should also be considered. [D(GPP)]
Treatment options and plans should be discussed
with the patient and decisions on treatment and
care should be made jointly with the patient.
Treatment plans must be tailored around the
patient’s needs and wishes to be involved, and his or
her capacity to make decisions. [D(GPP)]
– features suggestive of metastasis from a lung
cancer (for example, in brain, bone, liver or skin)
– cervical/supraclavicular lymphadenopathy.
If a chest x-ray or chest computerised tomography
(CT) scan suggests lung cancer (including pleural
effusion and slowly resolving consolidation), patients
should be offered an urgent referral to a member of
the lung cancer multidisciplinary team (MDT),
usually a chest physician. [D]
If the chest x-ray is normal but there is a high
suspicion of lung cancer, patients should be offered
urgent referral to a member of the lung cancer MDT,
usually the chest physician. [D]
Patients should be offered an urgent referral to a
member of the lung cancer MDT, usually the chest
physician, while awaiting the result of a chest X-ray,
if any of the following are present: [D]
>
persistent haemoptysis in smokers/ex-smokers
over 40 years of age
>
signs of superior vena caval obstruction (swelling
of the face/neck with fixed elevation of jugular
venous pressure)
>
stridor.
The public needs to be better informed of the
symptoms and signs that are characteristic of lung
30
LUNG C ANCER
DIAGNOSIS
31
Emergency referral should be considered for patients
with superior vena caval obstruction or stridor.
3.5.2
Research Recommendations
Further research is needed into whether the use of
low-dose CT in early diagnosis of patients at high
risk of developing lung cancer has an effect on the
mortality of lung cancer. A randomised trial should
compare no intervention with low-dose CT performed
at baseline and then annually for 5 years.
Further research is needed into the symptoms and
signs associated with early- and late-stage lung
cancer and the factors associated with delay in
presentation. For patients diagnosed with lung
cancer, analysis should be undertaken of the
symptoms at presentation, the time between onset
of symptoms and presentation, the stage at
presentation and the reasons for delay in
presentation.
4 Diagnosis
4.1
Introduction
Patients with lung cancer generally present with
symptoms and signs of the tumour as described
previously (e.g. cough, dyspnoea, weight loss,
anorexia, chest pain, haemoptysis and hoarseness).
These symptoms are characteristic of lung cancer but
many can be indicative of a number of other more
minor diseases or ailments. It is possible for a
tumour to grow quite large before causing any
symptoms. In addition, a proportion of patients are
diagnosed after their tumour is picked up
incidentally on CXR and may not present with any of
the classic symptoms of lung cancer. Solitary
pulmonary nodules (SPN) are commonly encountered
in clinical practice and are usually defined as lesions
up to 3cm in size. Determining whether a solitary
pulmonary nodule is benign or malignant is a
frequently encountered problem requiring a
multidisciplinary approach, often involving further
imaging and intervention.
A CXR is almost invariably performed as the initial
investigation. The vast majority of patients will then
have both a computerised tomography (CT) scan and
either bronchoscopy or image guided biopsy to obtain
a tissue diagnosis. The patients’ clinical status, the
tumour stage, the cell type and patient preferences
determine the diagnostic and staging tests that are
most suitable. Accurate diagnosis is important for the
future management for the patient.
In this chapter we review the evidence for the main
diagnostic tests that can aid the clinician to
establish a diagnosis. Formal staging will be
discussed in the next chapter. However, in practice,
staging is performed alongside diagnosis and some
of the techniques discussed will provide both
diagnostic and staging information.
4.2
Techniques included in this review
In this review we have examined the following
techniques used for diagnosing lung cancer: CXR, CT,
radionuclide imaging, positron emission tomography
(PET), sputum cytology, bronchoscopy, percutaneous
needle biopsy, biopsies of sites other than lung, anterior
mediastinotomy, surgical thoracoscopy with biopsy and
thoracotomy. Diagnostic techniques that examine
mediastinal lymph nodes (e.g. mediastinoscopy) will be
covered in the chapter on staging.
In this chapter we discuss imaging modalities used
to diagnose lung cancer followed by techniques that
aim to achieve tissue confirmation.
4.3
Methodology
The guideline review team undertook new systematic
reviews of all of the techniques listed above.
Guidelines on diagnosis issued by the American
College of Chest Physicians in 2003 were included
as the review was judged to have been
systematic26,27. A comprehensive systematic review
published in 2001 was also considered28 but was
less up to date for most topics. Studies of diagnostic
accuracy were quality assessed using a system being
piloted (described in the chapter on methodology)
and studies of the effectiveness of the test at
changing patient management were assessed as for
all other studies of clinical effectiveness. For studies
of diagnostic accuracy we report the sensitivity,
specificity, positive predictive value (PPV) and the
negative predictive value (NPV). Papers were rejected
if the true positives, true negatives, false positives
and false negatives could not be calculated.
The search strategy is described in appendix six.
32
LUNG C ANCER
4.4
Imaging
4.4.1
Chest X-Ray
When there is a suspicion of lung cancer, the CXR is
usually the first investigation performed. Lung cancer
usually presents itself radiographically as a solitary
pulmonary nodule or pulmonary mass, pulmonary
collapse, mediastinal lymphadenopathy, a pleural
effusion or as an area of consolidation.
We identified one systematic review on the topic28
that searched literature from 1966 to 2000. We
conducted our own systematic review in which we
searched for literature back to1994. However,
although CXR is in common usage throughout the
world as a diagnostic technique for lung cancer
there has been little work on the subject. The
systematic review28 found only a small number of
studies, which included patients of all stages and
cell types and the sensitivity and specificity of chest
x-rays could not be derived for a population
applicable to UK patients awaiting diagnosis
The typical effective dose received by the patient
undergoing a chest x-ray is 0.02mSv, which is
equivalent to a lifetime additional risk of fatal cancer
per examination of 1 in a million29.
Although there is a lack of published evidence, the
guideline development group considered that the
CXR is a mandatory first line of investigation,
enabling decisions on the next choice of
investigation to be made. It is unfortunately an
insensitive method of examination, and as such, if
lung cancer is suspected clinically and the CXR is
negative the patient should still be referred to a
chest physician. Where a CXR is incidentally
suggestive of lung cancer, the guideline
development group agreed that patients should be
identified to a chest physician within the local lung
cancer multidisciplinary team (MDT) so that their
further management can be initiated as soon as
possible and to prevent an oversight occurring from
an unexpected malignancy. The MDT should have a
mechanism in place to follow up these reports to
ensure the patient’s GP has a management plan in
place. This is discussed in more detail in chapter 3
on Access to Services.
DIAGNOSIS
4.4.2
sign that the lesion is benign although this too has
been challenged. There are also major practical
difficulties in measuring small size changes. Firstly,
the average life expectancy of SCLC patients is too
short to allow long-term assessment (the average
doubling time of SCLC is 30 days compared to 100
days for NSCLC32). Secondly, long evaluation times
mean that there is a risk of tumour spread. Lastly,
accurate measurement of small changes is affected
by exact positioning of the nodule. Two recent
studies33,34 of SPNs in small groups of patients found
that a repeat scan could detect growth rate
indicative of malignancy with a sensitivity and a
specificity both of 100%. These encouraging
preliminary results, if confirmed, indicate that
repeated thin section could be used to detect lung
malignant SPNs (Level IIDS).
Computerised tomography (CT)
A diagnosis of lung cancer can be achieved in a
number of ways using CT. Firstly, the overall CT
appearances may enable a diagnosis of malignancy
to be made, such as identifying either metastatic
disease or evidence of local tumour invasion into the
chest wall or mediastinum. In addition, careful
examination of the morphology of the lung lesion,
its degree of enhancement or demonstration of
growth on sequential examinations may allow a
presumptive radiological diagnosis of malignancy.
Morphological Features
Previous researchers have suggested a number of
morphological features particularly characteristic of
benign solitary pulmonary nodules (SPN). These
include various patterns of calcification such as
diffuse, concentric, laminar, dense central or a
‘popcorn’ pattern of calcification. However, we
identified only two studies that examined the
accuracy with which these features could be used to
predict whether a nodule is malignant (Table 8Appendix 1 separate document). One study found
that nodules with diffuse calcification were benign
in 100% of 154 cases, (Specificity 63%, PPV 77.5%,
NPV 100%)30 (Level II). A more recent study31
examined various morphological signs of 104
patients with SPNs, using spiral CT and high
resolution CT (HRCT). They found that the sensitivity
was 89% and 91% with spiral CT and HRCT
respectively and that the specificity was 61% (spiral
CT) and 57% (HRCT) (Level 1b). These figures were
based on using any one of the following features:
presence of spicules, the vessel sign, necrotic areas,
circumscribed pleural thickening, inhomogeneity,
ground-glass opacity of lung parenchyma adjacent to
SPN, lesion density, pleural retraction or bronchus
sign. Thus, sensitivity and specificity when using
morphological features of SPNs on CT to predict
malignancy does not seem to be good enough to
allow confident decisions about whether to pursue
further investigation of a suspect SPN.
Growth Rate
The growth rate of lesions has been used as a
predictor of malignancy, in particular stability of the
lesion size over time has been reported as a reliable
Contrast Enhancement
Two studies examined the differential uptake of
contrast agent in determining the diagnosis of an
SPN35,36. The sensitivity and specificity ranged between
88-100% and 36-76.9% respectively. The PPV and
NPV ranged between 62.3-90.2% and 71.4-100%
respectively (Level II). As with the other CT methods of
diagnosis, the low specificity is problematic.
Overall, CT provides anatomical information enabling
the exact positioning of the lesion, and some results
have shown that CT can have a high sensitivity.
However, the specificity is poor in a number of
studies. The typical effective dose received by the
patient undergoing a chest CT is 8mSv, which is
equivalent to a lifetime additional risk of fatal cancer
per examination of 1 in 250029.
A CT scan provides useful information that can be
used for decisions on further investigations such as
bronchoscopy or needle biopsy in the establishment
of a diagnosis of lung cancer.
4.4.3
Positron Emission Tomography
Unlike imaging with X-rays or MRI, positron emission
tomography allows functional information of cells to
be collected. 18F-deoxyglucose (FDG) is generally
used in the evaluation of lung cancer patients. FDG
is a glucose analogue labelled with positron emitting
fluorine. Most malignant tumours have a higher
33
glucose metabolism than normal tissue and therefore
take up more FDG than the surrounding tissue and
emit a greater number of positrons. Thus, areas of
malignancy show up as areas of greater activity on
the scan. The majority of the PET evidence is from
dedicated full ring PET scanners. In this document
the use of PET therefore excludes gamma camera
PET and half ring systems. The data is derived from
scanning patient from the brain to at least mid thigh
and using local views of thorax. The development of
PET-CT systems is likely to result in the need for a
single scan from skull vertex to mid thigh and may
not need local views of the chest.
Presently there are few PET scanners in English and
Welsh hospitals and the technique is not widely used
for the diagnosis of lung cancer patients. There is
however interest in its use in the investigation of
solitary pulmonary nodules and other focal lung
lesions and a number studies have investigated its
use in diagnosis.
A meta-analysis37 was found for which a systematic
review of literature was performed from January
1966 and September 2000 using the Medline and
Cancerlit databases. This review included studies
that 1) included at least 10 subjects with pulmonary
nodules or masses (at least 5 with malignant
lesions), and 2) included enough data to allow
calculation of sensitivity and specificity. We updated
this review by searching for papers published after
September 2000 on Medline and searching all years
of Embase as this database had not been covered by
the earlier review.
As well as the meta-analysis by Gould et al37, we
found 13 other papers that met our inclusion
criteria38-50. These are shown in Table 9. Gould et al37
found 40 studies which met their inclusion criteria.
They found the sensitivity to be 96.8% (read from a
receiver operator characteristic curve) at the median
specificity of 77.8%. (Level II). The range of
sensitivities in the 13 additional diagnostic studies is
72-100% and the specificity ranges from 67100%38-50. (Level II)
The spatial resolution of full ring PET scanners is
about 7-8mm and thus there has been some concern
that PET would not be effective at imaging smaller
34
LUNG C ANCER
DIAGNOSIS
nodules (<1.5cm). We have no evidence to confirm
this as the studies either did not test nodules smaller
than 1.5cm or did not break down the results
sufficiently to allow this analysis. However, the
metabolic activity of the tumour is likely to be the
major determinant rather than size alone.
One study assessed management change due to the
use of PET in diagnosis by using a before and after
questionnaire approach50 (Table 10). According to
referring physicians, PET resulted in beneficial
change of treatment in 50% of patients. Cancelled
surgery was the most frequent change in treatment
after PET (35% of patients) and improved diagnostic
understanding solely based on PET was reported in
26% of patients50. (Level 2+)
If the FDG PET is positive then further confirmatory
investigation is required (see sections below on
tissue sampling).
It is anticipated that the next wave of FDG-PET
scanners will be integrated PET-CT scanners and it
is likely that the diagnostic accuracy will continue
to improve.
4.4.4
NeoSPECT
NeoSPECT is a radiopharmaceutical containing Tc99m depreotide and is able to bind to somatostatin
receptors in tumour tissue to a greater extent than
normal tissue. This localisation to tumour should
result in more gamma photons being emitted from
the tumour than surrounding tissue and therefore
make the tumour capable of being localised by a
gamma camera.
An added advantage of FDG-PET in SPN assessment
is that metastatic disease can also be assessed at the
one scanning visit and either provide an alternative
site to biopsy or confirm whether a patient, who is
proven to have NSCLC, can proceed to operation (see
chapter 5 on staging).
The systematic review26 included 17 studies that
examined the effect of location of the pulmonary
nodule or mass. Most studies showed better
sensitivity for centrally located masses compared to
peripheral masses (pooled sensitivity 71% vs. 49%
respectively) (Level II).
Two prospective diagnostic studies51,52 examined the
use of NeoSPECT in the differential diagnosis of
solitary pulmonary nodules on a total of 153 patients.
(Table 11) The sensitivity, specificity, PPV and NPV for
the first study are 97%, 73%, 92% and 86%51
respectively and for the second study 100%, 43%,
64% and 100%52 respectively. (Level 1b and II)
The typical effective dose received by the patient
undergoing a PET scan with 400MBq of FDG is
10mSv, which is equivalent to a lifetime additional
risk of fatal cancer per examination of 1 in 2000
(compared with a natural lifetime risk of 1 in 3).
In summary, PET appears to have a good sensitivity
and a reasonable specificity for detection of
malignant SPNs and masses. However, for small
nodules <1.5cm the results may be less reliable.
Whether the specificity of PET is acceptable is
debatable. However, since prevalence affects the
probability of finding malignancy in the test, PET
may therefore be useful for low risk patients,
meaning that one could be quite confident about
accepting the results of a negative scan. In practice,
for those of intermediate risk, a tissue biopsy would
be performed, but if this was not possible or had
failed then PET may be useful as an additional
technique of investigation. The risk is dependent on
a variety of clinical and radiographic variables, such
as smoking history, haemoptysis, and size. As such,
duration of follow up and decision on biopsy will
vary, although the presence of a negative PET scan
enables a watch and wait policy to be implemented.
Our literature search identified a recent systematic
review26 and one further diagnostic study that was
not included in the review53. Pooled data from
28,477 patients in 16 studies in the review gave a
sensitivity of 66%, a specificity of 99%, a PPV of
91% and a NPV of 94%26. However, the indication
for performing sputum cytology in these patients
was mixed, which may have led to the large degree
of heterogeneity in the results (Table 12). In the
same review, a selection of 8 studies with 2455
patients, tested prior to bronchoscopy (and therefore
with a suspicion of lung cancer), gave a pooled
sensitivity of 22% (Level II). The additional
diagnostic study, not included in the review53, tested
60 consecutive patients suspected of lung cancer.
Again, in this population of suspected lung cancer
patients, the sensitivity was found to be rather low
at 33%, the specificity was 94%, the PPV was 93%
and the NPV was 38% (Level II).
In conclusion, it appears that sputum cytology has a
rather low sensitivity for detecting malignancy of
peripheral masses but for central masses it may be a
useful diagnostic technique, particularly for those
patients unable to tolerate or unwilling to have
bronchoscopy or other invasive diagnostic tests.
We found no studies on morbidity associated with
the technique.
The typical effective dose received by the patient
undergoing a NeoSPECT scan with Tc-99m is 11.84
mSv for a typical injected activity of 740 MBq, which
is equivalent to a lifetime additional risk of fatal
cancer per examination of 1 in1700.
There is limited evidence available on NeoSPECT at
the present time. The results in one study52 show
reasonable diagnostic accuracy, although the
specificity is poor. At present, there is insufficient
data to comment on the utility of NeoSPECT.
4.5
Tissue confirmation
4.5.1
Sputum cytology
Sputum cytology can occasionally detect pulmonary
tumours in the asymptomatic patient and is one of
the least invasive methods of detecting lung cancer.
35
bronchoscopy in diagnosing lung cancer. As
histocytology is the gold standard in diagnosis, there
are no false positive results but some studies do
include a follow-up to support their outcomes. We
divided the outcomes into those reporting for central
masses (endobronchial) and those reporting results
for peripheral masses (beyond the segmental
bronchus). We also examined the effect of the size of
the lesion on the sensitivity of the technique.
Central Disease
The results for central and peripheral lesions are
shown in Table 13. Bronchoscopy has a higher
sensitivity for central masses as sampling methods
are likely to be more accurate when the lesion is
visible. The results are broken down by sampling
method. The systematic review26 reported the results
from 3754 patients and found that endobronchial
biopsy provided the best sensitivity (74%, 20
studies), followed by brushings (59%, 18 studies)
and washings (48%, 12 studies). (Level II) The study
by Hashmi et al56 also found a high sensitivity for
endobronchial biopsy (82%, 88 patients). (Level II)
The sensitivity for bronchoscopic needle aspiration in
the review26 was 56%, (8 studies) but there was a
high degree of heterogeneity in the methods and the
results. The study by Xie et al55 found a sensitivity of
67% for bronchoscopy guided transtracheal and
transbronchial biopsy. (Level II). Fourteen studies in
the systematic review examined the sensitivity of
combining different methods (endobronchial biopsy,
brushing, washing and endobronchial/transbronchial
needle aspiration) and found it to be 88% for
centrally located lesions26.
Peripheral Disease
4.5.2
Bronchoscopy
Confirmation of a diagnosis of lung cancer can be
achieved by using bronchoscopy for patients who are
able and willing to tolerate the procedure. Guidelines
on assessment of patients’ fitness for bronchoscopy
have been published by the British Thoracic Society54.
Imaging prior to bronchoscopy can help to locate the
position of the lesion and will improve the success of
the technique (see section 4.5.2.1).
We identified one systematic review26 and two
additional diagnostic studies55,56 on the use of
The systematic review by Schreiber et al26 reported the
pooled results of 4136 patients in 30 studies on the
sensitivity of flexible bronchoscopy for peripheral
lesions beyond the visual segmental bronchi (Table
13). Brushings have the highest sensitivity (52%, 15
studies), followed by transbronchial biopsy (46%, 18
studies) and broncoalveolar lavage/washings (43%,
13 studies). Transbronchial needle aspiration had a
pooled sensitivity of 67%, but this was calculated
from only five studies and there was a large degree of
heterogeneity in the sample sizes. Twelve studies in
36
LUNG C ANCER
DIAGNOSIS
the systematic review26 examined the use of all
modalities combined, giving a pooled sensitivity of
69%, again much lower than the sensitivity for
diagnosis of central disease. Eight studies in the
systematic review26 presented results by size of lesion
for peripheral disease. Bronchoscopy (brushings
and/or biopsy) of lesions greater than 2cm in
diameter had a pooled sensitivity of 62%, whereas for
lesions smaller than 2cm in diameter the sensitivity
was 33%. (Level II)
(Table 14). Only two studies report on the accuracy
of bronchoscopy performed with and without
information from a CT scan in obtaining a diagnosis.
Laroche et al57 found that the sensitivity of
bronchoscopy performed blind to CT information was
71% and the sensitivity of bronchoscopy performed
with knowledge of CT information was 89%, a
statistically significant difference (p=0.012). (Level III
DS). The study by Bungay et al58 found that when
bronchoscopy was performed before CT the
sensitivity was 56% and when CT was performed
before bronchoscopy the sensitivity was 80%,
although this was not a statistically significant
difference. (Level III DS). The different results
reported by these studies may be a reflection of the
differences in the patient populations. The study by
Bungay et al58 excluded patients with pulmonary
collapse and included some patients with peripheral
lesions, whereas the study by Laroche et al57
included some patients with distal collapse but
excluded peripheral lesions.
Typical complications figures for bronchoscopy are
reported in the British Thoracic Society guidelines for
diagnostic flexible bronchoscopy54:
>
Mortality Rate in UK: 0.04%
>
Major Complication rate in UK (including
respiratory depression, airway obstruction and
pneumonia): 0.12%
>
Transbronchial biopsy: pneumothorax 1-5%
cases
>
The study by Laroche57 also reported changes in
management that resulted from the difference in
performing the tests in a different order. Of the
patients that had a CT scan first, 7% required no
further investigation as the CT scan was either
normal, consistent with benign disease or consistent
with widespread metastatic disease, and 18% had
an alternative procedure (e.g. needle biopsy) instead
of bronchoscopy due to the CT results (Level 1+).
However, the reasons for changes in management
were not always fully specified.
Haemorrhage (usually mild): 9%
Overall, bronchoscopy provides a reasonably accurate
method of determining a diagnosis in patients with
central disease and with lesions over 2 cm in
diameter. For peripheral disease, the sensitivity is too
low to recommend this technique for diagnosis in
preference to the other techniques available.
4.5.2.1 Should CT be performed prior to
Bronchoscopy?
Overall, the evidence indicates that by performing a
CT prior to an intended bronchoscopy, some
unnecessary bronchoscopies can be prevented and
the accuracy of bronchoscopy is improved.
We investigated whether it was appropriate to
perform a CT scan of the thorax prior to
bronchoscopy. Despite organisational barriers (such
as longer waiting times for scans than for
bronchoscopies), a CT scan prior to bronchoscopy
could not only provide valuable information
regarding the tumour position but could highlight
the presence of any metastatic disease. This would
allow recommendations for an alternative diagnostic
procedure to be made if clinically more appropriate.
There is no evidence on the use of CT before other
biopsy procedures. However, the GDG wished to
make a good practice point that CT should also be
performed before other biopsy procedures.
4.5.3
There is some evidence to suggest that the
additional imaging data significantly increases the
likelihood of obtaining a diagnosis at bronchoscopy
Percutaneous Transthoracic Needle
Aspiration/Biopsy
Transthoracic needle aspiration or biopsy involves
insertion of a small needle percutaneously to remove
fluid or tissue from the lung, which is then examined
for malignancy. Fluoroscopy, CT or ultrasound can be
used to guide the insertion of the needle to the site
of disease.
The literature search identified one systematic
review26 and four other studies of diagnostic
accuracy, that were not included in the review59-62.
The systematic review excluded studies with less
than 50 patients, and we used the same exclusion
criteria for our review. The data are reported in Table
15. The pooled sensitivity for 61 studies included in
the systematic review is 90% (95% CI: 88-92%) and
the specificity is 97% (95%CI: 96-98%)26. The PPV
and the NPV range from 82-100% and 0-96%
respectively. (Level II DS)The four additional studies
that we identified found similar results, reporting
sensitivities between 95-97% and specificities
between 96-100%59-62.(Level Ib and II DS) The
systematic review found two studies that compared
the use of cutting needle core biopsy to needle
aspiration and found that they had similar
sensitivities but that core biopsy had a better
specificity26. (Level II).
A systematic review of case series reporting mortality
and morbidity for a total of 4527 patients found
that a chest drain was needed in 10.4% of patients,
haemoptysis occurred in 3.6% of patients and there
was a mortality of 0.04%28. One additional case
series of 506 patients, not included in the review,
reported similar results (chest drain in 7.9% of
patients and mortality in 0%)63. Pneumothorax was
observed in 31 % of patients in the systematic
review26 and 23% of patients in the additional
study63(Level III).
The British Thoracic Society and the Royal College of
Radiology have also issued guidelines on radiologically
guided lung biopsy, which provide further detail on the
indications for the test, complications that may arise
and the technique to use64. (Level IV)
In summary, the evidence suggests that transthoracic
needle aspiration and biopsy have a good sensitivity
and specificity for diagnosis of lung cancer. The
complication rate is acceptable. For peripheral lung
lesions, it provides a more accurate way of
diagnosing lung cancer than bronchoscopy.
4.5.4
37
Biopsies of sites other than the lung
In some cases, for example patients presenting with
stage IIIb or IV disease or symptoms that suggest
metastases in specific organs (e.g. the liver), or in
patients with clinical or radiographic evidence of SCLC,
it may be more convenient to take a biopsy from the
chest wall, pleural effusion or the site of distant
metastasis. The site may be easier to biopsy than the
primary tumour and this technique has the advantage
of allowing confirmation of the stage of disease at the
same time. A search was performed, but no studies
were found that provided information on the sensitivity
and specificity for suspected lung cancer.
The guideline development group decided to make a
good practice point that biopsies should be taken
from the site of a metastases where this can be
achieved more easily than from the primary site.
4.5.5
Surgical techniques
Surgery plays an important role in the diagnosis and
accurate staging of lung cancer. However, a decision
to include a surgical procedure in the diagnostic
work-up must anticipate associated risks as well as
potential benefits. These benefits are closely tied to
the likely stage of the disease. This section examines
surgical methods of diagnosis. Evidence relating to
staging and techniques examining the lymph nodes
(e.g. mediastinoscopy) are discussed in the chapter 5
on staging.
4.5.5.1 Anterior Mediastinotomy
Anterior (parasternal) mediastinotomy has developed
primarily as a means of staging carcinoma of the
lung located in the left upper lobe65. It has also
been advocated to establish the diagnosis of primary
masses in the anterosuperior mediastinum, especially
in the setting of superior vena cava obstruction when
needle biopsy may be contraindicated66.
We identified only one study that reported results of
diagnostic accuracy for anterior mediastinotomy67
(Table 16). The overall sensitivity and specificity of
the technique for diagnosing various diseases was
98% and 65% respectively for 62 patients with hilar
or mediastinal masses. This study reported a
morbidity of 16% and a mortality of 1.6%. (Level II)
38
LUNG C ANCER
There is very limited evidence on the use of anterior
mediastinotomy in the diagnosis of lung cancer,
although the sensitivity appeared high from the one
study that evaluated it67. Its role is far more clearly
defined as a staging technique (see chapter 5
on staging).
4.5.5.2 Thoracoscopy
The use of video-assisted thoracoscopy (surgical
thoracoscopy) is a useful means of obtaining a
diagnosis of indeterminate solitary pulmonary nodules
without the need for thoracotomy when less invasive
methods may have failed to identify the lesion. The
surgical thoracoscopy approach is particularly valuable
in this setting because thoracotomy can be avoided
for the removal of nodules that ultimately prove to be
benign. A relatively small, typically less than <3cm in
diameter, and peripherally located nodule in the outer
third of the lung may be resected using such
thorascopic methods68.
The literature search identified three fairly large
series that examined the diagnostic accuracy of
thoracoscopy in assessing the status of solitary
pulmonary nodules (Table 17). Two studies reported
high sensitivities of 97%69 and 100%70 and one
study found a lower sensitivity of 41%71. (Level II DS)
The complication rate, reported by one study only, is
low, with conversion to thoracotomy occurring in two
patients (<1% conversion rate)70 Other studies with
much smaller number of patients have reported
significantly higher conversion rates 72,73 (Table 18).
No deaths occurred as a result of the diagnostic
thoracoscopy and morbidity ranged from 3.6% 22% and included significant lobar atelectasis,
pneumonia and prolonged leak. Chest drains were
used in all procedures. Postoperative length of stay
was 2- 4 days.
The results are mixed for the accuracy of
thoracoscopy in the diagnosis of solitary pulmonary
nodules. However, the technique appears to have a
moderately low complication rate.
4.6
Economics of diagnosis of lung cancer
The papers42,57,74-89 selected for economics of lung
cancer diagnosis are shown in Table 19 and Table 20.
DIAGNOSIS
4.6.1
Health Economics analysis of
FDG-PET in diagnosis
The value of FDG-PET lies in its ability to reduce the
number of futile (diagnostic) surgical operations by
diagnosing non-cancer cases earlier. This should
reduce surgical morbidity and surgical cost. FDG-PET
may misdiagnose some cancer cases (c.f. surgical
biopsy) and therefore PET negative cases may have
to be systematically followed up. FDG-PET scanning
is expensive compared with CT scanning but is less
costly than surgical biopsy (see Table 21) and
therefore in some circumstances PET could in theory
reduce health service costs by eliminating episodes
of futile surgery.
There are nine cost-effectiveness analyses (one from
Germany75, two from Japan82,83, four from the USA7779,88
and two from Australia42,74) that have evaluated
the use of FDG-PET scanning in solitary pulmonary
nodules. In addition, three more studies estimated
incremental cost but not effectiveness. All cost analysis
resulted in cost savings per patients examined by FDGPET for investigation of SPNs81,84,89 (see Table 20).
The cost-effectiveness studies used a variety of
comparator strategies including ‘watch and wait’, CT
alone, transthoracic needle biopsy and thoracotomy.
Gambhir et al77, evaluated thoracic FDG-PET after
indeterminate/positive CT, with wait and watch after
negative CT or negative PET. They looked at five
scenarios for example, 64-year-old, 1.5 pack per day
smoker (prevalence=0.83). For this group, CT
scanning had a lower cost and longer life expectancy
compared with the PET strategy. Generally, they
found that the optimal strategy depends on the
underlying prevalence (P) of cancer as follows:
>
0.12<P<0.69: CT➞ FDG-PET➞ Transthoracic
needle biopsy/surgery is optimal
>
0.69<P<0.90: CT➞ Transthoracic needle
biopsy/surgery is optimal
>
p>0.90: Transthoracic needle biopsy/surgery is
optimal
Keith et al42 adapted this model and concluded that
PET after indeterminate CT would dominate CT for
their hospital population in Australia.
Dietlein et al75 found that whole-body PET scanning
dominates both transthoracic needle biopsy and
surgery. Compared with watch and wait it costs
around £2,000 per life year gained (LY gained).
Kosuda et al82 looked at CT and chest-PET for all
SPNs versus CT alone. They found that chest-PET
added around £1,100 per life-year gained. They use
a rather low unit cost for a PET scan of $700.
Kosuda et al83 examined full-body-PET and CT vs CT
alone and conversely showed a cost-saving of
around £1,000 but a drop in life-expectancy of 0.01
years. Shepherd88 estimated that PET after
indeterminate CT would cost approximately £7,000
per LY gained compared with watch and wait;
however, extra caution should be applied to this
study, since it has not subsequently been published
as a full report.
The decision analysis of Gould et al79 on cost
effectiveness for five diagnostic strategies (computed
tomography, FDG-PET, transthoracic needle biopsy,
surgery and watchful waiting) showed the choice of
strategy depended on the pre-test probability of
malignancy and to a lesser extent the risk for
surgical complications. The use of FDG-PET was most
cost-effective when pre-test probability and CT
results were conflicting. In addition, use of FDG-PET
was also cost-effective in patients with intermediate
pre-test probability (55%) who are at high risk for
surgical complications.
Comber et al.74 evaluated whether the costeffectiveness of FDG-PET could be improved by using
it with quantitative contrast-enhanced computed
tomography (QECT). The baseline results (55%
prevalence of malignancy) showed that QECT with
FDG-PET strategy was the most cost effective
strategy (AUS$12,059/patient-£5,111/patient)
followed by the FDG-PET strategy
(AUS$12,300/patient-£5,212/patinet) for the
evaluation of solitary pulmonary nodules.
The published evidence from overseas seems to show
that for some patient subgroups PET scanning after
CT is cost-effective. The cost-effectiveness depends
on the prevalence of cancer among the patient
group. If the prevalence of cancer in the patient
group is very high, then PET is both more costly and
less effective than going straight to surgery. If the
39
prevalence of cancer is very low then PET is more
effective then watchful waiting but unlikely to be
cost-effective. If the prevalence of cancer is slightly
higher, then PET could be cost-effective. The studies
differed in terms of where the cut-offs should be, for
example, the upper prevalence cut-off beyond which
PET is not cost-effective varied between 0.4 and 0.9
between studies.
None of the published studies evaluated the use of
PET scanning within the NHS in the UK. They all
showed that cost-effectiveness is dependent on the
prevalence of cancer in the patient group, which can
vary between settings. Cost-effectiveness will also
depend on the precise sensitivity and specificity and
on the exact pathway to be followed subsequent to
scanning; these factors also vary between health
systems. This includes patients with a strong
suspicion of lung cancer and where surgical biopsy
has failed or is not possible.
This section has only considered the cost-effectiveness
of PET with regard to diagnosing lung cancer; evidence
for the cost-effectiveness of PET in the staging of
NSCLC is appraised in the following chapter.
4.6.2
Health Economics analysis of
Sputum Cytology
Only one economic evaluation explicitly explored the
role of sputum analysis in the diagnosis of lung
cancer. Raab et al86 conducted 9 decision analyses
that compared the use of sputum analysis as the first
procedure with no sputum analysis, in a US context.
The analyses differed according to whether the
lesion was central or peripheral and to the sequence
of the other diagnostic tests. For example, one
analysis for peripheral lesions compared the
sequence in the order of the tests undertaken:
>
Sputum analysis ➞ Fine needle aspiration (FNA)
➞ thoracoscopy
Compared with
>
FNA ➞ thoracoscopy
For all but one of the analyses the sputum analysis
arm dominated its comparator (i.e. with a lower cost
and a slightly increased life expectancy). This was
40
LUNG C ANCER
because some surgical procedures were avoided
through the use of sputum analysis. The main
sensitivity analysis concerned the prevalence of lung
cancer in the patient group. Essentially they found
that sputum analysis dominates in patient groups
with a prevalence of cancer greater than 0.5.
4.6.3
consequences of CT versus flexible bronchoscopy as
the first investigation for patients with suspected
lung cancer. They found that CT first has the
following advantages:
>
Avoids some invasive investigations - 19% avoid
bronchoscopy (12% FNA and 7% no invasive
investigation)
>
Improves accuracy of first invasive investigation
– (90% vs. 71% of malignancies were detected
with the first invasive investigation). Hence,
overall 11% avoided having a second invasive
procedure (19% vs. 8%).
In summary, the consequences of routine CT
scanning for suspected lung cancer are:
>
>
Health Economics Analysis of Bronchoscopy
There was a single eligible study examining the costeffectiveness of bronchoscopy. The US study by
Govert et al80 compared the following strategies
using decision analysis:
>
Flexible bronchoscopy alone
>
Flexible bronchoscopy with washings or
brushings
>
Flexible bronchoscopy with washings and
brushings.
They ascribed seven days of additional morbidity to a
complication arising from a surgical lung biopsy,
with a complication rate 0.03, a cost of this
complication of $20,000 and a cost of cytology of
$177. On this basis, and using retrospective
diagnostic data they estimated that the addition of
washings or brushings cost an additional $308 per
reduced quality day avoided. The addition of
washings and brushings cost an additional $5,500
per reduced quality day avoided. They concluded
that the cytology of either washings or brushings
was cost-effective but not both. By usual conventions
(i.e. a threshold of $50,000 per QALY gained), even
this seems to be poor value for money. However,
given that the cost of cytology in the USA is
substantially higher than in the UK, it is still likely
that either washings or brushings (as an adjunct to
forceps biopsy) is cost-effective in the NHS compared
with a £30,000 per QALY threshold.
4.6.4
DIAGNOSIS
Health Economics analysis of performing CT
prior to Bronchoscopy
Chest CT is widely considered an essential diagnostic
procedure for most patients with suspected lung
cancer, hence only one relevant economic evaluation
was found. Laroche et al57 conducted a randomised
controlled trial (n=171) in the UK to compare the
>
>
Reduces length of hospital stay (data not
presented)
>
The trial was not powered to detect differences in
the number of surgical complications. In theory, one
would expect fewer complications in the CT arm but
this is partially offset by the higher incidence of
pneumothorax for thoracic needle biopsy compared
with bronchoscopy.
The trial was not able to determine whether overall
health service costs were reduced or increased
because it was not known how many CT scans would
normally take place after bronchoscopy. However,
based on other costs the authors estimated that if
CT scanning after bronchoscopy is normally 60% or
more, routine CT scanning would reduce costs
(otherwise it would increase costs).
The study was an RCT but there is a potential for
selection bias, as the inclusion/exclusion criteria are
unclear. The authors note that they ‘attempted to
exclude patients with an obvious peripheral mass
amenable to percutaneous needle biopsy’. One factor
that diluted the outcomes measured is that all
patients in the trial underwent CT and even in the
bronchoscopy arm, subsequent intervention was
based not only on the results of the bronchoscopy
but also on the results of the CT scan.
4.6.5
Chest CT as the initial investigation (after CXR)
for patients with suspicion of lung cancer can
reduce the number of invasive investigations (by
an estimated 17%).
It could potentially reduce NHS costs if the
current CT rate (after bronchoscopy) is greater
than approximately 60%.
If the current CT rate is below 60% then it could
still be cost-effective, if there are associated
improvements in patient outcomes. There is no
evidence for this at present.
The incremental cost-effectiveness of CT before
bronchoscopy could vary considerably across the
NHS because it is determined by usual CT
scanning practice.
Health Economics analysis of Surgical Biopsy
One paper was identified that considered the cost of
different surgical diagnostic strategies. Osada et al85
were concerned with patients who had suspected
malignancy in CT but were undiagnosed after
bronchoscopy. They were attempting to determine
whether thoracotomy alone without needle or
surgical thoracoscopy biopsy based solely on chest
CT scan was feasible. They found that for this group,
93% (38/41) of these patients went on to
thoracotomy after surgical thoracoscopy biopsy and
therefore costs could be reduced by going straight to
thoracotomy. They added that even in the three
patients who did not show appropriate indicators for
thoracotomy in their surgical thoracoscopy biopsy
would have benefited from going straight to
thoracotomy because they required wedge resection
to be declared cancer-free.
4.6.6
41
Summary of Health Economics Findings
Sputum cytology as the first diagnostic investigation
could potentially improve patient outcomes and
reduce costs.
The cytological analysis of both washings and
brushings after non-diagnostic forceps bronchoscopy
biopsy is not likely to be cost-effective.
Routine chest CT before bronchoscopy can reduce
the number of invasive procedures. It is likely to
reduce surgical morbidity and could reduce health
service costs if the pre-test prevalence is relatively
high (> about 60%).
In patients with a suggestion of malignancy on CT
but no diagnosis after bronchoscopy, surgical
thoracoscopy biopsy to eliminate unnecessary
thoracotomies is unlikely to be cost-effective
compared with going straight to thoracotomy.
Diagnostic PET scanning could potentially both
reduce costs and improve patient outcomes for some
patients with SPNs. Further research is required to
establish cost effectiveness in a UK setting.
We should be cautious in interpreting the results of
studies in this review because:
All the studies except one were non-UK studies.
There are a number of problems associated with
using overseas studies. Estimates of effectiveness
may be inappropriate because of differences in the
population. The cost of resources used can vary
considerably between countries, for example, the
cost of clinical staff is lower in the UK than in some
countries. The resources used in the subsequent
treatment will vary between countries according to
local protocols. This may also impact on the
estimated health gain for patients diagnosed.
Studies varied in their assumptions. For example for
surgical complications Govert et al (1996)80
estimated only the morbidity whereas, Raab et al
(1997)86 estimated reduction in life expectancy.
Furthermore, all the studies compared often quite
complicated pathways. Patient selection would also
have affected the cost-effectiveness.
42
LUNG C ANCER
One study has evaluated the importance of patient
preferences for diagnostic strategy. Raab et al87
incorporated into their analysis the quality of life of
patients. They concluded that overall patient
outcome could be substantially affected by an
individual patient’s anxiety. They considered two
types of patients with the same risk of cancer. For a
patient who is averse to surgical risk, watchful
waiting gave the best overall quality of life and was
the most cost-effective strategy. In contrast, for the
patient who is less risk averse but averse to waiting,
going straight to surgery could be the most costeffective strategy.
4.7
Recommendations
4.7.1
Clinical Practice Recommendations
S TAGING OF LUNG C ANCER
Percutaneous transthoracic needle biopsy is
recommended for diagnosis of lung cancer in
patients with peripheral lesions. [B(DS)]
Surgical biopsy should be performed for diagnosis
where other less invasive methods of biopsy have
not been successful or are not possible. [B(DS)]
Where there is evidence of distant metastases,
biopsies should be taken from the metastatic site if
this can be achieved more easily than from the
primary site. [D(GPP)]
5 Staging of Lung Cancer
5.1
Patients should have had established, where
possible, a histological diagnosis of the cell type of
the lung cancer. Clinical examination is likely to give
some indication of the stage of the disease but
normally further tests are necessary to determine the
exact status.
Treatment is dependent on histology and on the size
and location of the primary tumour, the presence
and location of involved lymph nodes and the
occurrence of distant metastases. A number of other
prognostic factors may also influence the choice of
treatment. These include performance status, comorbidity, age, gender and biochemistry. Information
on the stage of the disease will be used in addition
to these factors to determine patient management.
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 adrenals. [D(GPP)]
Chest CT should be performed before:
an intended fibreoptic bronchoscopy [A; C(DS)]
>
any other biopsy procedure. [D(GPP)]
Bronchoscopy should be performed on patients with
central lesions who are able and willing to undergo
the procedure. [B(DS)]
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. [B(DS)]
Introduction
5.3
Once a diagnosis of Lung Cancer has been made it is
essential that the stage of the disease is ascertained
to enable decisions to be made about the future
management of the patient.
An 18F-deoxyglucose positron emission tomography
(FDG-PET) scan should be performed to investigate
solitary pulmonary nodules in cases where a biopsy
is not possible or has failed, depending on nodule
size, position and CT characterisation. [C; B(DS)]
Where a chest X-ray has been requested in primary
or secondary care and is incidentally suggestive of
lung cancer, a second copy of the radiologist’s report
should be sent to a designated member of the lung
cancer MDT, usually the chest physician. The MDT
should have a mechanism in place to follow up these
reports to enable the patient’s GP to have a
management plan in place. [D(GPP)]
>
43
Guidelines produced by the American College of Chest
Physicians (ACCP) on the staging of lung cancer were
retrieved and found to be relevant for this review, in
addition to a Health Technology Board for Scotland
(HTBS) report. New systematic reviews were
undertaken on all of the techniques listed above.
The full search strategy can be found in appendix six.
5.4
Staging Classifications
5.4.1
Non-Small Cell Lung Cancer (NSCLC)
The basis of staging in lung cancer is the
relationship between the anatomical extent of the
tumour at diagnosis and survival outcome. In 1973
the American Joint Committee on Cancer (AJCC)
proposed a scheme for lung cancer based on this
TNM system. The system was revised in 1986 and
most recently in 1997 being published on behalf of
the AJCC and the Union Internationale Contre le
Cancer (UICC). In the TNM classification system for
NSCLC (appendix two, figures one and two), the Tfactor represents the extent of the primary tumour,
the N-factor denotes the extent of regional lymph
node involvement, and the M-factor corresponds to
the presence of extra-thoracic metastasis.
A variety of investigations can be used to establish
the stage of the disease and in practice staging is
often carried out alongside diagnosis.
5.2
Techniques included in this Review
Non-invasive methods used to stage lung cancer
included in this review are Computerised Tomography
(CT), Positron Emission Tomography (PET) (excluding
gamma camera PET) and more recently PET-CT,
Magnetic Resonance Imaging (MRI), Bone
Scintigraphy (BS) and Ultrasound (US). Invasive
staging techniques evaluated include
mediastinoscopy, thoracoscopy, Video Assisted
Thoracic Surgery (VATS), Endoscopic Ultrasound
guided Fine Needle Aspiration (EUS-FNA) and
percutaneous Trans-Thoracic Needle Aspiration biopsy.
Methodology
5.4.2
Small Cell Lung Cancer (SCLC)
The simple staging system introduced by the
Veterans Administration Lung Cancer Study Group
(VALG) of ‘limited’ and ‘extensive’ disease is
generally applied in clinical practice and has proven
adequate for most clinical situations (appendix two,
figure three). In addition the revised TNM system has
limited use in SCLC, except in those patients
undergoing surgical resection.
44
5.5
LUNG C ANCER
S TAGING OF LUNG C ANCER
T-Stage Assessment
NPV 82% and PPV 68% (Level II DS) with
significant variability (range 38-100%).
Despite many prognostic factors, stage at
presentation has significant bearing on the lung
cancer patient’s eventual outcome. The T-stage
involves predominantly intra-thoracic assessment of
the primary tumour in terms of size, location and
relationship to surrounding structures.
In considering whether there is specifically local chest
wall invasion the reliability of CT was similar with a
sensitivity 64%, specificity 74%, NPV 91% and PPV
56%. For central T3/4 tumours, reliability of CT in
assessing whether there is mediastinal involvement was
limited with a sensitivity of 76%, specificity 80%, NPV
86% and PPV 67% (Level II DS).
Accurate discrimination between T1 and T2 has
limited clinical relevance, as it does not significantly
affect the choice of treatment. However,
differentiation between T2 and T3 disease, and T3
and T4 involvement will have important prognostic
and therapeutic implications.
CT remains the mainstay of radiological clinical
staging though MRI has been advocated as an
alternative. In assessing the current role of CT and
MRI in the T-staging of lung cancer appropriate
studies were systematically reviewed with
consideration to the reliability of differentiating T2
and T3, and T3/4 status, reflecting the presence of
invasion of mediastinal and chest wall structures
which has significant implications on whether or not
the tumour is resectable. Study inclusion was based
on patients with histologically proven NSCLC without
distant metastases who were being assessed for
surgery. All studies evaluated CT in assessing T-stage
either alone or against another modality (usually
MRI). Pathological staging following surgical
resection was the usual comparison.
An alternative to radiological staging is surgical staging
with video-assisted thoracoscopy (VATS) used
specifically to assess pleural and chest wall involvement.
Few studies have been published in this area.
5.5.1
Computerised Tomography (CT) in T-Staging
A recent systematic review of 15 studies evaluating
the reliability of CT in predicting T2/T3 and T3/4
status divided studies according to whether the CT
study assessed for chest wall invasion, or mediastinal
involvement or both90 (see Table 22). Within these
groups, studies showed similarity in patient groups,
location of tumour, radiological criteria for
assessment and outcome measures. The overall
reliability of CT in predicting T3 or T4 disease is
quite poor with a sensitivity 55%, specificity 89%,
these studies as they were performed prior to the
advent of spiral and multislice CT (see 5.5.5).
5.5.3
Much of the literature on VATS has dealt with its
role in the diagnosis and management of the solitary
pulmonary nodule (see chapter 4 Diagnosis). Several
small retrospective series have examined the role of
VATS prior to formal thoracotomy in looking for
pleural and chest wall involvement (T-status) with or
without N-stage assessment (see section 5.6). VATS
was found to be a safe procedure (see chapter 6
Surgery) but because of significant heterogeneity in
patient selection, methodology described and
comparisons used these papers were discarded.
Unfortunately no conclusions can be made regarding
the effectiveness of VATS in detecting radiologically
occult chest wall disease owing to the limited trial
data available. Further research in the use of VATS as
a staging tool is required.
In conclusion, to stage the extent of the primary
tumour a chest CT should be performed for patients
with lung cancer, although CT alone should not be
relied upon to assess chest wall and mediastinum
invasion. A recommendation to support this is in the
diagnosis chapter.
5.5.4
5.5.2
Our search retrieved one paper examining the
reliability of MRI in assessing T-status, (Table 23). This
study (N=170) showed no significant difference
between the two modalities (CT and MRI) in detecting
chest wall involvement (P=0.77)91. However, MRI was
marginally more accurate than CT in diagnosing
mediastinal invasion (Level III DS) (P=0.047)91. For
MRI the overall sensitivity was 56%, specificity 80%,
PPV 24% and NPV 22%, the prevalence was 29%.
The systematic review assessing the reliability of MRI
in predicting T3 or T4 status showed no significant
advantages over CT90 (Level II DS).
Overall, in regard to MRI and T3/4 assessment, from
the few studies in this area there appears to be no
general advantage over CT scanning. However, there
may be specific circumstances whereby MRI scanning
may provide additional information over and above
CT, although care should be exercised in interpreting
5.5.5
5.5.6
Pleural Effusion
Malignant pleural effusions are classed as T4 disease
in the NSCLC staging classification system. It is
important to determine the extent of the effusion so
that the appropriate treatment strategy can be
determined. The British Thoracic Society (BTS) have
developed guidelines based on a systematic review
of the literature93 and these should be referred to in
the management of patients with (suspicious)
malignant pleural effusions.
5.6
N-Stage Assessment
The most important aspect of intrathoracic staging is
the determination of nodal (N) involvement. Nstaging not only establishes the treatment that the
patient will be offered (perhaps most importantly, if
they are eligible for curative surgery) but in addition,
the prognosis of the patient. This review is concerned
with the accuracy of staging N2 and N3 disease. In
current clinical practice, apart from a sub-section of
patients with N2 disease, patients with mediastinal
disease are not eligible for curative surgery.
Future Considerations for T-Staging
Recent technical improvement in CT imaging with
helical and multi-detector CT leading to faster
scanning times whilst using thin sections leading to
and reduced motion/ respiratory artefacts, together
with vascular enhancement techniques, are likely to
improve current delineation of tumour invasion.
Multiplanar reconstruction methods with isometric
voxels in multislice CT are likely to provide improved
diagnostic information over conventional imaging.
Clinical evaluation is awaited.
Magnetic Resonance Imaging in T-Staging
reported that MRI provided better detail of tumour
involvement around the brachial plexus and
vertebral bodies.
Thoracoscopy in T-Staging
With the development of Video-Assisted
Thoracoscopic Surgery (VATS), staging thoracoscopy
may allow assessment of visceral pleural involvement
by tumour and provide information on T-status
beyond standard assessment.
The False Positive (FP) rate (1- PPV) is probably the
most important factor in determining whether or not
to consider surgical resection. It was relatively high
for both central and peripheral tumour groups (FP
rate of 23% and 44% respectively) and therefore CT
does not appear to be reliable in assessing chest wall
or mediastinal tumour involvement unless overt
evidence of invasion is demonstrated, such as bone
destruction or vascular invasion (Level II DS).
45
Pancoast tumours
Pancoast tumours arise in the apex of the chest,
often invading the lower portion of the brachial
plexus, the upper thoracic ribs and vertebral bodies,
the stellate ganglion and the sub-clavian vessels.
There is little data on the staging of Pancoast
tumours. One paper was retrieved. Heelan et al92
measured the diagnostic accuracy of MRI and CT in
the T-staging of Pancoast tumours (Table 25) and
CT and MRI scans, which represent conventional
imaging technologies for staging the mediastinum,
rely on an anatomic assessment of the area,
specifically, the size of the lymph node to predict
malignancy. While the cut-off size for lymph node
malignancy can vary from study to study, there is a
general consensus within the literature that 1cm on
the short axis is the threshold used to differentiate
non-malignant nodes from enlarged, malignant
nodes94. There has been recent interest in Positron
Emission Tomography (PET) scans for staging the
mediastinum. PET scans permit a metabolic
assessment of the region under suspicion by relying
on tumour cells metabolising an injected radioactive
tracer faster than non-malignant cells. The scanner is
able to detect such areas of high metabolic activity.
This review is restricted to the use of 18F-deoxyglucose
positron emission tomography (FDG-PET).
46
5.6.1
LUNG C ANCER
Computerised Tomography in N-Staging
We retrieved a recent systematic review that
evaluated the diagnostic accuracy of CT for staging
the mediastinum95. This was updated with our own
search, which located three new trials (Table 24).
Pooled sensitivity, specificity, PPV and NPV figures
from the review were 57% (95% CI 49-66%), 82%
(95% CI 77-86%), 56% (range 26-84%) and 83%
(range 63-93%) respectively (Level III DS), although
there was marked heterogeneity between the
individual reported figures. The additionally retrieved
studies ranged from 37-60% sensitivity, 73-91%
specificity, 51-85% PPV and 56-81 NPV (Level Ib
and II DS).
In conclusion, CT enables the detection of enlarged
mediastinal nodes, but the poor specificity makes
tissue sampling necessary to determine the patients
true nodal status if surgery is a therapeutic option
(Level Ib, II and III DS). A recommendation to
support this is in the diagnosis chapter.
5.6.2
FDG-PET in N-Staging
A recent systematic review on mediastinal staging
using FDG-PET was retrieved and updated95. We
retrieved three additional studies96-98 that met the
inclusion criteria (see Table 26). Pooled weighted
averages calculated from the review reported
sensitivity and specificity as 84% (CI 0.78-0.89) and
89% (CI 0.83-0.93) respectively and PPV and NPV
as 79% (range 0.4-1.0) and 93% (range 0.75-1)
respectively (Level II DS). The additional studies
reported sensitivities and specificities in the range of
61-68% and 72-84% and PPVs and NPVs in the
range of 56-88% and 64-87% (Level II DS). The
sensitivity and specificity of FDG PET is therefore
better than CT.
In conclusion, FDG-PET allows a reasonably accurate
determination of mediastinal disease. It is reasonable
not to proceed with tissue sampling in the presence
of a negative study of the mediastinum, but a
positive study may require tissue sampling because
there are false positive results associated with
infection and inflammation (Level II DS).
S TAGING OF LUNG C ANCER
5.6.3
Combined use of CT prior to FDG-PET
in N-Staging
5.6.4
There were several methodological weaknesses in the
studies included in this analysis. The majority of
studies were not controlled trials and tended to
focus on diagnostic accuracy rather than patient
outcomes such as surgery rates, survival or quality of
life. Despite this however, the consistency of results
reported from the studies suggest they are reliable.
Therefore there is evidence to support the use of
FDG-PET for potential candidates for surgery who are
negative for mediastinal disease on CT (Level II DS).
5.6.6
Twelve studies were retrieved in a recent systematic
review 103 and no additional studies were found (see
Table 30). A total of 910 patients were included, 99.7%
of whom had lung cancer. The overall sensitivity and
specificity was reported as 76% (95% CI 72-79) and
96% (95% CI 91-100%). The prevalence varied
among the studies, from between 30 and 88% which
may be responsible for the large range of NPVs. The
average weighted NPV and PPV was 71% (range 36100%) and 100%, respectively. TBNA has a better
sensitivity and specificity than EUS-FNA which has 88%
sensitivity and 91% specificity (Table 29). In conclusion,
TBNA allows an accurate assessment of accessible
mediastinal nodes (Level II DS).
The pooled weighted sensitivity, specificity, PPV and
NPV for this modality from the systematic review was
78% (95% CI 61-89), 71% (95% CI 56-82), 75%
(range 38-100) and 79% (range 25-76%),
respectively (Level II DS). The additional study
retrieved reported 70% (95% CI 50.6-85.3), 81%
(95% CI 68.6-89.6), 64% and 85%, respectively
(Level Ib DS). EUS alone has a better sensitivity than
CT for those nodes that can be visualised.
In conclusion, EUS allows a reasonable evaluation of
accessible mediastinal lymph nodes (Level Ib and II DS).
5.6.5
Endoscopic Ultrasound Guided Fine Needle
Aspiration (EUS-FNA) in N-Staging
EUS-FNA is commonly performed by oesophagoscopy
under conscious sedation. As a tissue sample is
taken during the procedure, the technique can act as
its own gold standard to verify the presence of
malignant disease.
A systematic review of five studies, which had little
variation in performance characteristics103, was
updated with one additional paper 98(Table 29). The
sensitivity, specificity, PPV and NPV of the review was
88% (95% CI, 82-93), 91 (95% CI 77-97), 98%
(range 96-100%) and 77% (range 68-100%)
respectively (Level II DS) compared to 63%, 100%,
100% and 68% in the additional study (Level II DS).
EUS-FNA allows a reasonably accurate assessment of
accessible mediastinal lymph nodes (Level II DS).
These results however, come from studies of patients
commonly with radiographic evidence of mediastinal
lymphadenopathy accessible by a biopsy needle.
Transbronchial Needle Aspiration (TBNA)
in N-Staging
TBNA, or the Wang technique as it is also known,
removes aspirate material or paratracheal or
subcarinal lymph nodes using a flexible
bronchoscope. This has a good specificity but is not
sensitive (Table 30).
The NCC-AC retrieved a systematic review which
incorporated five studies that assessed the use of
EUS to stage the mediastinum 95. We retrieved one
additional paper which met our inclusion criteria102.
Both are shown in Table 28.
A recent Heath Technology Board for Scotland
(HTBS) represents the most appropriate and up-to
date systematic review of potential candidates for
surgery99,100. The NCC-AC review team undertook a
search to update this review of 17 observation trials
and retrieved one additional paper that has been
incorporated into the results101 (Table 27).
Appendix three, Figure 1 shows the diagnostic
accuracy of combined use of CT and FDG-PET of all
retrieved studies, which is divided into those patients
who were designated CT negative at initial CT and
those deemed CT positive for lymph nodes. We
calculated the pooled weighted specificity and read
off the sensitivity from the summary receiver
operating characteristic (sROC) curve. While
sensitivity for diagnosing mediastinal disease is high
in both groups of patients, 90% and 94% for CT
negative and CT positive groups, respectively, the
specificity of CT positive patients was much lower
(71%) than CT negative patients (93%). This was
also reflected in the PPV and NPV of the groups
being 57% and 96% respectively, for patients who
were CT negative for lymph nodes and 76% and
92% respectively, for patients with a positive CT for
mediastinal lymph nodes. Thus, the high false
positive rate in CT positive patients means that a
positive PET result cannot be relied upon for
accuracy (Level Ib and II (DS).
The results reported should be interpreted in light of
the fact that the high sensitivity may be due to an
unusually small number of false negatives.
Endoscopic Ultrasound (EUS) in N-Staging
EUS provides high-resolution images that can be
used for the detection of accessible mediastinal
lymph nodes, which are commonly located in the
posterior mediastinum. Studies used a combination
of shape irregularity and echo heterogeneity to
establish the presence of malignancy.
There has been recent interest in combining the
results of CT and PET to increase diagnostic accuracy
in mediastinal staging. By using the results of a CT
scan prior to that of PET scans, it is possible to
assess both the anatomical and metabolic features
of the nodes.
47
5.6.7
Image Guided Transthoracic Needle
Aspiration (TTNA) in N-Staging
A variety of approaches can be utilised to perform
TTNA which may involve traversing lung parenchyma
to obtain histological proof of malignancy. It is most
commonly used to confirm mediastinal involvement
in patients who are not surgical candidates as it is
limited by an inability to sample multiple node
stations. Our search retrieved a systematic review of
five studies103 to which no additional studies were
added (Table 31).
A total of 215 evaluable people were included, 96%
of whom were confirmed to have lung cancer. The
overall sensitivity and specificity were 91 (95% CI
74-97%) and 100%. The NPV again was inversely
correlated with the prevalence, the pooled weighted
average being 83% (range 65-91%) (Level III DS).
TTNA allows an assessment of mediastinal nodes
(Level III DS).
48
5.6.8
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In conclusion, it is often difficult to compare invasive
staging methods as the patients having one test may
differ from patients having another. However,
standard cervical mediastinoscopy appears to have
reasonable sensitivity, a high NPV, and the ability to
assess directly the clinically relevant nodal stations.
Mediastinoscopy in N-Staging
Cervical mediastinoscopy gives access to the pretracheal and para-tracheal lymph nodes, as well as
lymph nodes between the left and right main
bronchus. Alternatively, an anterior mediastinotomy
via the second or third intercostal space on the left
side allows exploration of the aorto-pulmonary
window, particularly in patients with tumours of the
left lung. A modified technique, an extended cervical
mediastinoscopy has been described for assessing
the same region. In addition, video-assisted
techniques in combination with standard cervical or
extended mediastinoscopy have also been described
in small series.
5.6.9
Study inclusion for our review was based on patients
with histologically proven NSCLC without distant
metastases who were being assessed for surgery. All
studies evaluated mediastinoscopy in assessing
N2/3 disease either alone or against another
modality (usually CT).
The most recent systematic review of mediastinal
staging by standard cervical mediastinoscopy
included 14 studies (N=5867) (Table 32). The overall
sensitivity was 81% (95% CI, 0.76-0.85). The overall
NPV was 91% (range, 58-97%) with a prevalence of
37% (range, 21-54%). This gives an average false
negative (FN) rate of approximately 10%. However,
in at least four of the studies reviewed, the FN rate
was affected by detection of positive nodes at
surgery that were inaccessible by conventional
mediastinoscopy. In addition, the FN rate is likely to
be affected by the diligence with which nodes are
sampled at mediastinoscopy90.
The specificity and PPV for mediastinoscopy were
both reported to be 100%. These values cannot be
assessed as patients with positive lymph nodes were
not subject to any further procedures. However,
several commentators have suggested that the FP
rate is likely to be low 90,103.
5.6.10
The current wave of FDG-PET scanners are integrated
PET-CT scanners and it is likely that the diagnostic
accuracy of these machines will better than the
estimates from the published literature.
There has been interest in recent years in the
detection and diagnosis of non-palpable
supraclavicular lymph nodes using CT and US, with
promising results104.
5.7
Several observational papers examined the role of
VATS prior to formal thoracotomy in assessing
mediastinal lymph node stations that are generally
inaccessible to standard cervical mediastinoscopy.
Patient selection, lymph node station selection and
comparison groups were variable and so no studies
passed our quality assessment criteria. Therefore, no
conclusions can be made regarding its role and
further research is needed.
M-Stage Assessment
Distant metastases are present in most SCLC
patients and around 40% of NSCLC patients at
presentation105. The presence of distant metastases
leads to a classification of stage IV disease and these
patients are no longer candidates for radical therapy.
It is therefore important that metastases are
identified prior to treatment planning to minimise
the number of futile radical therapies.
Approximately 90% of NSCLC and SCLC patients
with distant metastases have symptoms indicative of
these sites105. In many ways this makes M-staging
straightforward although no test is 100% accurate
and patients without symptoms may still have occult
metastases. The clinician therefore faces a number of
decisions for the most efficient way to carry out Mstage assessment.
Thoracoscopy in N-Staging
Staging thoracoscopy or VATS provides access to
nodal stations that are not accessible by standard
mediastinoscopy, such as the aortopulmonary
window. In addition, it may allow assessment of
visceral pleural involvement by tumour and provide
information on T-status beyond standard assessment.
Future Considerations
There has been recent interest in improving
assessment on CT by including morphological
features of the nodes i.e. contour and
heterogeneity90.
Anterior Mediastinotomy and Extended
Cervical Mediastinoscopy
In the context of left upper lobe tumours, limited
information is available on the two additional
methods that allow access to the aortopulmonary
window (but not other stations particularly), anterior
mediastinotomy and extended cervical
mediastinoscopy. The American College of Chest
Physicians’ (ACCP) systematic review103 evaluated
two small observational studies (N=206) (Table 32
and Table 34) and noted that both methods had low
sensitivity (for anterior mediastinotomy 63% and
83%, and extended mediastinoscopy, 45% and
51%) compared with other invasive tests. But as an
adjunct to standard mediastinoscopy there was
improved sensitivity (for anterior mediastinotomy
87% in both studies, and extended mediastinoscopy
82% and 89%) and NPV (for anterior
mediastinotomy 89% and 92%, and extended
mediastinoscopy 82% and 89%) in patients with
left upper lobe tumours.
Previous guideline recommendations concerning
mediastinoscopy have reinforced the belief that it is
the “gold standard” among staging tests of
mediastinal lymph nodes. It is performed under a
general anaesthetic, either as a day-case or short
stay procedure, with low rates of morbidity and
mortality (see chapter 4 on Diagnosis).
5.6.11
5.7.1
Clinical Evaluation
The clinical evaluation is an essential part of the Mstage assessment. Not only will clinical investigations
indicate the presence of distant metastases but will
also direct further investigative tests.
Clinical examination consists of a history and
physical examination to include routine
haematological and biochemical blood tests and a
CXR. As common practice many patients will also
have had a CT scan of the chest and liver for
diagnostic purposes. The clinical signs that suggest
the presence of distant metastases are shown below.
49
Clinical findings that suggest the presence
of distant metastasis
General findings
weight loss ≥10%; fatigue; decreased
albumin; decreased hematocrit; increased
white blood cell count; increased platelets
Indication of
brain metastases
headache; nausea; other neurological
symptoms or signs
Indication of
bone metastases
skeletal pain; elevated alkaline
phosphatase (ALK-P); hypercalcemia
Indication of
liver metastases
Right upper quadrant pain;
hepatomegaly; elevated ALK-P, serum
glutamic-oxaloacetic transaminase,
lactate dehydrogenase or bilirubin
Indication of
adrenal metastases none
5.7.2
Clinical Evaluation to Detect Specific Sites
of Metastasis
5.7.2.1 Brain
A recent review was retrieved by our search that
comprised 17 studies which compared the ability
of the clinical examination against CT, MRI or PET
(reference standard) to detect brain metastases95.
Our update search retrieved no additional papers
(Table 35). Nine studies within the review included
patients with a negative clinical evaluation while
the remainder included patients with both positive
and negative evaluations. For both groups of
patients the pooled sensitivity was 76% (95% CI
64-84), the specificity 87% (95% CI 74-94), PPV
54% (range 21-100%) and NPV (range 79100%). Cerebral metastases are more likely in
patients with adenocarcinomas, N2 disease or
large primary tumours and therefore careful
clinical examination for cerebral metastases in this
group should be undertaken.
In conclusion, clinical evaluation detects around
76% of patients with brain metastases (level III DS).
5.7.2.2 Bone
A recent review was retrieved by our search which
comprised 17 studies that had each compared
clinical examination against radionuclide bone
50
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scanning (reference standard) for the detection of
bone metastases95. Our update search retrieved no
additional papers (Table 36).
that met our inclusion criteria and are included in
the results reported below (Table 38).
The summary receiver operator characteristic curve
(appendix three, Figure two) illustrates the
distribution of values for the detection of distant
metastasis. We calculated the pooled weighted
specificity and read off the sensitivity from the sROC
curve. This gave a sensitivity of 93% and specificity
96%. It seems conclusive that FDG-PET had a high
sensitivity and specificity for the detection of
extrathoracic disease (Level III DS).
The sensitivity, specificity, PPV and NPV of the
clinical evaluation to detect bone metastasis is 87%,
67%, 36% and 90%, respectively.
The clinical evaluation allows a reasonably accurate
determination of the presence of bone metastasis
(Level III DS).
5.7.2.3 Liver and Adrenal
In addition to the diagnostic accuracy of FDG-PET,
17 observational studies were included in the HTBS
report which reported the rate of unexpected distant
metastasis detected and subsequent patient
management changes99. The studies recruited a
combination of patients eligible for radical therapy
(surgery: three studies, radiotherapy: one study and
both: five studies). One additional paper96 that
comprised potentially surgical candidates, was
retrieved and incorporated into the results reported
in this section (Table 39).
Our search retrieved a recent review which comprised
12 studies that compared the ability of the clinical
examination against CT (reference standard) to detect
both liver and adrenal metastasis95. Our update search
retrieved no additional papers (Table 37).
In conclusion, while the sensitivity and NPV of the
clinical evaluation is high for the detection of
abdominal metastasis (92% and 95% respectively),
the specificity and PPV is low (49% and 32%
respectively) (Level III DS).
5.7.3
From the review and additional studies, an average
of 15% of patients had unexpected distant
metastases detected by FDG-PET (range 8-39%),
which resulted in management changes (as a result
of detected metastasis only) in 25% of patients
(Level 2++).
Imaging of Distant Metastasis
Studies that looked at the effectiveness of imaging
techniques to detect the presence of distant
metastasis can be split into two broad areas. Firstly,
we retrieved studies that evaluated the ability of a
whole body FDG-PET scan to detect the presence of
all distant metastasis and the subsequent
management changes which ensue. Secondly,
studies were evaluated that reported the diagnostic
accuracy of imaging techniques including CT, MRI
and FDG-PET to detect the most common sites of
lung cancer metastasis in the brain, liver, adrenals
and bone, this is discussed from 5.7.4 onwards.
5.7.3.1 All Sites
The HTBS systematic review of around 17
observational trials was the most recent and
comprehensive evidence of the effectiveness of a
whole body FDG-PET scan to detect distant
metastasis99. The literature mostly concerned
patients who were candidates for surgery (and was
not split into CT positive and negative groups). Our
update search retrieved two additional papers96,106
5.7.4
5.7.4.1 Brain
The brain is one of the most common sites of
metastasis for lung cancer patients; the incidence
of brain metastasis in necropsy studies vary from
30%-50%107. While screening for cranial
metastasis has been investigated, the low pick up
rate of positive scan without neurological signs and
symptoms and the high cost of scanning all
patients, means it is not thought to be either
clinically or financially worthwhile108. This section
will review the evidence of CT and FDG-PET to
accurately diagnose cranial metastasis.
One paper was retrieved that measured the ability of
CT to detect disease in potentially operable patients
free from sign and symptom of cranial metastasis108
(Table 40). An additional paper reports the accuracy
of FDG-PET (Table 41) and MRI plus CT in newly
diagnosed NSCLC patients109 (Table 42). The
diagnostic accuracy of CT plus MRI was the most
accurate imaging modality for the detection of
distant metastasis (sensitivity: 100%, specificity:
100%, PPV: 100% and NPV: 100%), followed by
FDG PET and finally CT (Grade III DS). Although
these results are encouraging, the heterogeneity of
the patients both across and within each study and
the small number of patients within each study make
it difficult to reach any firm conclusions. MRI is
believed to be the most sensitive technique to
demonstrate metastases in the brain and would be
the modality of choice, followed by CT if the patient
cannot tolerate the MRI scanner.
Imaging of Specific Sites of Metastasis
Studies that report on imaging modalities for
detecting distant metastases vary widely in quality
and results. The type of reference standard used
(which may be a repeat scan, alternative scan,
follow-up, histology or a combination of this list) and
the heterogeneity in patient populations both
contribute to the variety in results for each test.
Papers with reference standards other than at least a
follow-up of 6 months or histology were excluded. It
should also be noted that, in the majority of
instances, the literature fails to report either the
results broken down by stage (clinical or
pathological) or to compare the results of those
patients with symptoms against those without. More
research is needed in this area.
5.7.4.2 Liver
Due to its anatomical location, the liver is now
routinely imaged in combination with the patient’s
initial chest CT in the initial staging protocol.
Despite having relatively low incidence (in clinically
staged I-III patients, liver metastasis occur in
approximately 2% of patients)105, metastatic imaging
at such an early stage in the pathway can
immediately identify those not going onto a radical
treatment. Perhaps because of this low incidence
there are comparatively few studies with adequate
reference standards which evaluate CT, FDG-PET and
ultrasound for the detection of liver metastasis.
Three papers, with a total of 312 patients, reported
results on the ability of CT to detect malignancy in the
51
liver (Table 43)109-111. The pooled weighted results from
these studies were a sensitivity 97% and specificity of
94% (Grade III DS). One paper, with 78 patients,
reviewed the ability of PET to detect liver metastasis109
(Table 44). It reported a sensitivity of 100% and a
specificity of 100% (Grade III DS). These results were
compared to that of one paper with 77 patients which
reported results of ultrasound110, sensitivity 92% and
specificity 96% (Table 45) (Grade II DS). Although
the results from these studies appear encouraging, it
is difficult to draw any firm conclusions from this
small number of heterogeneous participants. There is
not sufficient evidence to depart from the current
practice of routinely scanning the liver during the
initial staging CT.
5.7.4.3 Adrenals
Many of the issues surrounding the detection of
adrenal metastases are associated with
distinguishing metastatic disease from adenomas,
which are also common in lung cancer patients. The
incidence of abnormal and subsequently malignant
adrenal glands appears to be exponentially linked to
clinical stage. We compared FDG-PET109,112,113 (Table
48), CT109,114,115 (Table 46), and MRI116-118 (Table 47)
against gold standard histology to determine the
status of adrenal metastases in lung cancer patients.
In summary, the sensitivity of FDG-PET is in the
range from 84% to 100%, whilst the specificity is in
the range from 80% to 100% (Grade III DS)
compared to MRI, sensitivity: 100%, specificity: 59%
(Grade II DS) and CT scans, sensitivity: 93% and
specificity: 92% (Grade II DS), yet it is important to
remember the heterogeneity of patients in each
study. The available evidence in this area is not
sufficient to depart from the current practice of
routinely scanning the adrenals during the initial
staging CT.
5.7.4.4 Bone Metastasis
Current methods of detecting bone metastases
include X-ray of the local area, bone scintigraphy, CT,
MRI and FDG-PET scans.
This review undertook the comparison of bone
scintigraphy109,119-121 (Table 49) and FDG-PET109,119,120
(Table 50) and MRI121 (Table 51) to diagnose bone
52
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metastases within groups of lung cancer patients.
Again, the breakdown of results was not specific
enough to include results by specific stage or
symptoms. However, the reported results from all
retrieved studies concluded that FDG-PET was the
most accurate (sensitivity: 93%, specificity: 98%
(Grade III DS)) followed by MRI (sensitivity: 92%,
specificity: 94% (Grade III DS)) and finally bone
scanning (sensitivity: 88%, specificity: 64% (Grade
III DS)). These results however, are based on small
numbers and heterogeneous groups of patients and
cannot be relied upon to make a recommendation
that departs from current clinical practice.
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5.7.5.2 Potential Candidates for Radical Radiotherapy
No systematic reviews were retrieved for this section
and a full literature search retrieved four
observational studies124-127 that reported therapy
changes (Table 53). A pooled weighted average for
therapy changes that ensued as a result of the FDGPET scan during work-up to radical radiotherapy was
42%. In addition to this, one study reported that
23% of patients were downstaged as a result of the
FDG-PET scan while two studies reported that
between 27-45% of patients were upstaged.
5.9
Economics of Lung Cancer Staging
5.9.1
Search Results
The studies on economic analysis pertaining to PET
scanning are summarised in Table 54 and Table 55.
The rest of the staging economics studies118,128-141 are
summarised in Table 56 and Table 57.
There were a number of cost-effectiveness studies
evaluating PET scanning; however, we focused more on
the report of the HTBS, the only one from a UK context.
In conclusion, those patients who are potential
candidates for radical radiotherapy would benefit from
a FDG-PET scan prior to their treatment (Level 2+).
The evidence concerning the cost-effectiveness of
PET scanning was largely inconclusive or
inapplicable. Given its potential clinical importance
and substantial cost, an original cost-effectiveness
study from an NHS perspective was conducted to
enable the GDG to make a decision in this area.
The Addition of FDG-Pet to Work-up to
Radical Therapy
The earlier evidence regarding FDG-PET reported on
the effect of the technology on both N and M
staging. There are however, some studies looking at
the outcome of FDG-PET on patient management
change, bringing together N and M staging during
work-up to surgery and radical radiotherapy.
5.7.5.1 Potential Candidates for Surgery
One RCT122 reported futile thoracotomy rate as its
primary outcome. This study has an unusually high
surgery rate considering the group of patients
recruited for it and included a high incidence of
thoracotomy for benign disease when compared to
current UK practice. In addition the comparator CT
scans were performed suboptimally in half of the
patients, without intravenous contrast, excluded the
liver and were non spiral. Nevertheless the results
can be interpreted as five patients need an FDG-PET
scan to avoid one futile thoracotomy. In addition,
one observational study123 incorporated patients
eligible for both surgery and radical RT reported that
83% of patients undergoing a pre-treatment FDGPET underwent a management change (i.e. change
from one radical treatment to another or from a
radical treatment to a palliative one) (Table 52).
In conclusion, potential candidates for surgical resection
would benefit from a FDG-PET scan (Level 2+).
5.8
Staging of Small Cell Lung Cancer
Small cell lung cancer (SCLC) patients are staged, as
described earlier, into two categories: limited and
extensive disease. Extensive disease refers to cases
where there is metastatic spread. Thus intrathoracic
staging in SCLC has little clinical relevance.
Most SCLC patients present with symptoms of
metastases and a systematic review found that two
thirds have extensive disease on presentation105. This
review also found, from combining the figures from
five studies with a total of 1,806 patients, that the
most common sites of metastases at presentation
were the liver and bone. Thus further investigation
for distant metastases is always indicated in SCLC.
For symptomatic patients the choice and site of
staging examination should be guided by clinical
examination. For asymptomatic patients a history
and physical examination should be followed by a
choice of one or more of the following tests: CT of
chest, upper abdomen (liver and adrenals) or bone
scan. Tests should be performed sequentially and the
testing stopped once a metastatic site is found128
(see 5.9.5). Detterbeck et al looked at the reliability
of neurological examinations for staging SCLC and
concluded that CT or MRI of the brain was not
worthwhile in asymptomatic patients105.
5.9.2
Report of the Health Technology Board for
Scotland (Bradbury et al, 2002)
Bradbury et al99 conducted a cost-effectiveness
analysis to evaluate different strategies for staging
NSCLC. They used a decision tree, which calculated
cost-effectiveness in terms of the cost per qualityadjusted life-year (QALY) gained.
The model evaluated the use of PET in patients that
had the following characteristics:
>
Definite diagnosis of NSCLC
>
Fit for surgery
>
Have already had CXR, bronchoscopy & chest CT
Therefore the model does not consider the use of
PET in patients who have symptoms that might
indicate metastasis and it does not assume that
routine scanning for metastasis has taken place
(other than with chest CT). However, it is assumed
that 10% have distant metastases that are only
detected by PET.
Appendix one, figure two shows strategies evaluated
for the patient group. The cost-effectiveness of each
strategy was evaluated separately for patients that
had enlarged nodes on their CT scan (CT node
positive) and those that had normal-sized nodes on
CT (CT node negative).
53
Bradbury et al conducted their own meta-analyses to
estimate the sensitivity and specificity of PET, as
reported above (see sections 5.6.2, 5.6.3, 5.7.3, 5.7.4
and 5.7.5). The unit cost of a PET scan (high
resolution with attenuation correction) was
estimated from a detailed costing of proposed
Scottish PET facility. Estimates of the other model
parameters (probabilities, life expectancies, quality of
life valuations and unit costs) were extracted from
the literature, mainly from Dietlein et al142.
Results - CT Node-positive
It was found that strategies 3 and 7 dominate the
other strategies, that is to say that compared with
one of these two, each of the other strategies was
both more costly and less effective. Strategy 3
(mediastinoscopy all and no PET) had second best
outcome. Only strategy 7 (mediastinoscopy after
positive PET) had a higher expected level of QALYs
at an incremental cost of £59,000 per QALY gained.
Hence PET scanning does not appear to be costeffective in CT positive patients, when using a
threshold of £30,000 per QALY gained. None of the
strategies were clearly differentiated apart from
strategy 2, which had the worst outcome and
highest cost.
Results - CT Node-negative
Strategies 1, 3 and 7 were found to dominate the
others. Strategy 3 had second best outcome. Only
strategy 7 had a higher expected level of QALYs at
an incremental cost of £10,500 per QALY gained.
Hence PET scanning appears to be cost-effective in
CT negative patients, however the model suggests
that those who are PET positive should be given a
follow-up mediastinoscopy, given its 100%
specificity for N2/3 disease.
The overall health outcome in terms of lifeexpectancy or quality-adjusted life expectancy was
very similar for all strategies (except strategy 2,
where everybody receives only best supportive care).
This suggests that the cost-effectiveness results are
not robust to changes in the model parameters.
54
5.9.3
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detection of bone metastases in patients with initial
diagnosis of lung cancer. F-18 NaF PET had greater
accuracy and higher costs compared to other methods.
However, this study evaluated the use of the procedure
in detecting bone metastases only and took into
account direct costs of these procedures only.
Therefore, the results are not comparable to other
studies reported where FDG-PET was used for detecting
nodal involvement and all distant metastases.
Overseas Economic Evidence for the use of
FDG-PET in Staging NSCLC
The other economic analyses are presented in Table
54 and Table 55. Of the eight previously published
studies, there were six cost-effectiveness, one costaccuracy and one cost analysis.
The three cost-effectiveness studies were all based
on decision analyses142-144. Their results were similar
in that all four studies seem to show that
mediastinoscopy after a positive PET was the most
effective strategy. Dietlein142 found that this strategy
is highly cost-effective in CT negative patients and
fairly cost-effective in CT positive patients. Scott et
al144 found, as did the HTBS report99, that this
strategy is only cost-effective in CT negative patients.
Gambhir et al143 did not evaluate PET separately for
CT negative and CT positive patients.
99
As with the HTBS report Bradbury et al , Dietlein et
al142, Scott et al144, and Gambhir et al143 found very
little difference in life expectancy (or in cost)
between strategies, implying that the models are
sensitive to the model parameters.
The cost-effectiveness analysis of Verboom et al.,145
based on a Dutch RCT, compared conventional work
up (CWU) with CWU+PET. Their results showed that
additional use of PET in the staging of patients with
NSCLC reduced unnecessary thoracotomies by 20%
when compared to CWU alone and was cost-saving.
Among the cost-effectiveness analysis, two were
based on prospective studies. Von Schulthess et al.146
compared CT and bone scanning with whole body
PET. They found that whole-body PET staging was a
dominant strategy over the other as PET staging was
more effective in terms of reducing unnecessary
operations and was cost-saving. Fritscher-Ravens et
al’s 98 analysis based on two-year prospective study
comparing computed tomography, PET and
endoscopic ultrasound (EUS) with FNA for the
staging of potentially operable patients with
suspected or proven lung cancer. The results
indicated that PET strategy was cost-effective.
Hetzel et al’s,147 cost-accuracy analysis compared the
use of F-18 NaF PET with planar bone scintigraphy (BS)
and single photon emission tomography (SPECT) for
Harewood et al.148 evaluated the costs of alternative
staging evaluations of enlarged subcarinal lymph
nodes (SLNs) in patients with NSCLC using decision
analysis. EUS-FNA biopsy has the least cost but the
study did not take into account the clinical
effectiveness and quality of life of patients.
5.9.4
Original Economic Evaluation of FDG-PET in
Staging NSCLC
We conducted an economic evaluation for two
groups of NSCLC patients that were identified as
having the most to gain from PET scanning:
>
Potentially operable patients with normal sized
lymph nodes on CT being considered for surgery
>
Patients being considered for radical
radiotherapy (mainly with enlarged nodes on CT)
thoracotomy (PET=M0 N0/1) or go on to
mediastinoscopy (PET=M0 N2/3)
Patients go straight to radical radiotherapy
>
Patients have a PET scan and then receive either
active supportive care (PET=M1+) or
thoracotomy (PET=M0 N0/1) or radical
radiotherapy (PET=M0 N2/3)
It is assumed that all patients (except those that
have successful surgery) go on to have active
supportive care including chemotherapy.
A detailed description of methods and results can be
found in appendix four. Some of the assumptions
remain unchanged from the HTBS model.
Substantial changes are as follows:
>
>
For both patient groups we have estimated costs and
health outcomes for different strategies using
decision analysis. Our decision analytic models are
adapted from those previously reported in the
literature, especially the HTBS model 99 and Dietlein
et al142. For each strategy the primary outcomes are:
>
Health service cost per patient
>
QALYs per patient.
For the patients being considered for surgery, three
strategies were compared:
>
Patients go straight to thoracotomy
>
Patients have a mediastinoscopy and then
receive either radical radiotherapy (Med=N2/3)
or thoracotomy (Med=N0/1)
>
Patients have a PET scan and then receive either
active supportive care (PET=M1+) or
>
We have re-estimated the underlying distribution
of disease. In particular, unlike the HTBS model
we do not assume that distant metastases have
the same prevalence in N0/1 patients as in
N2/3 patients.
>
For patients with numerous enlarged lymph
nodes on their CT scan we considered the most
appropriate comparator to be radical
radiotherapy, rather than thoracotomy or
mediastinoscopy.
>
In both our models we explicitly estimate the
number of patients receiving radical radiotherapy,
and we estimate the corresponding implications
for cost, survival and toxicity. The LY gained from
radical radiotherapy compared with active
supportive care was estimated to be 9 months.
>
For both thoracotomy and radical radiotherapy
we assume a conservative 50% reduction in
quality of life for eight weeks attributable to the
temporary effects of treatment.
For the patients being considered for radical
radiotherapy, only two strategies were compared:
>
>
When replicating their model, we found that the
authors of the HTBS model had (inadvertently)
used sensitivity and specificity that had been
calculated for CT positive patients when they
should have those figures calculated for CT
negative patients. We corrected this.
PET sensitivity and specificity in the HTBS model
were based on nodes alone (not on distant
metastases). For the detection of distant
metastases, in their base case analysis, they had
in effect assumed that the sensitivity was the
same for distant metastases as it was for nodes
in N0/1 patients but a 0% sensitivity in N2/3
patients. We have calculated sensitivity and
specificity specifically for detecting distant
metastases (see 5.7.3.1) and have applied them
consistently. We have also sought to take
account of the (modest) cost of following up
false positive PET scans for distant metastases
with biopsies.
We have updated the unit costs, including the
cost of a PET scan. The cost of mediastinoscopy
in the HTBS model seemed unrealistically low.
55
Appendix four shows the main outcomes for patients
being considered for surgery. The Mediastinoscopy
strategy is dominated by PET strategy (i.e. it is both
more costly and less effective). Compared with the
thoracotomy strategy, the PET strategy had:
>
fewer futile thoracotomies (avoided in 22% of
patients),
>
fewer surgical deaths (1% of patients are spared
a surgical death) and
>
more appropriate selection of patients for radical
radiotherapy.
This resulted in:
>
improved life expectancy (0.04 years per patient)
and
>
quality-adjusted life expectancy (0.04 QALYs per
patient).
Cost savings, mainly from thoracotomies averted,
offset much but not all of the cost of PET scanning.
The estimated incremental cost-effectiveness of the
PET strategy compared with the thoracotomy
strategy was £7,200 per QALY gained.
56
LUNG C ANCER
Appendix four shows the main outcomes for patients
being considered for radical radiotherapy. Compared
with the radical radiotherapy strategy, the PET
strategy had:
>
fewer courses of futile radical radiotherapy,
>
some patients benefiting from curative surgery,
but,
>
some missed radical radiotherapy courses, and
>
some futile surgery.
This resulted in:
>
improved life expectancy (0.01 years per patient)
and
>
quality-adjusted life expectancy (0.04 QALYs
per patient).
Again cost savings, this time mainly from radical RT
courses averted, offset much but not all of the cost
of PET scanning. The estimated incremental costeffectiveness of the PET strategy compared with
the radical radiotherapy strategy was £9,500 per
QALY gained.
For both groups of patients, the results were robust
to sensitivity analysis and the PET strategy is unlikely
to cost more than £30,000 per QALY gained in
either case (see appendix four). Therefore PET
scanning appears to be more cost-effective than a
number of treatments recommended by NICE.
5.9.5
Routine Extrathoracic Screening in Lung
Cancer
Three studies have evaluated routine extrathoracic
screening using technologies other than PET in
patients with potentially operable NSCLC Table 56
and Table 57).
S TAGING OF LUNG C ANCER
the life expectancy of the average patient. This gain
was found to be not cost-effective at a cost of about
£44,000 per QALY gained.
Richardson et al128 presented the cost of different
permutations of the following tests: bone scan,
abdominal CT, cranial CT and bone marrow
aspiration and biopsy (Table 56 and Table 57). At
the end of each permutation were chest CT plus
pulmonary function test. The population was all
patients with newly diagnosed SCLC and no clinical
evidence of extensive disease. In each case testing
was halted once evidence of extensive disease was
found. If all six tests did not indicate extensive
disease then the diagnosis was limited disease. The
lowest cost permutation was bone scan and the
order of the tests undertaken is as follows:
Bone scan ➞ Abdominal CT ➞ Bone marrow
aspirate & biopsy ➞ cranial CT ➞ thoracic CT ➞
pulmonary function test.
At $2,817, this was only $130 lower than the most
expensive permutation but was $1,400 less than
routinely conducting all six tests. Hence they included
that it matters more that tests are performed
sequentially and the testing stopped once a metastatic
site is found than the exact sequence of the test.
132
Colice et al constructed a decision analysis to
evaluate routine head CT compared to symptomatic
head CT to detect brain metastasis. The model was
developed for a US context. The details of the
model are not reported entirely transparently. They
found that routine scanning added just 1.1 days to
Houston et al137 performed a cost analysis
comparing Ga scanning versus conventional routine
testing for distant metastases (radionuclide liver and
bone scans, brain CT scan) in the staging of lung
cancer patients. The decision analysis showed that
Remer et al140 also carried out a decision-analysis of
different strategies for evaluating adrenal masses
including:
the Ga scan was more costly than routine staging
procedures. However, it should be noted that FDG
PET has superceded Gallium, if any radionuclide is
used, and Gallium is not used routinely for lung
cancer staging in the UK.
Tanaka et al141 and Canadian Lung Oncology Group
(Guyatt et al136) both evaluated routine CT (abdomen
& brain) & bone scan versus symptomatic scanning,
from a Japanese and Canadian perspective
respectively. Tanaka’s results were based on a
retrospective cohort, whereas the Canadian study
was RCT-based. The Canadian study saw a bigger
reduction in the number of thoracotomies than the
Japanese study (5/318 versus 3/755) and hence
they differed considerably in their cost implications;
Can$819 (£332) per patient cost saving versus
US$1,226 (£677) additional cost. However, this
might not be down to inconsistency, as the Canadian
group had a broader patient selection than Tanaka
et al141, who considered only T1-2/N0 patients.
On the basis of the limited evidence here, there is
not a strong case for extrathoracic screening in
patients that are asymptomatic for metastasis. It is
possible then that scanning of asymptomatic
patients is cost-effective in some subgroups but not
in others. None of the above studies explicitly
considered PET scanning for extrathoracic screening.
The studies in 5.9.2-5.9.4 evaluated PET both for
intrathoracic and extrathoracic staging. If PET were
to become routine for some patients then this would
almost certainly preclude the need for other
extrathoracic imaging for these patients, although
there may still be a role for CT scanning of the head,
given the lack of accuracy of PET in this area.
5.9.6
MRI Scanning in the Staging of Lung Cancer
There have been four studies (all from the USA) that
have evaluated MRI scanning in the staging of lung
cancer, two with regard to adrenal gland evaluation,
one on brain metastasis and one investigating the
use of MRI in staging SCLC.
Mayr et al139 found that high-dose MRI
(0.3mmol/kg) for brain metastasis could save about
$2,251 per patient compared with low-dose MRI
(0.1mmol/kg) by averting 3 craniotomies and 2
aggressive courses of radiation therapy in 27
patients with CT evidence of bone metastasis.
Jelinek et al138 compared MRI with CT, bone scan
and bone marrow biopsy. In a prospective cohort of
25 patients diagnosed with SCLC. They estimated
that the use of MRI could save approximately $481
per patient and an extra 5 patients were found to
have extensive disease.
Schwartz et al118 conducted a decision analysis based
on a prospective cohort (n=42) to compare chemical
shift MRI with CT-guided biopsy in patients with an
enlarged adrenal gland on CT. They included only
staging costs and found a saving of $15 per patient
with MRI due to 55% of patients avoiding biopsy.
57
a) CT with an adenoma or non-adenoma threshold
of 10H followed by MRI; and
b) CT with an adenoma or non-adenoma threshold
of 0H followed by CT biopsy.
They found that a) was most the cost-effective strategy
at a cost of $16,370 per LY gained compared with b).
As with Schwartz et al118, they only included the costs
of staging and not treatment costs.
In summary, the studies’ results suggest that MRI of
the adrenal gland after CT could be cost-effective. So
could the use of high-dose contrast MRI.
5.9.7
Thoracic CT and Mediastinoscopy
There has been a recent cost-effectiveness analysis135
and three older cost analyses129,131,134 evaluating the
use of chest CT before mediastinoscopy. Two are
Canadian studies131,134 and the others relate to the
USA129,135. The study by Black et al129 found cost
savings but is of minor interest given that the
comparison was with surgery not mediastinoscopy.
Both of the Canadian studies found modest cost
savings attributable to the introduction of CT
scanning to select patients for mediastinoscopy.
Esnaoloa et al135 also found cost savings attributable
to the use of CT before mediastinoscopy, however,
they found that mediastinoscopy without CT had
better patient outcomes and was more cost-effective
than CT for T2/3. The greater effectiveness of
routine mediastinoscopy is not surprising given that
it is considerably more accurate than CT. In T1
patients, where there is a lower risk of nodal
involvement the incremental effect of routine
mediastinoscopy was small (0.022 LY gained) and
not cost-effective (c£49,000 per QALY gained). They
recommend that mediastinoscopy be used selectively
in T1 patients; however, it is possible that the
modest health gains are cost-effective using UK unit
costs instead of US costs.
Hence the studies show that routine
mediastinoscopy is more effective but also more
58
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S TAGING OF LUNG C ANCER
costly than selecting patients for mediastinoscopy on
the basis of their CT results. Routine
mediastinoscopy may not be cost-effective in T1
patients even if it is cost-effective for T2 and T3
patients. However, this has not been evaluated
using UK NHS costs.
to local protocols. This may also impact on the
estimated health gain for patients diagnosed.
b) Studies varied in their assumptions. Not all
studies followed-up patients so that treatment
costs could be included and, among those that
did, treatment pathways varied. Patient
selection could also have affected the estimates
of cost-effectiveness.
Bonadies et al130 showed that, in a US context at
least, outpatient mediastinoscopy is substantially less
costly than inpatient mediastinoscopy.
Our own economic model shows that PET scanning
reduces the amount of futile surgery and futile radical
radiotherapy but is unlikely to reduce the overall cost
of staging and treatment. PET is likely to be costeffective in patients with normal-sized lymph nodes on
CT (this is supported by the published health economic
evidence). We also found that PET scanning is costeffective in patients being considered for radical
radiotherapy because some patients will be downstaged and others can avoid the morbidity associated
with radical radiotherapy.
As with all studies that are not UK-based, and US
studies in particular, we need to be cautious about
transferring the results; certainly prices but also
other parameters may be very different. The studies
compared different strategies, were based on small
sample sizes and had limited follow-up.
5.9.8
Conclusions and Discussion
The published evidence is inconclusive for the UK
but suggests the following:
>
>
>
PET scanning to select patients for surgery is
most effective and cost-effective in patients with
normal-sized lymph nodes on CT.
Routine scanning for extrathoracic metastases
(with imaging modalities other than PET) is not
evidently cost-effective (especially in N0
patients).
Routine mediastinoscopy is more effective than
mediastinoscopy on patients selected by CT
scanning. It appears cost-effective for T2/3
patients but may not be for T1 patients.
We should be cautious in interpreting the results of
studies in this review because of:
a) The setting of the studies was overseas in all but
one case. There are a number of problems
associated with using cost-effectiveness studies
set in health systems overseas. Estimates of
effectiveness may be inappropriate because of
differences in the population. The cost of
resources used can vary considerably between
countries. For example, the cost of clinical staff
is lower in the UK than in certain other
countries. The resources used in the subsequent
treatment will vary between countries according
5.10
Recommendations
5.10.1
Clinical Practice Recommendations for NSCLC
In the assessment of mediastinal and chest wall
invasion:
>
CT alone may not be reliable [B(DS)]
>
other techniques such as ultrasound should be
considered where there is doubt [D(GPP)]
>
surgical assessment may be necessary if there
are no contraindications to resection. [D(GPP)]
Magnetic resonance imaging (MRI) should not
routinely be performed to assess the stage of the
primary tumour (T-stage) in NSCLC. [C(DS)]
MRI should be performed, where necessary to assess
the extent of disease, for patients with superior
sulcus tumours. [B(DS)]
Every cancer network should have a system of rapid
access to FDG-PET scanning for eligible patients.
[D(GPP)]
Patients who are staged as candidates for surgery on
CT should have an FDG-PET scan to look for involved
intrathoracic lymph nodes and distant metastases.
[A(DS)]
Patients who are otherwise surgical candidates and
have, on CT, limited (1–2 stations) N2/3 disease of
uncertain pathological significance should have an
FDG-PET scan. [D(GPP)]
Patients who are candidates for radical radiotherapy
on CT should have an FDG-PET scan. [B(DS)]
Patients who are staged as N0 or N1 and M0
(stages I and II) by CT and FDG-PET and are suitable
for surgery should not have cytological/histological
confirmation of lymph nodes before surgical
resection. [A]
Histological/cytological investigation should be
performed to confirm N2/3 disease where FDG-PET
is positive. This should be achieved by the most
appropriate method. Histological/cytological
confirmation is not required: [B(DS)]
>
where there is definite distant metastatic disease
>
where there is a high probability that the N2/N3
disease is metastatic (for example, if there is a
chain of high FDG uptake in lymph nodes).
When an FDG-PET scan for N2/N3 disease is
negative, biopsy is not required even if the patient’s
nodes are enlarged on CT. [B(DS)]
If FDG-PET is not available, suspected N2/3 disease,
as shown by CT scan (nodes with a short axis >
1cm), should be histologically sampled in patients
being considered for surgery or radical radiotherapy.
[D(GPP)]
An MRI or CT scan should be performed for patients
with clinical signs or symptoms of brain metastasis.
[D(GPP)]
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. [D(GPP)]
5.10.2
59
Clinical Practice Recommendations for SCLC
SCLC should be staged by a contrast-enhanced CT
scan of the patient’s chest, liver and adrenals and by
selected imaging of any symptomatic area. [D(GPP)]
5.10.3
Research Recommendations
Further research is needed into the diagnostic
accuracy and efficacy of FDG-PET scanning in followup of patients after radical treatment for lung cancer
to investigate possible recurrence of the disease.
Further research is needed into the diagnostic
accuracy and efficacy of FDG-PET scanning in
staging patients with SCLC.
Further research is required to assess the diagnostic
accuracy and efficacy of FDG-PET in the assessment
of tumour response to chemotherapy and
radiotherapy.
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patients undergoing extended resections and
undergoing pneumonectomy176,177 (Level 3).
6 Surgery with Curative Intent for Patients
with Non-Small Cell Lung Cancer
6.1
Introduction
Surgery plays an important role in the treatment of
non-small cell lung cancer (NSCLC). This section
reviews this role in relation to the stage of cancer
and in isolation from other treatment modalities
such as chemotherapy and radiotherapy. In later
sections (see chapter 9 Combination therapy)
surgery is considered within multimodality therapies.
6.2
6.5
Risk of Surgery
6.5.1
Mortality
Techniques included in this review
6.4
The issue of operative mortality and advancing age
was recently addressed in a non-systematic review of
37 studies of surgery in the elderly with NSCLC (Level
3) 175. Though no pooled average was calculated, and
the populations were somewhat heterogeneous, a
trend was noted toward increasing surgical mortality
with increasing age (Table 58) (Level 3).
Methodology
A systematic review of the literature relating to the
surgical management of NSCLC was undertaken. In
addition, guidelines from the British Thoracic Society
(BTS) and the American College of Chest Physicians
(ACCP) and a systematic review by Detterbeck et
al.149-152 were reviewed.
The search strategy is listed in detail in the appendix six.
Preoperative selection of patients with
Non Small Cell Lung Cancer for surgery
Recent BTS guidelines153 covering specifically fitness
for surgery, regarding age; pulmonary function;
cardiovascular fitness; nutrition and performance
status (see appendix 2, Figure 4 for comparison of
Karnofsky and WHO/ Zubrod performance status
scales) were reviewed. The guideline development
group has accepted the recommendations reached in
the BTS publication.
Surgery for Stage I
Non Small Cell Lung Cancer
6.6.1
Introduction
Operative mortality following lung resections for
specific surgical procedures will be discussed under
the appropriate sections (Table 58) (Level 3).
6.5.2
Morbidity
Morbidity refers to adverse effects caused by an
intervention. Though poorly defined by most
authors, surgical morbidity can be further divided
according to major or minor complications. Based on
studies155,157,159,162,166,169,176-182 from a recent systematic
review154 in combination with three further
papers172,173,183 reported from 1980 to 2002 including
>150 patients undergoing open thoracic procedures
for resection of NSCLC, the overall weighted average
morbidity rate for patients undergoing all types of
pulmonary resections (N=10098) was 30% (Table
60) (Level 3). Highest morbidity rates were seen in
Based on a recent systematic review of eleven
studies170,187-190,190-195 that examined 5-year survival
after open resection of pathological stage IA and IB
NSCLC152 in combination with two further papers196,197
reported from 1980 to 2003 including >250 patients
(N=8037), the weighted average mean 5-year survival
was 69% for stage IA and 52% for stage IB NSCLC
(Table 61) .For stage I NSCLC, T status has prognostic
significance, with every study reported showing a
survival average for T1 compared to T2 patients. The
survival difference ranged between 12-23% for T1
versus T2 patients (Table 61).
Stage I disease is defined as NSCLC in the
parenchyma of the lung, no more proximal then 2
cm from the carina, not invading the chest wall or
parietal pleura and without nodal involvement (N0)
or metastatic disease (M0).
Stage I is further subdivided into IA (T1N0M0) and
IB (T2N0M0) and reflects differences in survival,
with the former having better 5-year survival. The
relationship between tumour size, patient prognosis,
and the appropriate cut-off for tumour size (currently
3cm) to classify T1 and T2 tumours is still a matter
of controversy184. Patients with stage I NSCLC,
provided they are medically fit, should be considered
for radical local therapy with curative intent185.
Expert opinion from a previous guideline on
diagnosis and treatment of lung cancer found that
surgical resection is the generally accepted treatment
of choice186 (Level 4). Adjuvant or neo-adjuvant
therapy will be reviewed in chapter 9 on
combination treatment.
The standard definition of operative death includes
mortality within the immediate 30 days following
surgery. Based on a recent systematic review154 of
sixteen studies155-170 in combination with a further
four papers171-174 reported from 1980 to 2002
including >250 patients undergoing open thoracic
procedures for resection of NSCLC, the weighted
average operative mortality for patients undergoing
all forms of pulmonary resection (N=41105) was
3.5% (range, 1.0 – 7.6%) (Table 58) (Level 3).
The systematic review considered surgical procedures
commonly used in treating lung cancer patients with
an intention to cure. They include pneumonectomy;
standard and extended lobectomies and sub lobar
resection particularly wedge resection. In addition, the
use of a minimally invasive technique such as VideoAssisted Thoracoscopy (VATS) is reviewed.
6.3
6.6
6.6.2
Patient selection in terms of the type of procedure
carried out will reflect the patient’s fitness to
withstand such a procedure. In studies comparing
lobectomy versus a limited resection (Table 62), the
selection criteria for a limited resection are often
vague, based on the surgeon’s experience, co-morbid
disease or parameters (such as pulmonary function)
that are not clearly stated.
6.6.3
The accuracy of pathological staging can also be
affected by the extensiveness of the nodal
dissection152
Type of Surgical Resection
Lobectomy, the removal of a lobe of the lung, and
pneumonectomy, removal of a whole lung define the
anatomical resection. Lobectomy has been the
standard surgical treatment for lung cancer even for
small tumours198,199 and is regarded as the procedure
of choice for patients with stage I NSCLC152. Limited
resection has mainly been performed in compromised
patients with impaired lung function200.
Patient Eligibility
An important distinction is whether patients are
classified as stage I using clinical staging (c), before
any treatment is carried out, or pathological staging
(p), with information available after surgical
resection. As clinical staging most often refers to
radiological staging with CT, clearly the accuracy
with which CT detects the presence of mediastinal
lymph node involvement (N1, N2 or N3 disease) will
influence reliability of clinical staging. The use of
mediastinoscopy may improve clinical staging, but
methods of staging are often not reported in studies
on stage I patients.
61
There are several types of limited lung resection
described. A segmental resection or segmentectomy
refers to anatomical dissection and complete removal
of a bronchopulmonary segment of lung. A wedge
resection is just what it says, and involves securing the
air leak and bleeding by suturing or ‘stapling’ across
non-anatomic planes of the lung. As a procedure it is
most suitable in the context of thoracoscopy.
6.6.4
Limited Resection versus Lobectomy
A systematic review of the literature identified one
recent review that included thirteen observational
studies152. A further three non-randomised studies are
also reported201-203 (Table 62) (Level 3). Only one
prospective, randomised trial of limited resection versus
lobectomy was identified 204 (Table 62) (Level 1+).
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in-hospital mortality was 3% (range, 0-6%). The
authors did not report on morbidity.
6.6.4.1 Effectiveness
Amongst the observational studies reported, we
found significant heterogeneity. Several studies
looked at only segmentectomy with or without
lymph node exploration 201-203,205-207. A number of
studies included some stage II patients. Inclusion of
a comparison group (lobectomy) was variable.
Limited resection was performed as the procedure of
choice as most patients would have tolerated a
lobectomy. Size of tumour reported amongst studies
varied, with most including tumours of <2cm,
reflecting increasing interest in whether the survival
advantage of lobectomy over limited resection is less
marked with smaller tumours201-203,206. The weighted
average 5-year survival for segmentectomy versus
lobectomy was 62% versus 80% respectively (Table
62) (Level 3). Two studies reported on loco-regional
recurrence at 5-years201,206, showing local recurrences
to be more frequent after segmentectomy.
Lobectomy is the most common procedure employed
for resection of lung cancer. A systematic review of
the literature regarding morbidity and mortality
associated with open lobectomy for lung cancer
identified one recent review154 that included
eighteen observational studies155,156,159-161,163,165-170,200,211214,216
and a further three series172,174,215 (N=24221)
(Table 59). The weighted average 30-day or inhospital mortality was 3% (range, 0-9%) (Table 59)
(Level 3). The authors did not report on morbidity,
though one series reported a complication rate of
28% for lobectomy157 (Table 60) (Level 3).
6.6.4.3 Conclusions
Based on the completed systematic review for stage I
(IA & IB) NSCLC patients with no medical
contraindications, surgery is the primary treatment
choice (Level 4), aiming for clear surgical margins. For
patients who are able to tolerate a lobar resection,
lobectomy rather than a limited resection (wedge
resection or segmentectomy) is an acceptable
alternative (Table 62) (Level 1+). Pending further
research, patients with stage I or II non small cell lung
cancer who would not tolerate lobectomy because of
comorbid disease or pulmonary compromise, should
be considered for limited resection or radical
radiotherapy. (Table 62) (Level 3). Further research on
the role of limited resection in comparison to lobar
resection for small lung tumours is required.
Seven observational studies reported on wedge
resection as a compromise operation as compared to
lobectomy163,179,200,208-211. Heterogenity was noted in
what constituted a poor risk patient. The weighted
average 5-year survival for wedge resection as a
compromise procedure versus lobectomy was 51%
versus 63% respectively (Table 62) (Level 3).
The only prospective, randomised trial of limited
resection versus lobectomy allocated 247 eligible
patients to either approach204 (Table 62) (Level 1+).
Lobectomy had a non-significant survival benefit at
5-years (73% versus 56%, P=0.06), and though the
rate of distant recurrence was not significantly
different, the loco-regional recurrence rate for the
limited resection group was 75% greater than the
lobectomy group (Level 1+).
6.6.4.2 Mortality and Morbidity
A limited resection, such as a segmentectomy or a nonanatomic wedge resection may be performed through
either a standard thoracotomy or using a video-assisted
thorascopic (VATS) approach. A systematic review of
the literature identified one recent review154 that
included fourteen observational
studies155,156,159,161,163,166,168,170,200,205,211-214 undergoing wedge
resection by a standard thoracotomy. In addition, three
further observational studies were included172,174,215
(N=6550) (Table 59). The weighted average 30-day or
6.6.5
Mediastinal lymph node evaluation
in stage I NSCLC
Various surgical techniques for mediastinal lymph
node evaluation at the time of limited or lobar
resection have been developed. Options include
>
No mediastinal lymph node biopsies
>
Mediastinal lymph node sampling of suspicious
lymph nodes
>
Systematic mediastinal lymph node sampling
>
Radical en bloc resection of mediastinal lymph
nodes and surrounding mediastinal fat
(lymphadenectomy)186.
However, in systematically reviewing studies
comparing techniques (Table 63), variations in
definition of lymph node dissection were apparent.
The importance of which technique is employed
refers to differential benefit to definitive staging and
survival and the potential associated morbidity.
The outcomes of interest are
>
A beneficial difference in survival attributable to
lymphadenectomy
>
A beneficial difference in loco regional
recurrence
>
A difference in morbidity
>
Better staging data
6.6.5.1 Effectiveness
The systematic review identified five RCTs that
included stage I patients and evaluated the role of
routine or systematic mediastinal lymph node
sampling and radical lymphadenectomy in relation
to survival difference and pathological staging (Table
63). Observational studies were disregarded.
One prospective RCT comparing radical mediastinal
lymphadenectomy with mediastinal lymph node
sampling (N=182, all stages) found no differences in
survival or loco-regional recurrence in stage matched
patients217 (Level 1+). However, in regard to staging,
the same author later analysed the data218. Though
no differences were found between the two
techniques in identifying pN2 disease, more patients
with multi-station nodal involvement were found as
expected in the radical lymphadenectomy group
(57% versus 17%, P=0.007) (Level 1+). The same
authors, Izbicki et al219, in a further RCT (N=169, all
stage) confirmed early findings, and also showed no
survival difference in the pN0 subgroup. However,
they did show a marginal benefit in patients with
pN1 or limited pN2 (one station involved only) with
radical lymphadenectomy improving survival
(p=0.058) (Level 1+). An RCT that specifically
evaluated the two techniques in relation to small
peripheral tumours (<2cm) and clinical stage I
patients found no survival difference and advocated
no radical systematic mediastinal node sampling in
such patients (Level 1+)220.
63
Two recent RCTs did find a survival advantage for a
more radical approach to mediastinal node
dissection. One RCT compared radical mediastinal
lymphadenectomy with mediastinal lymph node
sampling in 169 eligible patients with stage I-IIIA
NSCLC221. Amongst stage I patients (N= 42 versus.
31) 5-year survival was 62% versus 42% (P=0.044)
for radical lymphadenectomy and mediastinal lymph
node sampling respectively (Level 1+). A further RCT
compared systematic mediastinal lymph node
sampling to mediastinal sampling of suspicious
nodes in 471 eligible patients with stage I-IIIA
NSCLC222. Amongst stage I patients (N= 58 versus.
98) 5-year survival was 82% versus 58% (P=0.0104)
(Level 1+). Both studies found a survival benefit
toward more aggressive techniques of mediastinal
lymph node evaluation in stage I patients.
6.6.5.2 Morbidity
In comparing complications associated with the
various techniques employed to evaluate mediastinal
lymph nodes, one RCT found no significant
difference between radical lymphadenectomy and
mediastinal nodal sampling (38% versus 47%,
P=NS)217 (Level 1+). However, in looking at specific
postoperative complications, haemorrhage (>2units)
and air leak (>5days) were more commonly recorded
following radical lymphadenectomy (11 versus 5
patients with haemorrhage (P=0.051) and 9 versus.
4 patients with air leaks (P=0.075)) (Level 1+). In
contrast, an RCT comparing the two methods in
patients with small peripheral tumours220 noted the
morbidity of the radical lymphadenectomy group was
significantly higher (27% versus 3% P-value not
stated) (Level 1+).
6.6.5.3 Conclusions on mediastinal lymph nodes
evaluation in stage I NSCLC
Due to the inconsistency of the results, we cannot
conclude that one technique has an advantage over
the other in terms of survival (Level 1+). Furthermore,
no conclusion can be drawn regarding whether one
technique of mediastinal node dissection has greater
morbidity than another (Level 1+). However, based on
consensus opinion in the literature regarding improved
accuracy of staging with a systematic approach to
lymph node sampling, the group have included a good
practice point on its use.
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The results of a RCT which began in 1999 to reevaluate the therapeutic benefits of radical
lymphadenectomy in patients with N0,1 NSCLC
is awaited.
6.6.6
Open resection versus thorascopic resection
The development of minimally invasive VideoAssisted Thoracic Surgery (VATS) has significantly
altered the management of patients with
undiagnosed indeterminate or solitary pulmonary
nodules. Increasingly, VATS is being used for
resections in lung cancer. A systematic review of the
literature identified papers that examined the role of
VATS in lung resections, most of which were
concerned with technique, feasibility and safety of
the procedure. Few papers examined the
effectiveness of VATS resection as compared to
conventional open lung resection. We noted a degree
of variability in the techniques used to perform the
thorascopic resection in papers identified. Because of
problems associated with clarity of definitions used
for VATS, Video-assisted mini-thoracotomy was
included in review, though we found few papers.
6.6.6.1 Effectiveness
The systematic review identified nine observational
studies but no RCTs that included stage I patients
and evaluated the role of thorascopic resection as
compared to open resection in relation to survival
difference and pathological staging223-231 (Table 64).
The average weighted 5-year survival in patients
with stage I NSCLC following VATS lobectomy was
76% in the four studies that had followed-up
patients for that length of time227-230 (Table 64)
(Level 3). It compares favourably with 5-year survival
following open resection (69% for stage IA and
52% for stage IB, Table 62). However patient
selection based on the observational studies
reviewed, is likely to be highly selective (size of
tumour <5cm in most of the studies reviewed).
Furthermore, the extent of lymph node sampling and
reporting of sampling varied amongst the studies.
6.6.6.2 Morbidity
The intra- and postoperative outcomes, including
complications associated with VATS, reported in two
SURGERY WITH CURATIVE INTENT FOR PATIENT S WITH NON-SMALL CELL LUNG C ANCER
RCTs232,233 and eight observational retrospective case
series are presented223-230 (Table 65). One prospective
RCT232 comparing VATS lobectomy with musclesparing thoracotomy and lobectomy (N=55) found
no differences in operative time, intra-operative
complications or blood loss between the two
techniques (Level 1+). Postoperative complications
were higher in the thoracotomy group (53% versus
24%, P<0.05), but the length of stay, and incidence
of post-thoracotomy pain was not significantly
different (Level 1+). The other RCT233 compared
Video-assisted mini-thoracotomy with muscle sparing
thoracotomy for performing lobectomy in 67
patients. No significant differences in postoperative
complications, postoperative pulmonary function and
length of hospital stay were noted (Level 1+).
However, postoperative thoracotomy pain, as
measured in the first 8 days using a visual analogue
scale was significantly different (P<0.006) in favour
of the minimal-invasive procedure (Level 1+).
Eight retrospective case series (N=1469) with >50
patients reported on VATS lobectomy in terms of its
technical feasibility and safety. One other smaller
study (N=44) was included as it had evaluated
pulmonary function in the two groups234. Overall, the
weighted average operative mortality of VATS
lobectomy was 0.7% (range 0 –3%) and a weighted
average postoperative morbidity of 12% (range 221%). This compares favourably to the average
weighted mortality and morbidity for conventional
open lobectomy of 3% (range, 0-9%), and 28%
(from one series157) respectively (Level 3).
The average weighted conversion to open procedure
was 11% (range 0-17%), and the average weighted
mean operating time was 127mins (range, 75144mins) with significant variability in operating
time noted (Level 3). The weighted average length of
stay was 5 days (range, 3-7days). One study reported
on pre- and postoperative pulmonary function in
patients undergoing either VATS lobectomy or open
lobectomy. Though not stated by the author, Kaseda
(1998) in the original paper, preservation of
pulmonary function was better in the VATS group
(P<0.0001)234 (Level 3). One RCT however found no
significant difference233 (Level 1+).
resection with clear surgical margins is currently the
generally accepted treatment of choice235 though no
RCTs were identified that directly compared surgery
against other modalities.
6.6.6.3 Conclusions
VATS lobectomy as compared to conventional open
lobectomy appears to be a safe procedure with
comparable, and maybe lower morbidity and
mortality (Level 3). Regarding its perceived benefits
over conventional surgery there is currently little
evidence to support significant preservation in
pulmonary function with VATS233,234 or a shorter
length of stay (Level 1+). Early postoperative
thoracotomy pain was reported as significantly less
in one RCT233 and a non-significant trend toward less
pain in the VATS group in another232 (Level 1+).
Further evaluation of the short-term outcomes of
minimally invasive thorascopic resection is required.
6.7.2
Surgery for Stage II Non Small Cell Lung
Cancer (N1 disease)
6.7.1
Introduction
Based on a recent systematic review149 of eleven
studies170,188,190,193,236-242 that examined 5-year survival
after resection of pathological stage IIA and IIB
(N1) NSCLC in combination with two further
papers187,243 (Table 66) including >50 patients
(N=3495), the weighted average mean 5-year
survival was 45% for stage IIA and 33% for stage
IIB (N1) NSCLC (Level 3). As with stage I, for stage
II NSCLC, T status has prognostic significance, with
every study except one243 showing a survival
advantage for T1 compared to T2 patients (Level 3).
The survival difference ranged between 2-19% for
T1 versus T2 patients.
Stage II NSCLC is defined as a T1 or T2 cancer with
N1 nodal involvement but no distant metastasis, or
a T3 cancer with no nodal or distant metastasis. It is
further divided into IIA (T1N1M0) and IIB (T2N1M0
and T3N0M0).
Though T3N0 tumours are included in the IIB stage,
this section deals primarily with T1 and T2 cancers
with N1 nodal disease. This was because it was felt
by the guideline group that the biological
implications of direct invasion of chest wall or
mediastinum without nodal involvement (T3N0),
may not be the same as tumours which have spread
to intrapulmonary nodes but do not involve chest
wall or mediastinum directly (T1,2N1) despite similar
survival. Furthermore, T3N0 make up only a small
proportion of stage II cancers149. Thus in essence this
section deals with N1 disease with T3N0 tumours
discussed in section 6.8.
As with stage I NSCLC, patients with stage II NSCLC,
provided they are medically fit, should be considered
for radical local therapy with curative intent. Surgical
Patient Eligibility
The number of lung cancer patients with clinical
stage II disease is small, representing 5-10% of
patients treated in the most recent surgical
series190,193. They have therefore, often been
included in studies with either stage I or stage
IIIA patients. However, pathologically stage II
NSCLC represents approximately 15-25% of
resected cancers187. Direct comparison of studies is
made difficult by several revisions of the staging
system affecting the definitions of what
constitutes stage II disease. Only papers that
clearly distinguished stage II patients were
included. As with stage I NSCLC, differences
between clinical and pathological staging
influence apparent outcomes.
Based on observational studies only, survival
following VATS resection seems to be equally
favourable as compared to open resection (Level 3),
though the VATS resection groups are likely to be a
highly selective group. Further evaluation, through
prospective, randomised trials is required
6.7
65
6.7.3
Sleeve Resection versus Pneumonectomy
A sleeve lobectomy offers an alternative surgical
technique in centrally located tumours where
otherwise pneumonectomy would be necessary.
Bronchial sleeve resection was introduced as a
means of conserving lung parenchyma in patients
with compromised pulmonary function. More
recently, sleeve resection has been proposed
routinely in the management of patients with
anatomically appropriate centrally located tumours,
even in patients with sufficient pulmonary reserve
to permit pneumonectomy 244.
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In identifying appropriate studies comparing sleeve
lobectomy with pneumonectomy, we found
difficulties in the classification of tumours resected
by a sleeve lobectomy and subsequent staging.
p=0.6) (Level 3). The mean median survivals were
70.5+/-16.2 months for sleeve lobectomy and
55.2+/- 6.6 months for pneumonectomy (p=0.024)
(Level 3). The systematic review noted the likelihood
of isolated local and regional recurrence was
substantially higher after sleeve lobectomy (20%)
than it was after pneumonectomy (10%) (Level 3).
Further economic analysis of this review is presented
in section 6.11.
Effectiveness
The NCC-AC identified two recent systematic reviews
that examined studies comparing sleeve lobectomy
with pneumonectomy149,244. One review included
studies examining the role of sleeve lobectomy as a
compromise procedure149, the other considered only
studies where the majority of patients undergoing
sleeve lobectomy had acceptable lung function244.
Only three studies appeared in both analyses (Table
67). The studies included comprised retrospective
analyses of outcomes in patients treated with sleeve
lobectomy with matched or unmatched control
subjects who underwent pneumonectomy. The
number of patients undergoing sleeve lobectomy as
a compromise procedure was variably reported. We
identified no RCTs in the literature search.
6.7.4
The second systematic review and meta-analysis
compared outcomes of sleeve lobectomy (N= 860)
with pneumonectomy (N= 746) in twelve studies for
stage I and II NSCLC in patients who had acceptable
lung function244 (Table 67). The distribution of
stages between the two groups differed significantly
(p<0.001). The mean age did not differ (61.0yrs
versus 60.5yrs respectively). There was no difference
in mean 5-year survival (51.4+/-10.1% for sleeve
lobectomy versus 49.1+/-5.5% for pneumonectomy;
Surgery for Stage IIB-IIIA Non Small Cell
Lung Cancer (T3 disease)
6.81
Introduction
NSCLC classified as T3 disease includes tumour that
has extended into the chest wall, diaphragm or
mediastinum, as well as tumour involving a main
stem bronchus. In addition, involvement of the lower
brachial plexus at the apex of the lung (Pancoast
tumours) is also included, but as curative treatment
usually involves combination modalities it is
considered in chapter 9.
Morbidity
Based on a recent systematic review of twelve
studies, the average weighted operative mortality
was 4.1% (CI, 2.3-5.9%) after sleeve lobectomy and
6% (CI, 1-11%) after pneumonectomy (p=0.3)244
(Table 67) (Level 3). Operative mortality for sleeve
lobectomy appears similar to standard lobectomy
(see section 6.6.4). Details of postoperative
morbidity were not given.
6.7.5
The first systematic review examined comparative
studies of >50 patients undergoing sleeve resection
(excluding sleeve pneumonectomy) for NSCLC149
(Table 67). In total, ten studies were included
(N=1083), though difficulties in comparing such
studies were identified. In particular, the stage of
tumour resected was often unclear with little detail
given on T and N status. Five of the studies noted
>90% of patients undergoing sleeve resection as a
compromise procedure. The weighted average 5-year
survival for stage II disease was 41% (Level 3). The
weighted average for local recurrence following
sleeve resection was 15% (Level 3). However, the
author noted that most studies have reported data
using the 1976 staging system (TINI included in
stage I; only T2NI in stage II).
6.8
The current classification system incorporates T3
disease within stage IIB (T3N0M0), stage IIIA
(T3N1-2M0) and stage IIIB (T3N3M0) based on
survival outcomes. Though the overall survival
appears to support the current classification, issues
related to tumour behaviour, recurrence patterns and
treatment strategies may be different from that of
T2N1 (stage IIB) or T1-2N2 (stage IIIA)246. The
behaviour and survival of different categories of
T3N0-1 tumours may also be different. Therefore,
the systematic review of literature regarding the
surgical treatment of T3 tumours divided the search
results according to chest wall, mediastinal or main
stem bronchus involvement. The NCC-AC reviewers
searched the published data on T3 tumours based
on stage, according to local involvement or surgical
technique (such as extended resection).
Conclusions
The advantage of sleeve resection over
pneumonectomy is the preservation of lung tissue
that is uninvolved with cancer. It has, therefore,
traditionally been advocated as a compromise
procedure in patients with limited pulmonary
reserve who are unable to tolerate a
pneumonectomy245. However, from the systematic
review that included studies with significant
numbers of patients undergoing sleeve resection as
a compromise procedure, the weighted average 5year survival was less (41%) compared to a review
of studies of patients who undergo elective sleeve
resection as an alternative to pneumonectomy
(51%)( Level 3).
The operative mortality and long-term outcome of
sleeve lobectomy were comparable to pneumonectomy
in patients with acceptable lung function (Level 3).
Isolated local and regional recurrences were higher in
the sleeve lobectomy group (Level 3). Therefore, sleeve
lobectomy offers an acceptable alternative to
pneumonectomy for stage I and II patients who have
an anatomically appropriate (central) tumour and for
reasons of lung function, pneumonectomy is more
hazardous (Level 3).
6.8.2
Patient Eligibility
T3N0-1 tumours comprise about 5% of NSCLC and
in resected patients about 10% of NSCLC246.
Furthermore, in four surgical case series (N=492)
involving >75 unselected patients with T3 disease
who were found to be pathologically N0,1,
approximately 60% of the patients have N0 disease
and 40% N1 disease246 (Table 68) (Level 3). The
same series found the weighted average with chest
wall involvement was 51%, compared to 29% for
mediastinal involvement and 16% for main stem
bronchus involvement (Level 3).
Accuracy of staging and variable reliability of
modalities such as CT and MRI in assessing clinical
T3 disease and likely local invasion has been
discussed in chapter 5.
67
We identified a recent systematic review246 that
included twelve studies which reported 5-year
survival after resection of pathological staged T3
patients, and reviewed this in combination with one
further paper 243 including >40 patients (N=1499)
(Table 69). The weighted average mean 5-year
survival was 40% for all T3 disease, 44% for T3N0
and 26% for T3N1 (Level 3).
6.8.3
Chest Wall involvement
Studies examining outcome in patients with a
peripheral lung tumour invading the parietal pleura
or deeper into the chest wall muscle or ribs were
reviewed by the NCC-AC team. Approximately 17
retrospective series188,247-262 reporting actuarial
survival of >20 patients have been systematically
reviewed246, with two further studies included263,264.
Overall, regardless of completeness of resection, the
weighted average five-year survival for all T3
patients with chest wall involvement was 33% (Table
70) (Level 3). The weighted average five-year
survival for T3N0 patients with chest wall
involvement was 40% and for T3N1 patients 22%
(Table 70) (Level 3). Therefore, predictably, an
important prognostic factor appears to be the
presence or absence of lymph node metastases.
Despite difficulties in comparing series because of
differences in inclusion criteria, the systematic
review246 noted a trend to higher survival in those
studies reporting on only patients who had complete
resections compared with those that included
patients with incompletely resected tumours. In a
recent non-systematic review of four studies that
studied patients undergoing complete versus
incomplete resection of T3 chest wall NSCLC235
weighted average 5-year survival following
incomplete resection was 7% compared to 27% for
complete resection (Table 71) (Level 3).
Long-term survival therefore appears to be
influenced by the completeness of the resection, with
very few patients surviving beyond two years with
micro- or macroscopic residual disease235,246.
6.8.3.1 Effectiveness
Two retrospective studies263,264 have shown that, in
patients undergoing complete resection, the depth of
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chest wall invasion, as determined histologically, may
affect prognosis, with better five-year survival when
the invasion did not extend beyond the parietal
pleura (Table 72) (Level 3). Furthermore, the
technique of resection of chest wall lesions that are
not clearly deeply invasive has also been examined.
Several small case series showed a more aggressive
approach (en-bloc resection) had better survival as
compared to less aggressive method (extra-pleural
resection)249,261 (Table 72) (Level 3) However, a later
series found no difference among patients who were
resected by either technique provided a complete
resection was achieved247 (Table 72) (Level 3).
SURGERY WITH CURATIVE INTENT FOR PATIENT S WITH NON-SMALL CELL LUNG C ANCER
of the carina are few in number. As with mediastinal
invasion, little data is available on prognostic factors,
and no conclusions can be drawn.
6.8.6
Currently there is no evidence apart from a few
contradictory retrospective series supporting either
approach to resection of T3 NSCLC with chest wall
involvement that is not clearly deeply invasive (Level 3).
6.9
Surgery for Stage IIIA Non Small Cell
Lung Cancer (N2 disease)
6.9.1
Introduction
Stage IIIA NSCLC is a heterogeneous group that
includes patients with ipsilateral mediastinal (N2)
disease, but also includes T3N1 patients. This
subgroup of T3N1, because of its likely biological
behaviour was reviewed along with T3N0 under
surgery for T3 disease (section 6.8). Based on one
case series190, 10% of all patients had local
advanced stage IIIA N2 disease at initial
presentation. This group is probably the most
challenging and controversial subsets of NSCLC both
from a perspective of staging as well as treatment266.
As such, stage IIIA (N2) patients are often regarded
as on the border between the generally resectable
stage I and II patients and the unresectable stage
IIIB patients.
On the little evidence available, no conclusions can
be drawn on the management of T3 disease with
mediastinal involvement.
Main Bronchus invasion
Only 16% of patients with T3N0-1 disease reported
in a four case series review had main bronchus
invasion246 (Table 68) (Level 3). Therefore, studies
examining five-year survival in patients with
involvement of the main stem bronchus within 2cm
6.9.2
Patient Eligibility
The NCC-AC reviewers examined papers dealing with
the surgical treatment of T1-3N2 disease. Most
publications were retrospective, based on
pathologically staged patients and therefore not
of patients who were N2 positive on CT but who did
not have a complete resection was 36% as
compared to 16% of patients who had undergone a
more rigorous selection (negative CT +/- negative
mediastinoscopy). However, little difference was
found between the two approaches in relation to
weighted percentage undergoing complete resection
(23% versus 25%) with only a quarter of patients
with N2 disease undergoing a complete resection.
The authors concluded that a less rigorous approach
to stage IIIA (N2) patients in terms of selection for
surgery makes little difference to the number of
complete resections achieved but does increase the
number of patients who underwent an exploratory
thoracotomy without complete resection 151.
Several differences were noted among patients
classified as stage IIIA (N2) that added to the
general heterogeneity of studies reviewed. In
particular, whether patient selection was in a surgical
series, and therefore based generally on
postoperative pathological staging, as opposed to
non-surgical series with patient selection based on
radiology. In addition, patients in surgical series are
likely to have a better performance status than
patients in non-surgical reports.
Wide ranges of approaches to preoperative patient
selection were identified. At one extreme are
patients undergoing minimal selection, with positive
N2 disease (usually on mediastinoscopy) who have
had attempted resection; compared to a highly select
group of patients with obscure N2 disease and
negative mediastinoscopy who had N2 disease
discovered at the time of resection. Many studies fall
somewhere between the two, with staging based on
CT and selective mediastinoscopy. The guideline
development group believes the use of PET will alter
staging methods and criteria and it is likely that
fewer N2 cases will be discovered at surgery.
Mediastinal involvement
The most common mediastinal structures involved in
patients with NSCLC T3 disease are the main
pulmonary vessels, the pericardium and the
mediastinal pleura or fat246. The prognosis in such
patients appears to be worse than in patients with
peripheral tumours243,246 (Table 70) (Level 3). Few
studies were identified that examined this group of
patients specifically. Furthermore, very few studies
have considered outcome based on structures
involved. The largest case series (N=151) showed no
significant difference in 5-year survival based on
what site was primarily involved265.
6.8.5
Conclusions
The completeness of resection appeared to be an
important prognostic factor for both central and
peripheral T3 tumours (Level 3). In addition, lymph
node status is also important, though the evidence
for this is stronger and more consistent in the
context of chest wall involvement (Level 3). The
depth of chest wall invasion may influence
prognosis, though the surgical technique of choice in
relation to parietal pleura invasion only remains
debatable (Level 3). Studies of central T3 tumours
involving mediastinum and main bronchus were
fewer in number and more difficult to assess, mainly
because of problems in accurate staging. Overall, the
prognosis was poorer for central T3 tumours as
compared to peripheral T3 tumours (Level 3).
In terms of operative morbidity of chest wall
resection incorporating either technique, no study
demonstrated a significant difference
statistically247,261,264 (Table 72) (Level 3).
6.8.4
easily applied prospectively to preoperative patients
outcome. Another concern was the lack of rigorous
pre-treatment staging, with preoperative patient
selection in most retrospective series involving
combinations of radiological staging with CT alone
or with mediastinoscopy on selected cases. Papers
that assessed curative surgical intent in N2 patients
were included. Studies examining the role of a
combined modality approach were not included but
are reviewed under Combination therapy (chapter 9).
6.9.3
Effectiveness
The likelihood of being able to achieve a complete
resection would appear to depend on the degree of
selection of patients preoperatively. A recent review
examined resectability by reviewing 14 studies of
greater than 20 pN2 patients from 1980 to 2000151
(Table 73). The studies were broadly divided
according to whether the studies were relatively
selective (five studies, N=554) or not (nine studies,
N=1287). This was generally based on radiographic
criteria (cN2 versus cN0,1), and mediastinoscopy on
selected patients. The average weighted percentage
69
The overall weighted 5-year survival of stage IIIA
(N2) patients in the non-selective group of studies
who had undergone complete resection was 26% as
compared to 21% in studies which adopted a
relatively selective preoperative staging assessment151
(Table 73) (Level 3)
Recognition of the importance of different
approaches to patient selection is reflected in
survival data, with patients having favourable or
‘occult’ (minimal N2) disease appearing to have
improved survival as compared to those patients
with clinically ‘bulky’ nodal disease. Some authors,266268
in attempting to develop rational treatment
guidelines have chosen to classify N2 disease into
four subsets. These are shown below.
Subsets of Stage IIIA (N2) (Source: Robinson et al, 2003266)
Subset
Description
IIIA1
incidental nodal metastases found on final
pathological examination of resection specimen
IIIA2
Nodal (single station) metastases recognised
intra-operatively
IIIA3
Nodal metastases (single or multiple station)
recognised by pre-thoracotomy staging
IIIA4
Bulky or fixed multi-station N2 disease
The benefits of resection are discussed in relation to
these four subsets of N2 disease.
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completely resectable. Based on data from studies of
surgery alone, 5-year survival of N2 patients who are
macroscopically completely resectable at operation is
approximately 25% (Level 3), with best outcome in
patients with minimal disease and complete
resection (Level 3).
6.9.3.1 Incidental N2 disease (IIIA1-2)
Incidental N2 disease includes patients who are found
to have N2 disease only on a final pathological
examination of the resected specimen (stage IIIA1) or
as a single nodal station metastasis unexpectedly
found at the time of resection (stage IIIA2) despite
careful preoperative staging with CT and
mediastinoscopic evaluation of suspicious lymph
nodes266. In three studies (N=182) in which patients
had no radiological evidence of N2 disease the average
weighted 5-year survival was 33%151 (Table 73) (Level
3). Furthermore, in two studies (N=85) that required a
negative mediastinoscopy, weighted 5-year survival
was slightly better at 35%151 (Table 73) (Level 3).
6.10
6.10.1
6.10.2
6.9.4
Conclusions
Regardless of the method of preoperative staging,
only a quarter of all clinical N2 patients are
6.10.4
versus pneumonectomy for patients with stage I and II
disease. Hospital costs for surgery and other therapies
(chemo-radiotherapy, radiotherapy, and resection) were
calculated retrospectively. But details of other therapies
were not given. There was no difference in mean fiveyear survival (51.4 ± 10.1% for sleeve lobectomy versus
49.1 ± 5.5% for pneumonectomy). The QALY
calculations favoured sleeve lobectomy over
pneumonectomy (4.37 versus. 2.84 QALY) due to the
higher utility associated with sleeve lobectomy. Sleeve
lobectomy was cost-effective compared with
pneumonectomy at $1,300 per additional QALY gained.
VATS versus. open thoracotomy
Minimally invasive VATS surgery has been advocated
as a cost-effective advance on open lung surgery.
However, the assessment of cost-effectiveness is not
straightforward. Although some cost savings might
be achieved if patients spend less time in the
intensive care unit (ICU) and less time in hospital227
these might be offset by an increase in the cost of
the operation itself. VATS can take longer than open
surgery227,269 and requires expensive equipment and
consumables270,271. If VATS is more costly then it
could still be justified economically but only if there
are associated improvements in patient outcomes.
Introduction
Patient Eligibility
Four studies269-273 reported in Table 75 and Table 76
compared the cost of VATS with that of open
thoracotomy from retrospective studies that included
all or mostly NSCLC patients. Lewis et al272 and
Nakajima et al273 found a lower cost for VATS,
however in both cases there was a strong suggestion
that the case-mix was very different in each arm,
therefore these studies are not suitable for
comparative purposes. This bias is not present in the
study by Sugi et al269, which finds VATS to be more
costly than open thoracotomy. However this study
had a sample size of just 30. Liu et al270,271 also find
VATS to be more costly, however they recommend a
less costly modified version of VATS, of their own
devising. They reduce costs by using a form of
conventional suturing that avoids excessive use of
expensive endoscopic stapling devices. The methods
used by Liu et al to cost the different surgical
options were not reported, so it is not easy to assess
whether this study is also susceptible to the bias
observed in some of the other studies.
Effectiveness
The weighted operative mortality was 18% (range,
4-30%) (Level 3). The weighted 2-year and 5-year
survival was 41% and 27% respectively (Table 74)
(Level 3). Little information regarding prognostic
factors was identified from the literature search.
6.9.3.3 Unresectable, Bulky N2 disease (IIIA4)
Generally regarded as the presence of lymph nodes
>2cm in short-axis diameter measured by CT, and
including multi-station nodal disease, extra-nodal
involvement and groupings of multiple, positive
lymph nodes. This subset is reviewed in chapter 9
(Combination therapy).
6.11.1
T4 disease includes primary tumour involvement of
the trachea or carina, superior vena cava, aorta,
intra-pericardial pulmonary arteries, oesophagus and
vertebral bodies. One systematic review150 was
identified that included eight surgical case series
(N=322) of T4 patients undergoing carinal
resections (Table 74).
6.10.3
Economics of surgery for Non Small Cell
Lung Cancer
The papers that were found compared VATS with open
thoracotomy, sleeve resection versus pneumonectomy
or else evaluated lung surgery clinical care pathways.
There were no papers evaluating surgery compared
with best supportive care.
Stage IIIB NSCLC incorporates patients with N3
disease and T4 tumours. It is generally considered to
be inoperable, though surgery with curative intent
has been applied to patients with T4N0,1 disease,
typically in the context of carinal resections. This
section deals primarily with this subgroup of
patients, with further consideration of stage IIIB is
given in the radiotherapy (chapter 7) and
combination therapy chapters (chapter 9).
6.9.3.2 Potentially Resectable N2 disease (IIIA3)
The presence of N2 disease detected
radiographically or at mediastinoscopy had generally
been regarded as a sign of inoperable lung cancer
266
. Two studies (N=79) within a systematic review151
have examined survival of patients following
complete resection who were positive at
mediastinoscopy. The studies showed a 5-year
survival of between 9% and 18% (Table 73) (Level
3). It is less than the outcome of N2 patients with
negative mediastinoscopy but involves few patients.
A systematic review of five studies (N= 735)151 that
radiologically identified N2 disease prior to resection
found a variable 5-year survival ranging from 8-31%
(weighted average 23%) (Table 73) (Level 3).
However, three of the studies included used adjuvant
radiotherapy +/- chemotherapy in addition. The
stage IIIA3 subset has been targeted for combination
therapy and is reviewed further in chapter 9
(Combination therapy).
Surgery for stage IIIB (N3 and T4 disease)
Non Small Cell Lung Cancer
6.11
Conclusions
No conclusions can be drawn from the little data
available on the curative surgical treatment of
patients with stage IIIB NSCLC.
6.11.2
Sleeve Lobectomy versus. pneumonectomy
Ferguson and Lehman244 constructed a decision model
to assess the cost-effectiveness of sleeve lobectomy
71
6.11.3
Clinical care pathways
Three US studies274-276 conducted before-and-after
evaluations of clinical care pathways for lung surgery
(Table 75 and Table 76). Most but not all patients
had NSCLC. They achieved reductions in length of
stay of up to 10 days and cost savings of up to
$12,000. Wright et al275 described the components
of their clinical pathway as:
>
Institution of chest physiotherapy
>
Patient instruction in the pre-admission testing
area (opposed to the first visit postoperatively)
>
Early discontinuation of prophylactic antibiotics
>
Epidural catheters are removed usually the day
before the chest tubes are removed so that
adequate time is available to adjust to oral
analgesic medication
>
Improved pain control
>
Aggressive nausea control policy
>
Printed patient info
>
Surgeon-led MDT meetings
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SURGERY WITH CURATIVE INTENT FOR PATIENT S WITH NON-SMALL CELL LUNG C ANCER
Cost savings were mainly attributable to the reduced
bed use. Zehr et al276 attributed their reductions in
resource use and cost to: early mobilisation; prudent use
of x-ray & lab analysis; and early post-op extubation.
Patton and Schaerf274 gave the following as factors
contributing to the success of their clinical pathway:
>
Close coordination between surgeons and other
hospital departments
>
Intensive preoperative education to reduce
patient anxiety and reduce recovery time
>
>
6.11.4
Patient-controlled analgesia, nerve blocks, nonnarcotic analgesia and pre-emptive
rehabilitation, which limits the risk of
complication
The use of thoracoscopy to reduce recovery time.
Conclusions & discussion
There is no direct evidence that curative surgery for
NSCLC is either cost-effective or not cost-effective
compared with best supportive care, however one
can infer that this is the case for patients at early
stages of disease given that surgery adds years to
life expectancy.
There is not strong evidence that VATS is either more
costly or less costly than open thoracotomy. Thoracic
surgery is undergoing innovations at the current
time. It is important that future developments are
properly evaluated in terms of both patient
outcomes and resource use.
One study showed that sleeve resection was more
cost effective than pneumonectomy. The quality of
life of patients might have been improved through
sleeve resection as the quality of life might be
related to the amount of lung resected. Despite
similar five-year survival rates obtained for these
procedures, the result of incremental cost
effectiveness was dominated by improvements in
quality of life of patients who had sleeve resection.
The cost of lung cancer surgery is substantial and
much of the cost is associated with postoperative
care. It has been shown that clinical care
pathways can enable the reduction of length of
stay and health service costs in certain US
contexts. The magnitude of such reductions is
unlikely to be achievable in the UK NHS, where
length of stay is already shorter than in the USA.
However, the notion that by reducing surgical
complications we might be able to reduce service
costs as well as improve patient outcomes is
seductive. Further research is needed to identify
interventions that could speed up recovery time in
the context of the UK NHS.
6.12
Recommendations
6.12.1
Clinical Practice Recommendations
Surgical resection is recommended for patients with
stage I or II NSCLC who have no medical
contraindications and adequate lung function. [D]
For patients with stage I or II NSCLC who can
tolerate lobar resection, lobectomy is the procedure
of choice. [C]
Pending further research, patients with stage I or II
NSCLC who would not tolerate lobectomy because of
comorbid disease or pulmonary compromise should
be considered for limited resection or radical
radiotherapy. [D]
For all patients with stage I or II NSCLC undergoing
surgical resection – usually a lobectomy or a
pneumonectomy – clear surgical margins should be
the aim. [D(GPP)]
Sleeve lobectomy offers an acceptable alternative to
pneumonectomy for patients with stage I or II
NSCLC who have an anatomically appropriate
(central) tumour. This has the advantage of
conserving functioning lung. [C]
For patients with T3 NSCLC with chest wall
involvement who are undergoing surgery, complete
resection of the tumour should be the aim by either
extrapleural or en bloc chest wall resection. [C]
All patients undergoing surgical resection for lung
cancer should have systematic lymph node sampling
to provide accurate pathological staging. [D(GPP)]
In patients with stage IIIA (N2) NSCLC detected
through preoperative staging, surgery alone is
associated with a relatively poor prognosis.
Therefore, these patients should be evaluated by the
lung cancer MDT. [D(GPP)]
6.12.2
Research Recommendations
In stage I (IA and IB) NSCLC, further randomised
trials on the survival and morbidity after limited
resection in comparison to lobar resection for small
lung tumours (less than 2 cm) are needed.
In patients with clinical stage I (IA and IB) NSCLC
who are suitable for surgical resection, further
research on the survival and morbidity after
anatomical resection by thoracoscopic techniques in
comparison to open resection is needed.
In patients with stage IIIA (N2) NSCLC detected
through preoperative staging, surgery alone is
associated with a relatively poor prognosis. Research
should be conducted in a multidisciplinary setting
into the survival and morbidity after surgery alone in
comparison with multi-modality treatments.
73
74
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RADIC AL RADIOTHERAPY ALONE FOR TREATMENT OF NON-SMALL CELL LUNG C ANCER
7.3
Radical radiotherapy is external beam radiotherapy
delivered to a high dose. This may be delivered
“conventionally” in daily 2Gy fractions (treatments)
five days per week to a total dose of 60Gy or more,
or with radiobiologically equivalent doses using
fractions of more than 2Gy per day, for example, in
daily fractions of 2.5-2.75Gy to a total dose of 5055Gy over four weeks. Hyperfractionation refers to
the use of two or more fractions daily using fractions
of less than 2Gy. Accelerated treatments are those
completed in a shorter overall time than
conventional treatments.
Increased radiation doses may, in theory, result in
both improved tumour control and increased normal
tissue damage. The use of techniques to minimise
normal tissue damage, particularly lung damage as
pneumonitis, may enable a higher dose to be
delivered to the tumour. The current standard is to
use custom-made lead blocks or a multi-leaf
collimator to minimise the dose to adjacent normal
tissue in conjunction with three-dimensional (3-D)
treatment planning where the target volume is
contoured directly onto CT slices. This conformal
therapy has now replaced older 2-D CT and non-CT
based planning techniques. Newer techniques to
improve dose delivery (e.g. intensity-modulated
radiotherapy, IMRT, or stereotactic radiotherapy) or
which minimise the impact of tumour motion during
treatment are under evaluation.
The aim of radical radiotherapy is to obtain control
of the primary tumour and involved hilar or
mediastinal nodes. In general, the impact of radical
radiotherapy on overall survival is less in more
advanced disease where the incidence of distant
metastases is higher277. The risk of lung damage
In our initial search, we found a Cochrane Review on
radical radiotherapy for stage I/II NSCLC in patients
not sufficiently fit for or declining surgery279 and a
systematic review on the use of radical radiotherapy
alone for treatment of stage IIIA and IIIB NSCLC280.
The NCC-AC team undertook additional searches to
update these reviews.
when larger volumes are treated means that there is
a limit of tumour bulk above which the risks become
unacceptable278.
Introduction
Radical radiotherapy is suitable for treating a wide
variety of non-small cell lung cancer (NSCLC)
patients. As well as being used alone, it can be used
postoperatively or in combination with
chemotherapy. Radical radiotherapy may be the
treatment of choice for patients where, due to
comorbid disease, other types of treatment are not
tolerated or where the patient chooses not to have
surgery or chemotherapy.
In this chapter, we describe the use of radical
radiotherapy where it is the only treatment modality
given for patients with NSCLC. Combination
treatments (e.g. sequential or concurrent
chemoradiotherapy or where radiotherapy is used in
combination with surgery) will be discussed in
chapter 9. We discuss lower dose (palliative)
radiotherapy administered for the relief of symptoms
in chapter 12. The chapter is in two parts, reflecting
two distinct patient groups, those with stage I and II
disease and those with stage III NSCLC, as the
prognosis and the approach to treatment differs
between these groups.
7.2
Techniques included in this review
In this chapter, we investigated the treatment of
NSCLC patients with radical radiotherapy. We searched
for literature that provides evidence for the use of
radiotherapy alone in treating NSCLC. We did however
consider papers that compared the use of two different
regimens of radiotherapy, where the same
chemotherapy drugs and dose are used in both arms of
the trial. We considered all types of fractionation and
both conformal and non-conformal techniques.
Patients should be encouraged not to smoke during
radical radiotherapy. A detrimental effect of smoking
has been clearly demonstrated in other cancers
including small cell lung cancer (chapter 11), although
this has not yet been shown for NSCLC patients.
We excluded papers that reported treatment doses of
less than 40Gy, those that only provided evidence on
the use of radiotherapy in combination with other
treatment modalities and those that included
patients without pathologically confirmed NSCLC.
7 Radical Radiotherapy Alone for Treatment
of Non-Small Cell Lung Cancer
7.1
Methodology
7.5
Radical Radiotherapy for Stage I and II
Medically Inoperable Non Small Cell Lung
Cancer Patients
7.5.1
Introduction
Although surgery offers the best outcome in terms
of survival for patients with stage I and II NSCLC
(see chapter 6), radical radiotherapy has an
important role in the management of medically
inoperable patients. The term ‘medically inoperable’
refers to a diverse group of patients who are either
considered unfit for surgery (due to insufficient
respiratory reserve, cardiovascular disease or general
frailty) or who decline surgery.
The search strategy is listed in appendix six.
7.4
Assessment of patients for
Radical Radiotherapy
The suitability of patients for radical radiotherapy
depends on a number of factors including stage and
performance status (see appendix 2, Figure 4 for
comparison of Karnofsky and WHO/ Zubrod
performance status scales). Our literature search
found no studies or systematic reviews for inclusion
on pre-treatment assessment. The guideline
development group decided to highlight some good
practice points in this area. They considered that it
was good practice to ask all patients to undergo
pulmonary function tests, including lung volumes
and transfer factor, prior to consideration of radical
radiotherapy. Although no satisfactory “cut-off” for
FEV1 (either as an absolute value or as % predicted)
has been established, clinical oncologists recognise
the need for caution in those with particularly low
FEV1. In practice, patients with an FEV1 <1.0 can be
treated with radical radiotherapy provided the
amount of normal lung irradiated is small. In the
absence of precise limits of lung function or the
volume of lung that may safely be irradiated, clinical
oncologists exercise clinical judgement in
determining where radical radiotherapy may not be
appropriate for patients with bulky tumours because
of the excessive risk of lung damage. Because it is
likely in the future that many screen-detected
tumours will be in patients with poor lung function,
this topic will become increasingly important and is
an area where further research is needed.
75
7.5.2
Effectiveness
We examined the effectiveness of radiotherapy alone
in treating stage I and II medically inoperable NSCLC
patients. We considered the use of conventional
radiotherapy treatment, optimal dose, the volume of
chest to be irradiated and the effectiveness of
alternative fractionation regimens.
We found no evidence comparing radical
radiotherapy to no treatment or palliative
radiotherapy, or comparing surgery with
radiotherapy. However, one study performed
multivariate analysis on data from patients treated in
the same centre with radiotherapy or surgery and
found that treatment modality did not have an effect
on survival281 (see Table 77).
Survival
Overall survival from a systematic review of data
from one randomised and 35 non-randomised
retrospective studies (pooled data from 2617
patients) was 70% at one year, 45% at two years,
32% at three years and 17% at five years279 (Table
77). Most of these studies used conventional (once
daily) fractionation, although five studies used twicedaily fractionation. (Level 2++)
76
LUNG C ANCER
In the absence of randomised trials of radical
radiotherapy versus supportive care alone, we obtained
indirect evidence of effectiveness from consideration of
the natural history of untreated NSCLC. In one study,
none of 50 untreated patients with stage I/II NSCLC
survived more than three years282.
The survival figures for radiotherapy are poor in
comparison to the five-year survival of patients who
are treated with curative surgery alone. In our review
(see chapter 6) we found that stage IA, IB, IIA and
IIB patients had five year survival of 69, 52, 45 and
33% respectively, when treated surgically. However,
confounding factors need to be taken into account
when making comparisons between these two
groups. A proportion of patients are upstaged during
surgery as the true extent of the disease becomes
apparent. Thus, surgical results are based on
pathological staging and radiotherapy results are
based on clinical staging, whereby a proportion of
patients are likely to be ‘under staged’. In addition,
the patient groups are not equivalent. Most patients
receiving radiotherapy alone were those not fit for
surgery and had coexisting medical conditions and/
or were in a frail condition. A direct comparison with
surgical survival rates is therefore difficult to make.
RADIC AL RADIOTHERAPY ALONE FOR TREATMENT OF NON-SMALL CELL LUNG C ANCER
stage I and IIA patients showed that two year survival
was 37% for CHART and 24% for conventional
radiotherapy to 60Gy284. The four year survival was
18% for CHART and 14% for conventional
radiotherapy284. The results demonstrate that CHART
is superior to conventional radiotherapy to 60Gy for
stage I and II NSCLC. (Level 1++).
The evidence also indicates, although not strongly,
that higher doses are associated with improved
outcome. The recent Cochrane systematic review279
found better response rates and survival for
subgroups of patients treated with higher radiation
dose compared to those receiving a lower dose,
although the reason for the choice of dose was rarely
stated in these non-randomised trials (Level 2++). It
is possible that less fit patients or those with more
advanced disease may have received a lower dose.
Overall treatment time
The outcomes of treating patients of different stage
are reported in a systematic review279. The review
included thirty-five non-randomised retrospective
studies. Weighted overall survival for studies
including patients only with stage I NSCLC was 50%
at two years and 19% at five years. For studies
including patients with stage II or all stages, the
weighted overall survival was 39% at two years and
14% at five years. The same systematic review279
found some evidence, from studies that performed
multi- or uni-variate analysis, that patients with
smaller tumours have better survival at five years (T1
had better survival than T2 tumours). (Level 2++)
A retrospective study of the effect of overall
treatment time found that protracted treatment
times were associated with significantly poorer
(p<0.0002) two-year local progression free survival,
for a group of N0 and N1285 (Level 2+).
One randomised controlled trial283 compared the use
of continuous hyperfractionated accelerated
radiotherapy (CHART) (54Gy at 1.5Gy three times
daily over 12 days) to conventional radiotherapy to
60Gy (at 2Gy per day over six weeks). Analysis of
Mediastinal irradiation
The Cochrane review279 found no clear evidence to
support routine irradiation of the mediastinum. Studies
of the stage I patients who had not received irradiation
of the mediastinum found that isolated regional
relapse was uncommon (0-3%). In addition, one study
in the review did not find a significant effect on
survival if the mediastinum had been irradiated in
stage II patients279(see Table 77)(Level 2++)
Performance Status
In the systematic review by Rowell and Williams279
the majority of patients in the studies were of good
performance status (WHO 0-1 or Karnofsky 70-100).
7.5.4
Weight loss prior to treatment is associated with
poorer outcome. Two studies within the systematic
review279 found survival was adversely affected by
weight loss whilst one study reported that survival
was unaffected (Level 2++).
From the evidence presented above, we do not
recommend radical radiotherapy for those with poor
performance status (WHO ≥2). Weight loss is seen as
a relative contra-indication. Age per se should not
influence a decision to offer radical radiotherapy.
7.5.5
The evidence for the effect of age on the outcome
after radical radiotherapy is conflicting. Most
studies however, do not show an adverse effect of
age279 (Level 2++).
Morbidity and Quality of Life
Radiotherapy can cause pulmonary toxicity leading
to early acute pneumonitis (occasionally fatal) or
development of chronic pulmonary fibrosis.
Oesophagitis is common when the mediastinum is
included in the treatment volume. Patients receiving
radiotherapy may also experience skin reactions,
pericarditis and late oesophageal strictures. There is
however a lack of documented evidence on
treatment related morbidity and quality of life.
Reporting of these outcomes was either poor and
inconsistent, in studies included in the systematic
review, or did not break the results down for stage I
and II patients279.
A cohort study of 46 stage I medically inoperable
patients reported a gradual increase in dyspnoea
and a significant deterioration of general symptoms
including fatigue and appetite loss after
radiotherapy286 (Level 2+).
Conclusions
The systematic review by Rowell and Williams279
collated the results of 35 non-randomised trials and
found that there is a benefit in treating medically
inoperable stage I and II NSCLC patients with radical
radiotherapy (Level 2++). The review also found RCT
evidence showing that continuous hyperfractionated
accelerated radiotherapy (CHART) provides a better
outcome than 60Gy conventionally fractionated283,
which was also confirmed in a later subgroup
analysis of the stage I and II patients284(Level 1++).
The frequent attendance of patients receiving
CHART may mean that hostel accommodation will
need to be provided at the radiotherapy centre.
Where CHART is not available, conventional
radiotherapy to a dose of 64-66Gy in 32-33
fractions over 61/2 weeks or 55Gy in 20 fractions over
4 weeks should be considered.
Age
7.5.3
Patient Eligibility
The systematic review by Rowell and Williams279
found variation between studies in the proportion of
patients that declined surgery. These patients are
likely to have less comorbidity and better
performance status than those considered unfit for
surgery, and therefore have better outcomes. This
may be a source of the variability seen in the results
of the trials in the review.
Weight Loss
Although most reported studies of once daily
fractionation have used 2Gy fractions to total doses
of 60Gy or greater, the fractionation most commonly
used in the UK for stage I/II NSCLC is 55Gy in 20
fractions over 4 weeks. This is believed by most
oncologists to be biologically equivalent to a dose of
approximately 64Gy in 32 fractions over 61/2 weeks.
Stage
Radiotherapy dose and fractionation
Comparisons, in three studies with adequate data,
showed that the median survival time was lower in
patients with poor performance status. This was
confirmed by multivariate analysis in two studies.
One further study in the review found no difference
in survival by performance status. Although there is
little data on patients with poor performance staus
and that this data is at times conflicting, overall,
patients with poor performance status had a worse
outcome. Overall, there is insufficient data on
patients with PS 2 to support a recommendation for
radical radiotherapy (Level 2++).
77
7.6
Treatment of Stage IIIA and IIIB Non
Small Cell Lung Cancer patients
7.6.1
Introduction
Untreated stage IIIA and IIIB NSCLC patients have a
poor prognosis. In this section we examined the
effectiveness of treatment with radical radiotherapy
alone in stage III NSCLC patients, the suitability of
different patient groups for this treatment and the
associated morbidity.
Some of the studies included in this section include
a small number of stage I and II patients. Although
78
LUNG C ANCER
the data for these patienets cannot be separated the
numbers are small and the effect on the results is
unlikely to be significant.
7.6.2
Effectiveness
We examined the effectiveness of radiotherapy alone
in treating stage IIIA and IIIB NSCLC patients. We
considered the use of conventional radiotherapy
treatment, evidence for the optimal dose, the volume
of chest to be irradiated and the effectiveness of
alternative treatment regimens including
hyperfractionation and continuous hyperfractionated
accelerated radiotherapy (CHART).
We identified a systematic review280 that included
seven randomised controlled trials of over 100
patients283,287-292. We found no more recent studies
with over 100 patients to update this review. The
two-year survival for patients with stage IIIA and IIIB
NSCLC treated with conventional radiotherapy (i.e. 5
fractions per week, 1.8-2Gy per day to a total dose
of 60Gy or equivalent) ranges from 12.5% to 24%
(Table 78) (Level 1+).
We identified no trials that compared the use of
radiotherapy with no treatment or active supportive
care. However, a systematic review that examined
the natural history of NSCLC, found that two year
survival ranged between 0-4% for untreated stage
III disease293. Table 78 shows that two-year survival
with radiotherapy alone appears range between
12.5% to 24%, suggesting that radiotherapy does
provide a survival advantage over no treatment.
Stage of disease
Seven studies294-300 (both retrospective and
prospective), from a systematic review280, provide
evidence on comparative survival figures for stage
IIIA versus stage IIIB NSCLC. Although stage IIIA
and IIIB patients frequently receive the same
radiotherapy treatment, Table 79 shows that in all
but one of the studies stage IIIA patients had
significantly better survival (Level 1+).
Outcomes following radical radiotherapy is
associated more with disease bulk than stage301. In
practice, this means that a small T4N0 cancer may
have a better prognosis than more bulky earlier
stage disease.
RADIC AL RADIOTHERAPY ALONE FOR TREATMENT OF NON-SMALL CELL LUNG C ANCER
However, specific subsets of patients with stage IIIB
may be excluded from radical radiotherapy both in
trials and in routine clinical practice because of a
higher incidence of distant metastasis and the need to
irradiate a larger volume. The presence of
supraclavicular and contralateral hilar (N3) nodal
involvement is regarded by many as a contraindication
to radical radiotherapy. Patients with pleural effusion,
particularly if cytology positive, are also regarded as
ineligible for radical radiotherapy.
comparing the use of conventional radiotherapy
(60Gy at 2Gy per day over six weeks) to CHART
(54Gy at 1.5Gy three times daily over 12 days) in
563 patients found that CHART gave better local
tumour control and survival283 (Table 81). Two-year
survival improved from 21% to 30% with CHART.
Subgroup analysis indicated that the benefit from
CHART was confined to the group with squamous
histology (two-year survival improved from 20% to
33%) (Level 1++).
Radiotherapy dose and fractionation
The CHARTWEL (CHART- Week-End Less) regimen
has been designed to allow treatment to be carried
out only during the week. Two-year local control
rates were 37% and 55% in sequential groups
treated with CHARTWEL 54Gy and 60Gy (without
neoadjuvant chemotherapy)305; this compared
favourably to the two year local control rate of 23%
seen in the CHART arm of the CHART trial283.
Evidence is scarce on the optimal dose for
radiotherapy for stage IIIA and IIIB patients, or the
effectiveness of radical versus palliative doses. One
study, Perez et al.302 compared doses of 40, 50 and
60Gy and found slightly better survival and local
control at the higher dose at two years (Table 80)
(Level 1+).
a retrospective multivariate analysis of randomised
controlled trials found that performance status was a
major independent prognostic factor in patients with
locally advanced NSCLC who are treated with
radiotherapy307,308 (Table 83) (Level 2+).
Weight Loss
A systematic review also found that evidence was
inconsistent on whether weight loss was an
independent prognostic factor280. Few studies included
those with weight loss of >5%. We only found one
study that performed univariate analysis on the effect
of weight loss. The authors reported that weight loss
>5% was not found to be a significant factor
influencing overall survival308 (Level 2+).
7.6.3
Cox et al.304 examined doses between 60Gy
conventionally fractionated and doses between 64.8Gy
and 79.2Gy treating twice daily. They found no
statistically significant difference to indicate a
consistent survival advantage with increasing dose.
However, they found 69.6Gy to be superior to 60Gy in
stage III patients with good performance status and
without weight loss. Higher doses offered no further
improvements in survival (Table 81) (Level 1+).
A study by the Radiation Therapy Oncology Group
(RTOG) and the Eastern Cooperative Oncology Group
(ECOG)288 observed better survival in the
hyperfractionated arm of the study than in the
conventional radiotherapy arm, although the
difference was not statistically significant (Level
1++). Patients were only included if they had
minimum weight loss and a Karnofsky performance
status >70 (Table 81). A randomised study
We investigated whether interruptions to a course of
radiotherapy affected outcomes. A retrospective
study (Table 82) found that longer overall treatment
times were significantly (p<0.001) associated with
poorer survival in a group consisting of 80% stage
III patients306 (Level 2+).
We found only one study (Table 84) that examined
quality of life before, during and after radical
radiotherapy for stage III patients, although 12% of
patients in this study had stage I or II disease.The
study noted improvement in quality of life in 33% of
patients and a worsening in 24%. However, a
significant gradual decrease in the mean quality of
life score was found over the 12 month follow up
(p=0.02)309 (Level 2+).
Mediastinal irradiation
There has been some debate whether to perform
elective mediastinal irradiation. Any increase in
treatment volume is likely to lead to an increase in
the amount of normal tissue being irradiated,
increasing morbidity. Although this is accepted as
current practice in many parts of the world, we
found no evidence in this area and therefore cannot
support extending the treatment volume to include
uninvolved lymph nodes. Despite this however, the
mediastinum will frequently receive a significant
dose when elective mediastinal irradiation has not
been intentionally performed.
Performance status
We found little evidence on the relationship between
performance status and outcome as many studies
required good performance status (WHO PS 0-1) for
study entry (e.g. Saunders 1999283; Saunders
2002305, Sause 2000288). Two studies that performed
Morbidity and quality of life
Radiotherapy can cause pulmonary toxicity leading
to early acute pneumonitis (occasionally fatal) or
development of chronic pulmonary fibrosis.
Oesophagitis is common when the mediastinum is
included in the treatment volume. Skin reactions,
pericarditis and late oesophageal strictures are
also recorded.
Overall treatment time
We examined the effectiveness of conventionally
fractionated and hyperfractionated radiotherapy, but
there are very few randomised studies that compare
the two treatments. A systematic review that
performed a meta-analysis of three studies did not
find a statistically significant benefit in two year
survival of one schedule over the other (OR 0.67 in
favour of hyperfractionated radiotherapy,
p=0.091)303(Table 81) (Level 1+).
79
7.6.4
Patient Eligibility
Many stage IIIA and IIIB NSCLC patients will have
combination treatment, but radiotherapy alone is
useful for those patients of good performance who
do not wish to have chemotherapy or those who may
not be able to tolerate chemotherapy, for example if
they have comorbid conditions.
From the evidence presented above, radical
radiotherapy is not recommended for those with
poor performance status (WHO ≥2). Weight loss is a
relative contra-indication.
80
7.6.5
LUNG C ANCER
Conclusion
It is difficult to draw definitive conclusions about the
effectiveness of using radiotherapy alone to treat
stage IIIA and IIIB NSCLC because there is a lack of
evidence comparing radiotherapy alone with best
supportive care or with other treatment modalities.
However, comparing the survival figures of stage III
patients treated with radiotherapy alone to those
from studies of the natural history of untreated
NSCLC, it appears that the use of radical
radiotherapy alone can provide some survival
benefit. Although this section considers radical
radiotherapy alone, the majority of patients
considered sufficiently fit for radiotherapy will also
receive chemotherapy (section 9.9).
The overall two year survival for stage IIIA and IIIB
patients ranges between 12.5%-24% (Level 1+).
Stage IIIB patients and those with poor performance
status are less likely to do well treated with
radiotherapy alone (Level 1+). There is no strong
evidence about the optimal radiation dose but (as in
section 7.5.5) there is evidence that CHART is more
effective than conventional radiotherapy to 60Gy
(Level 1++). Where CHART is not available,
conventional radiotherapy to a dose of 64-66Gy in
32-33 fractions over 61/2 weeks or 55Gy in 20
fractions over 4 weeks should be considered.
7.7
7.7.1
Economics of Radical Radiotherapy for
Non Small Cell Lung Cancer
Introduction
For certain patient groups, radical radiotherapy
offers advantages to patients in terms of improved
life expectancy and quality of life. The disadvantages
of this management strategy are the associated side
effects and the cost of the resources (staff,
equipment and consumables). These resources could
potentially be put towards alternative beneficial
uses, therefore it is important to assess whether the
health gains are large enough to justify the cost.
7.7.2
CHART versus conventional radiotherapy
Coyle and Drummond310 carried out a cost analysis
alongside the multi-centre randomised controlled trial
reported by Saunders et al311. The trial compared
CHART with conventional radiotherapy to 60Gy.
RADIC AL RADIOTHERAPY ALONE FOR TREATMENT OF NON-SMALL CELL LUNG C ANCER
Resource use and cost data were collected
prospectively over three months for 284 patients in 10
UK trial centres. The patients had NSCLC stages I-III.
Table 85 shows the resource usage recorded and
Table 86 the associated cost. CHART required more
out-of-hours radiotherapy than conventional RT and
patients spent more time in hospital, while patients
receiving conventional RT spent more time travelling
(costs have been inflated to 2002 prices using the
Hospital and Community Health Services pay and
prices index312). Radiotherapy was more costly in the
CHART arm. Cost savings from reduced use of
ambulances largely offset the increased inpatient
costs associated with CHART. Overall, CHART cost
an extra £900 per patient.
Subsequent to conducting this analysis, we identified
a study that performed similar calculations. Wake et
al315 calculated a substantially higher figure £11,227
per LY gained. This figure is not accurate because a)
the life-years gained was approximated by assuming
it to be the difference in median survival and b) they
assumed that the annual incremental cost would be
four times the size of that observed in three months,
whereas the time horizon was chosen in order to
capture the vast majority of the cost differences.
Wake et al considered other strategies, including
combination therapy; hence this study is appraised
in Chapter 9 on combination therapy for NSCLC.
7.7.3
The trial did not indicate substantial differences in
quality of life between arms overall – some symptoms
were worse in the CHART arm but by 6 weeks CHART
patients were doing better. Assuming health-related
quality of life (HRQL) over the remaining lifetime is on
average 60% of full health (see appendix four) this
would suggest an incremental cost-effectiveness of
£3,500 per QALY, well below the £30,000 per QALY
gained threshold. Table 88 shows a sensitivity analysis.
Even when making fairly extreme assumptions (lower
95%CI for LY gained, upper 95%CI for cost and
only 40% HRQL) the cost per QALY gained is still
below £30,000.
Coyle and Drummond310 suggest that the costs of
CHART could be substantially reduced if more use was
made of hostel accommodation instead of wards. Also,
centres with slightly longer standard working hours
might be able to reduce costs by carrying out more
CHART within ‘normal’ working hours.
7.7.4
lung cancer is cost-effective then it would appear
that CHART is the strategy of choice in relevant
patient groups (although there could be other
fractionation strategies that are just as cost-effective
but have not yet been evaluated). Implementation of
CHART would require greater use of out-of-hours
radiotherapy machines and bed usage. However, the
number of patients that would require this treatment
is not that great. The cost of CHART could be
reduced if more CHART is performed during normal
working hours and if hostel accommodation is used
instead of ward beds. CHART is likely to be relatively
more effective and cost-effective in patients at
earlier stages of disease. Dale and Jones320 use a
radiobiological model to show that in the long term
non-standard fractionation could actually reduce
costs by preventing recurrence of disease.
Conformal radiotherapy
Conformal radiotherapy can potentially improve
patient outcomes by better targeting of radiation to
the malignant tissue. Hohenberg and Sedlmayer316
compared, retrospectively, the costs of 3-D conformal
radiotherapy and radiotherapy without the use of a
multileaf collimator for patients with non-small cell
lung cancer in three Austrian hospitals (results
reported in English by Horwitz317). They found
conformal radiotherapy to be more costly – see Table
89 (costs have been converted from Austrian
Schillings using purchasing power parities). The
increased costs were due to the need for:
Coyle and Drummond310 did not attempt to estimate
the incremental cost-effectiveness of CHART, so for
this guideline an approximate measure of costeffectiveness was derived as follows. Table 87 shows
the two year survival figures reported by Saunders et
al311. We derived figures for life expectancy from the
two year survival figures using the Declining
Exponential Approximation of Life Expectancy
(DEALE) method313,314, which assumes a constant
death rate in each arm. This gives an estimate of 0.4
life-years gained per patient at a cost of £2,100 per
life-year gained.
>
more expensive linear accelerator equipment;
>
additional time for CT localisation & planning;
and
>
additional time for patient positioning and
verification.
Economics conclusions and discussion
CHART appears to be more costly than conventional
radical radiotherapy to 60Gy but relatively costeffective. The evidence for this is relatively strong
with both resource use and survival data coming
from a multi-centre RCT set in the UK NHS. There is
no direct evidence for lung cancer patients that
either strategy is cost-effective compared with best
supportive care (i.e. no radiotherapy); however,
Glazebrook318 and Barton et al319 have found
radiotherapy generally to be highly cost-effective. If
we assume that conventional radical radiotherapy for
81
A study showed that conformal radiotherapy is more
costly than radiotherapy without multileaf
collimation. Conformal radiotherapy could still
potentially be cost-effective, if there are health gains,
but as yet, there is no direct evidence of health
improvements. Conformal radiotherapy has become
the standard since this study was conducted.
7.8
Conclusion
Radical radiotherapy is indicated for stage I, II and
III patients of good performance status (WHO 0-1)
whose disease can be encompassed in a
radiotherapy treatment volume without undue risk of
normal tissue damage. Contra-indications to radical
radiotherapy include pericardial effusions,
cytologically positive pleural effusions and
supraclavicular nodes. Contralateral hilar or
contralateral mediastinal nodes are relative contraindications for stage III NSCLC.
82
LUNG C ANCER
7.9
Recommendations
7.9.1
Clinical Practice Recommendations
CHEMOTHERAPY FOR NON SMALL CELL LUNG C ANCER
Radical radiotherapy is indicated for patients with
stage I, II or III NSCLC who have good performance
status (WHO 0, 1) and whose disease can be
encompassed in a radiotherapy treatment volume
without undue risk of normal tissue damage.
[D(GPP)]
8 Chemotherapy for
Non Small Cell Lung Cancer
All patients should undergo pulmonary function
tests (including lung volumes and transfer factor)
before having radical radiotherapy for NSCLC.
[D(GPP)]
8.1
Patients who have poor lung function but are
otherwise suitable for radical radiotherapy should
still be offered radiotherapy, provided the volume of
irradiated lung is small. [D(GPP)]
Patients with stage I or II NSCLC who are medically
inoperable but suitable for radical radiotherapy
should be offered the CHART regimen. [A]
Patients with stages IIIA or IIIB NSCLC who are
eligible for radical radiotherapy and who cannot
tolerate or do not wish to have chemoradiotherapy
should be offered the CHART regimen. [A]
Stage IIIB or IV non-small cell lung cancer (NSCLC) is
generally not considered to be curable, with five-year
survival rates of less than 1%. However,
chemotherapy can be useful in improving symptoms
and quality of life in these patients. Chemotherapy
also improves survival and although the increase is
modest, it must be considered alongside the poor life
expectancy in this group. The benefits must be
carefully weighed against the risks of toxicity for the
individual patient.
addressing other clinical questions. We therefore
include data on the second generation drugs;
cisplatin and carboplatin (platinums); ifosfamide,
vinblastine, vindesine and mitomycin C. The HTA
report examined four third generation
chemotherapy drugs (docetaxel, paclitaxel,
gemcitabine and vinorelbine) in the treatment of
NSCLC. Since the HTA report was published
docetaxel has been granted a licence to be used as
first line therapy in the UK, and we have therefore
looked for new evidence for its use in first and
second line treatment.
There is the possibility of treating patients with first,
second and even third line systemic treatment, although
many NSCLC patients treated with chemotherapy will
only be suitable for first line treatment.
Our review excludes new cytotoxic or biologically
targeted agents, which were not licensed for use in
the UK at the cut-off date for the literature search.
The Guideline Development Group decided to use
the term ‘active supportive care’ (ASC) rather than
‘best supportive care’ (BSC) in this document to
emphasise the nature of the care as an active
process including other treatments such as
radiotherapy. However, many trials use the term BSC
and our evidence tables reflect this.
If CHART is not available, conventionally
fractionated radiotherapy to a dose of 64–66 Gy in
32–33 fractions over 61/2 weeks or 55 Gy in 20
fractions over 4 weeks should be offered. [D(GPP)]
7.9.2
Introduction
Research Recommendations
The development of this chapter included a review
and update of the following technology appraisal.
The appraisal is therefore now obsolete and has
been replaced by this guideline.
Research should be conducted into whether NSCLC
patients with poor lung function have better survival,
morbidity and quality of life when treated with
radical radiotherapy alone compared to no treatment
or treatment with chemotherapy or
chemoradiotherapy
Doxetaxel, paclitaxel, gemcitibine and vinorelbine for
non-small-cell lung cancer. NICE Technology
Appraisal No. 26 (2001).
8.2
83
8.3
Methodology
Studies undertaken and completed after the
publication of Detterbeck323 and Health Technology
Assessment 2001322 by NICE were included.
The literature search identified a number of previous
systematic reviews on chemotherapy for NSCLC. These
included: Socinski et al323, Health Technology
Assessment322,324, two Cochrane reviews321,325 and
Cancer Care Ontario Practice Guideline Initiative326-329.
Additional studies were found by the literature search.
The inclusion criteria for studies was as follows:
>
All studies had to be randomised control trials in
NSCLC
The drugs included in this review
>
This review updates the Cochrane review321 (2000)
and the Health Technology Assessment (HTA)
report322 published in 2001, in addition to
Studies not covered by Detterbeck 2001 and the
HTA report 2001
>
Not covered by Cochrane 2000 and 2002
reviews
84
LUNG C ANCER
>
CHEMOTHERAPY FOR NON SMALL CELL LUNG C ANCER
The same systematic review323 also reported that in
some studies, male patients, those with metastases,
those with increased lactate dehydrogenase levels
(LDH), patients with >5% weight loss and patients
>65 years of age were likely to demonstrate poorer
survival having received chemotherapy (Level 1+).
Not covered by Cancer Care Ontario Practice
Guideline Initiative 2001 & 2002.
The detail of the search strategy can be found in
appendix six.
8.4
8.6
In late stage NSCLC, chemotherapy offers the
patient the possibility of symptom relief, improved
disease control, better quality of life (QoL) and
increased survival. However, not all patients with
advanced disease (stage IIIB and IV) are fit enough
to receive systemic treatment. In less fit patients,
the risks of toxicity may outweigh the potential
benefits of chemotherapy. In 2001 NICE estimated
that between 1,320 and 5,280 lung cancer
patients received chemotherapy each year324, but
the Royal College of Physicians330 estimates that
over 16,000 NSCLC patients a year are eligible for
chemotherapy.
A recent systematic review323 which summarised
prognostic factors from 12,419 patients in ten trials
of chemotherapy for NSCLC identified performance
status (PS) to be the most important factor in the
selection of patients for systemic treatment (Level
1+) (see appendix 2, Figure 4 for comparison of
Karnofsky and WHO/ Zubrod performance status
scales). Patients with PS WHO 0, 1 (or Karnofsky
score of 80-100) are candidates for chemotherapy
and patients with a performance status of WHO >
2 (or Karnofsky score of 10-50) should not be
offered chemotherapy as there is no evidence that
they will gain a palliative benefit or survival from
such treatment (Level 1+). Selection of patients
with PS WHO 2 or Karnofsky 60-70 for
chemotherapy however, remains contentious.
Although up to 20% of patients within some of the
trials reviewed were PS 2, these patients have
significantly lower survival rates and are likely to
experience greater toxicity than patients who have
a better PS (Level 1+)(See Table 90).
The extent (stage) of the disease is also important
when considering patients for chemotherapy
although the weight of this particular prognostic
factor remains controversial323.
8.5
Chemotherapy + Active Supportive Care
(ASC) versus ASC
A systematic review undertaken by Cancer Care
Ontario Practice Guideline Initiative328 (whose
evidence base included four meta-analyses and
eight randomised trials) concluded that there is a
modest survival benefit (ranging between 1.8 and
4.5 months) for platinum based chemotherapy plus
ASC over ASC alone in the treatment of advanced
NSCLC (Level 1+). The later randomised trials of
single third generation drugs in their review also
showed increases in median survival of 7-8
weeks331 (Level 1+). This updated the HTA
review322,324 which had found evidence of gains in
quality of life, compared to ASC, for the third
generation drugs, when used in NSCLC patients
with good performance status. Our search
identified a further randomised trial332. The results
are consistent with the earlier findings that
platinum based chemotherapy increases median
survival (by approximately 9 weeks)(Level 1+)
see Table 91.
The HTA review included three suitable studies334-336
and our literature search identified three further
studies (reported in four papers) which randomised
one group of patients to a regimen comprising
second generation agents and one group to a third
generation regimen 337-340. In all the trials the
platinum based regimens used cisplatin plus another
second generation drug in comparison to a third
generation drug. There was good homogeneity
within the patient selection for the trials. In terms of
clinical effectiveness, differences in one year survival
rate and median survival did not reach statistical
significance (Level 1+). Few trials reported toxicity in
detail, see Table 92.
In their review, Socinski et al323 observe that the rate
of symptom relief appears to be higher than the
objective response rate in all reported studies,
suggesting that palliation can be achieved with
tumour shrinkage that does not meet the standard
criteria for objective response323.
8.7
In the Cancer Care Ontario Practice Guideline
Initiative review328, the authors also noted that there
was a distinct lack of quality of life data obtained
using standardised scales in the randomised trials
included. The authors concluded that, in terms of
quality of life, there was generally an improvement
of those patients treated with chemotherapy of any
type in comparison to those treated with ASC (Level
1+). The more recent trial (Spiro et al, 2003332)
found no difference in quality of life (Level 1+)
see Table 91.
A recent systematic review323 describes three trials
which randomised one group of patients to a
cisplatin containing regimen and one group to a
regimen containing carboplatin323 with the same
additional chemotherapeutic agents. The NCC-AC
search identified rour randomised trials to update
this review341-344. (Few trials retrieved during the
literature search randomised patients to either
cisplatin or carboplatin based arm with the same
additional agents administered to each group).
Second Generation versus Third
Generation Regimens
Second generation chemotherapeutic agents
include ifosfamide, vinblastine, vindesine,
mitomycin C and platinums (carboplatin and
cisplatin). The platinums have become commonly
used in the treatment of lung cancer and are
associated with side effects including nausea,
vomiting and myelosuppression. Administration of
antiemetics and IV fluids can reduce the incidence
of some of these side effects and can make the
administration of such agents more tolerable333.
More recently, the third generation drugs
(gemcitabine, paclitaxel, vinorelbine and docetaxel)
have been shown to have significant activity
against NSCLC, alone or in combination. This
section will review the evidence comparing third
generation drugs (either singly or in combination)
versus a second generation drug (or second
generation drugs in combination).
Patient Eligibility
Carboplatin versus Cisplatin
Cisplatin was frequently used in the 1980s and
1990s for the treatment of both NSCLC and SCLC.
Carboplatin, an analogue of cisplatin, has a more
favourable toxicity profile and has been successfully
substituted for cisplatin in specific situations. It is
envisaged that carboplatin, which can be
administered without the need for prehydration
and may be used in patients with poorer renal
function, may therefore allow a wider range of
patients to be eligible for chemotherapy.
85
In these studies, no significant differences in
response or survival were detected (Level 1+). One of
the later randomised trials343 found more frequent
thrombocytopenia in the carboplatin arm and more
nausea and vomiting in the cisplatin arm. (This trial
was not powered to detect differences in response
rates). Another of the recent trials341 found similar
numbers of grade 3 and 4 adverse events overall
(40% for cisplatin, 41% for carboplatin). See Table
93. Therefore until further comparative data
emerges, either carboplatin or cisplatin can be
administered for NSCLC patients receiving platinumcontaining regimens, taking account of their
toxicities, efficacy and convenience.
8.8
Third generation chemotherapy treatment
8.8.1
Different combinations of third generation
drugs + Platinums
We identified six recent randomised trials341-343,345-347
plus one study348 included in the HTA systematic
review322 assessing different combinations of third
generation drugs with a platinum as first line
treatment for advanced NSCLC.
The trials compared a range of regimens and
although some combinations were superior within
trials, the levels of outcomes obtained were not
consistent across trials. Where similar combinations
appear in different trials (albeit with different
dosages) the range of response rates and survival
across the trials is larger than that observed within
trials (see Table 94). There is, therefore, no strong
evidence that one regimen is superior over any other.
Higher response rates do not necessarily translate into
improved survival in these trials. Toxicity analyses were
86
LUNG C ANCER
similarly complex, reflecting the known profiles of the
agents’ side effects. Details of specific endpoints are in
Table 94. Two trials reported (non-clinical) quality of
life341,347 but did not detect differences that reached
statistical significance.
CHEMOTHERAPY FOR NON SMALL CELL LUNG C ANCER
8.8.3
Before the advent of the third generation drugs for
NSCLC, platinum based chemotherapy was the
standard of care. We reviewed the evidence to assess
the effectiveness of third generation drugs in
combination, to replace the platinums. Comparisons
of a platinum based regimen that includes one of
the third generation drugs compared with third
generation drug alone have yielded conflicting
results. Our search identified two relevant trials357,358
within the HTA review and six more recent
randomised trials337,342,355,359-361 (Table 96 ). Only two
of the trials detected a significant difference in
response between third generation agents with or
without platinum in various combinations (Level 1+).
None detected a difference in survival (Level 1+).
Only two of the studies examined quality of life359,360
neither detecting significant differences between the
different regimens (Level 1+).
The HTA report concluded that it was likely that the
optimal treatment is a third generation drug
(gemcitabine, paclitaxel or vinorelbine) in
combination with a platinum based drug (cisplatin,
carboplatin). The Guideline Development Group
agreed with this, with the addition of docetaxel, and
decided to make this a good practice point. However,
there is insufficient evidence that any one particular
combination is superior to another (Level 1+).
8.8.2
Three drugs versus two drugs combinations
Triplet chemotherapy regimens, either platinum or
non-platinum based have been tested in phase I and
II studies. However, it is difficult to compare
effectiveness as different combinations of agents
and different dosages are assessed in each trial.
There are concerns about excessive toxicity that need
addressing through phase III studies.
There is currently insufficient evidence that three
drug combinations are superior, in terms of survival,
than two-drug combinations, but there is some
evidence that they are more toxic depending on the
agents used.
We identified two recent randomised trials assessing
duration of treatment362,363 (See Table 97). One of the
later randomised trials363 compared a defined
duration of therapy versus continuous therapy
followed by second-line therapy in advanced-stage
IIIB/IV non-small cell lung cancer. In this trial, 230
patients were randomised to receive either four cycles
The trial in the Cochrane review325 and HTA review322
randomised 204 non-small cell lung cancer patients to
receive either docetaxel or active supportive care. The
dose of docetaxel was reduced from 100 mg/m2 to 75
mg/m2 following an unacceptably high toxic death
rate in the initial patients. The overall tumour response
rate is 5.8% in the chemotherapy treated patients as
compared to nil in the active supportive care group of
patients325 (Level 1+). The median survival was 4.6
months for patients given active supportive care when
compared with 7 months for the chemotherapy group
and 1 year survival was 19% in the active supportive
care group and 29% in the chemotherapy group325
(Level 1+). All quality of life parameters favoured the
docetaxel arm, the differences in pain and fatigue
experienced reached statistical significance365. The later
trial, which compared docetaxel and paclitaxel for
patients who had previously received platinum based
chemotherapy and had a life expectancy of at least 12
weeks, reported median survival of 184 and 105
days respectively.
The majority of patients within these trials to
determine the optimum number of cycles of
chemotherapy either did not have a major response
to treatment or were unable to tolerate more than
three or four cycles (Level 1+). As the trials were not
able to answer the more specific question of whether
patients who are responding to chemotherapy, and
tolerating chemotherapy well, benefit from treatment
beyond three to four cycles, the evidence on the
duration of treatment remains inconclusive.
Duration of therapy in advanced Non
Small Cell Lung Cancer
The optimal duration of therapy in patients with
advanced NSCLC has not yet been identified. Many
patients with advanced NSCLC have co-morbidities
which adversely affect their performance status and
tolerance of chemotherapy. In recent phase III
randomised trials of combination therapy, the typical
median number of cisplatin or carboplatin based
chemotherapy cycles delivered is three or four as any
additional cycles result in cumulative toxicity
experienced. There have been various strategies used
to determine the number of chemotherapy cycles for
advanced NSCLC: treat until progression; treat for
two cycles beyond maximal response; or treat for a
defined number of cycles- usually six to eight.
We identified a Cochrane review containing one
randomised trial, comparing docetaxel with ASC325,
which was also included in the HTA review322, and a
further randomised trial364 comparing docetaxel and
paclitaxel for this group of patients (see Table 98).
The first trial363 found no difference in quality of life
between the two arms. The second trial362 found
quality of life improves for those randomised to
receive three rather than four cycles.
Toxicity reflected the agents’ known profiles and is
described in detail in Table 96.
8.9
Our review is based on the relevant trials from the
HTA review334,336,349-352, a systematic review323, and
four recent randomised trials comparing three and
two drug combinations353-356 (See Table 95). There
is no consistent evidence that either type of
regimen is superior to the other. Where significant
differences in response rates were detected these
showed benefit of a platinum containing doublet
over triplet therapy, and benefit of triplet therapy
over a platinum sequential doublet353 (Level 1+).
Response rates are not necessarily indicative of
differences in survival; quality of life, in a single
trial, shows benefit of a platinum doublet. These
observations will continue to be informed by later
trials. Toxicity reflects the different agents’ known
side effects.
of carboplatin and paclitaxel every 3 weeks (Arm A)
or identical doses of carboplatin and paclitaxel every
3 weeks until progression (Arm B). In both arms,
patients received weekly paclitaxel of 80mg/m2 at
progression. Patients in Arm B received between 0-15
cycles of chemotherapy, but the median number of
cycles received in both groups was 4 because of
disease progression or the patient’s inability to
tolerate further chemotherapy. In the second trial362
308 patients were randomised to receive either six or
three cycles of mitomycin, vinblastine and cisplatin
every 21 days. However, the median number of cycles
administered was 4 and 3 respectively. There was no
difference in tumour response or survival in either
trial. Toxicity reflected the agents known profiles and
is reported in Table 97.
Third generation drugs + Platinums vs. Third
generation drugs + Non platinums
Toxicities occurred in the frequencies anticipated
from agents’ known profiles and are reported in
Table 98.
8.12
8.10
Dosage of chemotherapy treatment
We were not able to identify evidence that
specifically examined this issue. A wide range of
cisplatin doses have been used, but good
comparative data are not currently available. There is
a need for research to identify optimum dosage of
chemotherapeutic agents.
8.11
Economics of chemotherapy for Non
Small Cell Lung Cancer.
Chemotherapy can potentially improve survival,
reduce symptoms, improve quality of life and lead to
a reduction in healthcare costs (e.g. terminal care,
radiotherapy costs). However these advantages have
to be weighed against the additional costs of
chemotherapy, which include the cost of drugs,
supportive medications, administration and
chemotherapy-related toxicity.
Second-line chemotherapy in Non Small
Cell Lung Cancer
Second-line chemotherapy has only recently been
tested in randomised trials. The role of secondline treatment has been unclear because few
patients have adequate performance status and
survival is limited.
87
8.12.1
Chemotherapy versus
Best Supportive Care 1st line
We identified and tabulated 10 economic
evaluations322,366-376 that compared chemotherapy
with best supportive care. Four of the studies were
88
LUNG C ANCER
conducted in the UK and the rest were conducted in
Canada (Table 99 and Table 100).
Maslove et al366 carried out a retrospective cost
analysis of 194 NSCLC patients from eight UK
centres included in the Big Lung Trial 377. The trial
compared three courses of cisplatin-based
chemotherapy plus best supportive care with best
supportive care alone in patients with advanced
disease. The costs were followed-up to death. The
mean aggregate episode cost was significantly
higher for chemotherapy patients compared to
patients receiving BSC. However, the mean costs for
all resources except those related to chemotherapy
administration were not significantly different
indicating that the resource impact of chemotherapyrelated toxicity did not differ significantly between
the two groups. The mean weekly cost was similar
between the two patient groups suggesting that the
additional costs for chemotherapy patients related to
them having longer intervention episodes.
Chemotherapy patients were 5.2 times more likely
than BSC patients to be hospitalised during their
episode (p<0.001) and had more out-patient
attendances (p=0.001). Patients randomised to BSC
alone were more likely to have had radiotherapy
(odds ratio 0.51, p=0.022). The study did not report
effectiveness, however Maslove (2001)366, suggests
that chemotherapy patients incur a cost of about
£300 per extra week of survival, which is equivalent
to £15,600 per LY gained.
Billingham et al367 assessed the cost-effectiveness of
mitomycin, ifosfamide and cisplatin plus palliative
care versus palliative care. The study was a
retrospective study of a subset of patients (116,
South Birmingham) from the randomised MIC2 trial.
The study, which followed-up costs to death,
demonstrated that MIC increased survival by 2.4
months at an incremental cost of £2,924, which
translates into an incremental cost-effectiveness ratio
of £14,620 per LY gained (95% CI: £6168-£21,612).
The MIC2 trial also reported that this survival gain
was achieved without compromising patient’s quality
of life.
Clegg et al322, for the Health Technology Assessment
Report, developed three UK economic models to
compare the cost-effectiveness of four chemotherapy
regimens (paclitaxel, docetaxel, gemcitabine and
CHEMOTHERAPY FOR NON SMALL CELL LUNG C ANCER
vinorelbine, all with or without cisplatin) with BSC
using a synthesis of relevant trial data and a number
of different sources of resource use and cost data.
Results here relate to the third modelling approach
used (cost-effectiveness analysis versus BSC). The
results and limitations of the first two models are
outlined in Clegg et al322
Costs were followed-up to death. The regimens with
the least incremental cost-effectiveness ratios versus
BSC are vinorelbine, vinorelbine + cisplatin and
gemcitabine. Gemcitabine + cisplatin and paclitaxel
+ cisplatin show reasonable cost-effectiveness. All
these regimens retain their cost-effectiveness under a
number of scenarios and assumptions tested in the
sensitivity analysis. However, the single agents
paclitaxel and docetaxel have relatively high costeffectiveness ratios. The sensitivity analysis examined
the effect of different scenarios on the costeffectiveness results. It tested number of cycles, %
patients not completing cycles, number of
administrations, drug costs, reduced dose, cost of
antiemetic drugs, BSC cost, use of mean survival
rates rather than median, quality of life adjustment,
outpatient administration and survival. The results
were most sensitive to changes in survival. The
quality of life adjustment used utility values derived
by Berthelot et al369. The incremental cost per quality
adjusted life years (QALYs) for those regimens that
utility values were available for slightly increased
cost-effectiveness in all cases except one. Clegg et
al322 also considered quantitative information on the
relative quality of life impact of chemotherapy
regimens and BSC. Their overall conclusions were
that chemotherapy for NSCLC is cost-effective taking
into account both survival and quality of life.
Lees et al368 compared the cost-effectiveness of
gemcitabine plus BSC versus BSC using the
perspective of the UK NHS. The study used data
collected in a RCT of 300 patients and assumed that
gemcitabine was administered on an outpatient
basis. The trial was designed to measure quality of
life, not survival, and therefore the results are
presented as a cost per progression-free survival
where progression relates to time to radiotherapy.
Costs were not followed-up to death. The study
reported that gemcitabine + BSC was associated
with an incremental cost per progression-free LY
gained of £5,228 compared to BSC alone.
The remaining six studies were conducted in Canada.
Four of these studies are based on the same
economic model framework369,370,372,374 and two are
retrospective analyses of an old (1984) Canadian
RCT 375,376 A wide range of regimens were
considered. In terms of incremental cost-effectiveness
versus BSC all estimates were below $20,000
(Canadian dollars) and in some cases chemotherapy
was the dominant strategy (increased effectiveness
at reduced costs). In terms of incremental QALYs,
only two studies included a quality adjustment, and
they presented very different results. Berthelot et
al369 found that quality adjusting LYs gained
increased the cost-effectiveness ratio by about 50%,
but regimens remained relatively cost-effective versus
BSC (range: Vinblastine + cisplatin dominated BSC
to paclitaxel (135) + cisplatin = $21,500 per QALY
gained). However, Kennedy et al375 found that BSC
was the dominant strategy in terms of cost per QALY
gained. This was mainly due to the divergence of
utility values used for the studies. Kennedy et al
1995375 used mean utility values of 0.34 for
chemotherapy and 0.61 for BSC whereas Berthelot et
al369 used 0.52 to 0.63 for chemotherapy
(depending on regimen) and 0.53 for BSC.
8.12.2
Chemotherapy versus chemotherapy 1st line
We identified and tabulated 18 economic
evaluations that compared two or more
chemotherapy regimens. Only one of the studies was
conducted from the perspective of the UK NHS
(Table 101 and Table 102).
>
Three of the studies presented cost-effectiveness
in terms of incremental cost per LY gained
(Table 103):
Earle and Evans378 used an economic model
framework to evaluate the cost-effectiveness of
paclitaxel + cisplatin versus etoposide + cisplatin.
The incremental cost-effectiveness ratios ranged from
$30,619 to $138,578 per LY gained depending on
location of administration of paclitaxel (inpatient or
outpatient) and the addition of a growth-colony
stimulating factor (G-CSF). Evans370, used the same
economic model framework to assess the costeffectiveness of vinorelbine with or without cisplatin
versus etoposide + cisplatin and vinblastine +
cisplatin. Again the cost-effectiveness ratios varied
89
widely depending on the location of administration
of vinorelbine and the addition of cisplatin to
vinorelbine. The third study, Smith et al379,380, used
effectiveness data from a European RCT and applied
US costs to estimate the cost-effectiveness of
vinorelbine + cisplatin versus vindesine + cisplatin.
The resulting incremental cost-effectiveness ratio was
$15,500 per LY gained and $25,800 per QALY
gained. Smith 1995 did not assess costs to death. It
is not clear for the other two studies whether lifetime
costs were assessed or not.
>
Three of the studies also assessed cost-effectiveness,
but used different effectiveness endpoints:
A UK study368 evaluated the cost-effectiveness of
gemcitabine + cisplatin compared to a number of
other newer and older chemotherapy regimens. For
all these comparisons data on effectiveness were
derived from relevant RCTs and resource use and cost
data were derived from a number of different
sources. A number of assumptions with regard to
resource use had to be made. The results suggest
that gemcitabine + cisplatin is more costly with
improved effectiveness compared to older
chemotherapy regimens (etoposide + cisplatin, MIC,
MVP) and is the dominant strategy (more effective,
reduced costs) compared to other newer
chemotherapy regimens (paclitaxel + cisplatin,
paclitaxel + carboplatin, docetaxel + cisplatin,
vinorelbine + cisplatin). It is unclear whether costs
were followed-up to death.
Annemans et al381, compared the cost per responder
between paclitaxel + cisplatin and teniposide +
cisplatin in four countries. The study found that the
average cost-effectiveness ratios for the two groups
were similar despite the high cost of chemotherapy
drug cost in the paclitaxel arm. This was because the
high drug cost was partly outweighed by lower
hospitalisation costs for administration and lower
chemotherapy-related toxicity costs. The study did
not follow-up costs to death and assumed certain
costs to be equal between the two groups.
The third study, Palmer and Brant382, was a costeffectiveness study of four cisplatin-based
chemotherapy regimens (gemcitabine, vinorelbine,
etoposide and mitomycin + ifosfamide). Average
cost-effectiveness ratios (cost per tumour response)
90
LUNG C ANCER
were not statistically different between the four
treatment groups. Gemcitabine + cisplatin had the
most favourable cost-effective ratio. Costs were not
followed up to death.
>
The final 12 studies were cost-minimisation
studies or cost analyses:
Ramsey et al383 conducted a cost-minimisation
analysis using data collected prospectively in a RCT
of paclitaxel + carboplatin versus vinorelbine +
cisplatin. There was no statistically significant
difference in survival or cancer-related quality of life
between the treatment arms. The mean lifetime
cancer-related health care cost for the vinorelbine +
cisplatin group was significantly lower than for the
paclitaxel + carboplatin group ($40,292 versus
$48,940, P=0.004). The mean difference was
$8,648 (95% CI=$2,634 to $14,662). The majority
of this difference was due to the higher cost of
chemotherapy drugs in the paclitaxel arm. There
were no notable differences in downstream costs.
The chemotherapy drug cost and medical procedures
cost was significantly higher in the paclitaxel arm
(p=0.0003 and p<0.0001 respectively) and the
chemotherapy administration costs were significantly
higher in the vinorelbine arm (p<0.0001).
Rubio-Terres et al384 conducted a cost-minimisation
analysis of docetaxel+ cisplatin, paclitaxel + cisplatin
and paclitaxel + carboplatin. Equivalent efficacy was
demonstrated in a RCT. An economic model was
constructed to estimate the treatment cost per
patient over a median of 4 cycles (no follow-up of
costs to death). The mean treatment cost for the
docetaxel + cisplatin regimen was lower than that
for the paclitaxel regimens. Statistical significance for
the difference was not tested. The difference was
mainly due to the lower cost of chemotherapy drugs
in the docetaxel arm.
Chen et al385, in a cost-minimisation analysis, also
found that chemotherapy drug cost was responsible
for the difference in treatment costs between
paclitaxel + carboplatin and paclitaxel plus
gemcitabine (maximum of 6 cycles, no follow-up of
costs to death). Total treatment costs and
chemotherapy drug costs were significantly higher
for the paclitaxel + gemcitabine arm (p=0.034 and
p=0.035 respectively).
CHEMOTHERAPY FOR NON SMALL CELL LUNG C ANCER
Skowron et al386, in a cost analysis, found that
chemotherapy drug cost and in-patient
administration cost constituted the highest cost
components of chemotherapy in a retrospective cost
analysis of 87 patients undergoing etoposide +
cisplatin or vinorelbine + cisplatin or gemcitabine +
cisplatin. No statistically significant difference was
found in one year survival between the three groups.
Chemotherapy cost was the highest cost component
in the gemcitabine + cisplatin group and the cost of
administration was the highest cost component in
the other two treatment groups. However a number
of important costs were not included in the study
including a follow-up of costs to death and
chemotherapy-related toxicity costs.
Khan et al387, in a prospective cost-minimisation study
comparing carboplatin and cisplatin (+/- other
chemotherapy regimens) found that the cost per
patient and cost per course was higher for carboplatin
than for cisplatin (statistical significance not tested).
This difference was predominantly due to the higher
cost of carboplatin. Again, costs were not follow-up to
death and some cost elements were excluded.
significantly higher for gemcitabine + cisplatin
(p>0.0001) and hospitalisation costs were higher
(but not significantly) for etoposide + cisplatin.
Follow-up of costs to death were not included.
Supportive care treatments include antiemetics
(control of chemotherapy-induced emesis),
antimicrobials (control of chemotherapy-induced
infection) and cytoprotective agents (protection of
normal cells from chemotherapy-related toxicity). No
economic evaluations were identified for any of
these treatments in a pure NSCLC population.
Clegg et al322 however, considered the effect
antiemetics would have on the cost-effectiveness
ratios of several chemotherapy regimens. The older
antiemetic drugs (e.g. metoclopramide) have
negligible costs and therefore would make little
impact on cost-effectiveness, however the newer
agents (e.g. ondansetron) are more effective but
more expensive. In the Clegg et al322 model adding
antiemetics would slightly increase incremental costeffectiveness ratios versus BSC. However, although
they would increase drug costs, it is likely that they
would also impact on efficacy (i.e. fewer patients
discontinuing therapy, fewer dose reductions) and
other costs (i.e. reduction in costs of managing
chemotherapy-related toxicity).
Chemotherapy versus
Best Supportive Care 2nd line
We identified two studies that assessed the costeffectiveness of second line chemotherapy with
single-agent docetaxel versus BSC.
Leigh et al395 conducted a retrospective costeffectiveness analysis using efficacy data from a RCT
and resource use and cost data from one
participating hospital in Canada (Table 104 and
Table 105). Costs were followed-up to death. The
incremental survival benefit of docetaxel versus BSC
was 2 months (p=0.047) and the incremental cost
per LY gained was $57,749 (Canadian dollars). For
the sub-group of patients treated with the
recommended dose of docetaxel (75 mg/m2) the
survival benefit was 4 months and the cost per LY
gained was $31,776. Second line docetaxel costs an
additional $10,600 per patient for an extra 4
months of life.
Vergnenegre et al388, in a prospective study found that
effectiveness, in terms of objective response rate, was
similar between two chemotherapy treatment groups
(mitomycin + vinorelbine + cisplatin versus mitomycin
+ vindesine + cisplatin). Mean cost per patient for 3
cycles of chemotherapy were also similar. Costs were
not followed-up to death.
The five studies that are gemcitabine costminimisation studies are either authored or
supported by the producer of gemcitabine. Four of
the studies were economic models using efficacy
data from relevant RCTs and supplemented by expert
opinion389-392. Costs were not followed-up to death
and critically a number of assumptions had to be
made. It was assumed that gemcitabine would be
administered on an outpatient basis and the cost of
gemcitabine was either assumed or excluded from
the analysis altogether. The fifth study393 was a costminimisation study comparing gemcitabine +
cisplatin versus etoposide + cisplatin. Efficacy and
resource use data were collected prospectively in an
RCT. No significant differences were found in terms
of survival or mean cost per patient between the two
treatment groups. Chemotherapy drug cost was
These treatments can be costly and therefore it is
important to assess their cost-effectiveness.
Schiller et al394 retrospectively identified costs for
gemcitabine plus cisplatin (Gem/Cis) vs plus
cisplatin (Vin/Cis) , paclitaxel plus cisplatin
(Pac/Cis), paclitaxel plus carboplatin (Pac/Car),
docetaxel plus cisplatin (Doc/Cis). The cost
analysis was based on the results of two RCTs 342,351.
Cost of chemotherapy acquisition, drug
administration, hospitalisations and medical
resources were calculated from the perspectives of
the national health services of five European
countries. Gem/Cis was associated with a lower
cost than other drug combinations.
8.12.3
Clegg et al322 (described above) using an economic
model estimated the incremental cost-effectiveness
of docetaxel to be £17,546 per LY gained compared
to BSC (Table 100).
8.12.4
91
8.12.5
Discussions
A number of important considerations need to be
kept in mind when interpreting the results from
these studies including:
> A number of different methods were used for
capturing data and data analysis.
>
The studies assessed a combination of different
stages of disease.
>
All the studies claimed to calculate direct
medical costs, however, a number of different
perspectives were used and some studies did not
include all relevant costs.
>
Length of follow-up varied between the studies.
Only a proportion of studies assessed costs
to death.
>
Some studies made assumptions on the median
number of cycles, doses used and method and
location of administration. There is a great deal
of uncertainty around these issues.
Supportive care treatment
Supportive care treatments administered alongside
the chemotherapy regimen aim to reduce or
eliminate the toxic side-effects of chemotherapy.
92
LUNG C ANCER
>
>
The studies used a number of different
effectiveness endpoints for the economic
evaluation including LYs gained, QALYs, tumour
response, progression-free LYs.
The studies were conducted in a number of
different countries and the results of an
economic evaluation conducted in one country
may not be generalisable to another country
because of differences in clinical practice
Cost-effectiveness of first-line chemotherapy
Chemotherapy generally seems to improve survival at
an additional cost relative to BSC. The cost per LY
gained seems to be below £20,000 for most
regimens that have been evaluated.
The evidence for this is from four economic
evaluations set in the UK NHS, three of them using
effectiveness data from a multicentre RCT and either
prospectively or retrospectively collected data on
patient-specific actual resource use.
None of the studies considered the addition of
carboplatin rather than cisplatin. Carboplatin could
be administered on an outpatient basis and
therefore could be a lower cost, more cost-effective
alternative, depending on relative drug prices and
the costs of treating side effects. Cisplatin is given
as an outpatient basis in some units, but its
administration costs are likely to be greater because
it has to be administered over a much longer period.
To properly assess the cost-effectiveness of
chemotherapy, one needs to assess the effectiveness,
not just in terms of improvements in survival but
also in terms of quality of life (see below).
The choice of first-line chemotherapy regimen
The data suggest that newer regimens generally
improve survival at additional cost relative to older
regimens. Only one study was set in the UK and did
not report cost per LY gained or QALYs.
There are only a limited number of studies that
compare the relative cost-effectiveness of one of the
newer regimens compared to another. Only one US
study that followed-up costs to death reported a
statistically significant difference in cost per patient
CHEMOTHERAPY FOR NON SMALL CELL LUNG C ANCER
(vinorelbine + cisplatin had significantly lower cost
per patient than paclitaxel + carboplatin). The
majority of the cost difference was due to the
additional cost of chemotherapy. Since, drug
acquisition costs in the UK are more favourable for
vinorelbine; this would sugest that it could be costeffective in the UK. However, these results might not
strictly be applicable to the UK NHS, because, the
patient groups may be dissimilar and the same
intervention may have very different resource
impacts in different health systems.
Hospitalisation (for administration of chemotherapy
or for chemotherapy-related toxicity) as well as
chemotherapy drug cost is driving the differences in
the cost of drug regimens.
The differences in the estimated cost-effectiveness of
different drug regimens are dependent, not just on
the efficacy and toxicity of the drugs but also on the:
>
Drug price (which can vary substantially,
especially when drugs become subject to generic
competition)
>
Number of cycles/administrations assumed;
>
Whether administration was on an outpatient or
inpatient basis;
>
Prevalence of dose reductions/cancellations.
>
The HTA report did not consider differences
between regimens in the cost of treating toxicity.
Second-line chemotherapy
Second-line chemotherapy generally seems to
improve survival at an additional cost for appropriate
patients. The evidence for this is relatively limited
given that there have only been two studies (one
Canadian and one UK).
There were no studies that assessed the incremental
cost-effectiveness of supportive care treatments in an
NSCLC population.
Quality of life issues
Quality of life is an important consideration in
situations where treatment provides only modest
survival gains. It is also an important consideration in
treatments that may induce toxicity and therefore
quality of life is likely to differ between chemotherapy
regimens depending on their toxicity profile. However,
only four of the economic evaluations made an
attempt to quality adjust survival and from these it is
unclear what effect adjusting survival gain with
patient’s quality of life would have on incremental
cost-effectiveness ratios. For a person in perfect health
£20,000 per LY gained would equal £20,000 per
QALY gained. So for people in less than perfect health
the cost per QALY gained would be expected to be
higher, unless chemotherapy is actually improving the
quality of life for these patients.
Berthelot et al369, in their assessment of several
chemotherapy regimens versus BSC, found that
chemotherapy was either relatively cost-effective per
QALY gained or dominant with the cost per QALY
gained being about 50% higher than the cost per LY
gained. Clegg et al322 used Berthelot’s utility values
to quality adjust survival and found that the
chemotherapy regimens remained relatively costeffective compared to BSC. The costs per QALY
gained were all slightly higher than the costs per LY
gained in all but one case. However, another study375
found BSC to be the dominant strategy. The only
other study to assess utility values379 compared three
chemotherapy regimens not including BSC. The main
reason for the difference in results relates to a
divergence in utility values estimated by Kennedy.
Kennedy used mean utility values of 0.34 for
chemotherapy and 0.61 for BSC, Berthelot used 0.52
to 0.63 for chemotherapy (depending on regimen)
and 0.53 for BSC and Smith 1995 used 0.60 for
cisplatin-based regimens and 0.7 for single agent
regimens. In each case utility values were derived
from a number of oncologists so it is unclear why
such a substantial divergence arose.
Clegg et al322 also reviewed the quantitative
information on quality of life and concluded that
chemotherapy does not reduce overall quality of life
and in some cases it may be improved relative to
BSC as metastases that are not controlled are also
associated with adverse symptoms that impact on a
person’s quality of life. Using Berthelot’s utility
scores the HTA report found chemotherapy regimens
to be cost-effective relative to a threshold of
£30,000 per QALY gained, ranging from £3,000 to
£16,000 per QALY gained.
8.12.6
93
Conclusion on economics aspects of
chemotherapy for Non Small Cell Lung Cancer
It is likely that chemotherapy as an adjunct to best
supportive care for patients with NSCLC is costeffective (value for money), however, estimates of
cost-effectiveness are contingent on the estimated
changes in overall health-related quality of life.
More research is needed in this area. Chemotherapy
drug regimens differ in terms of their effectiveness,
cost and toxicity profiles, however the uncertainty
around estimates means that it is not possible to
rank different regimens in order of cost-effectiveness.
94
8.13
LUNG C ANCER
Conclusions
COMBINATION TREATMENT FOR NON SMALL CELL LUNG C ANCER
8.14
Recommendations
8.14.1
Clinical Practice Recommendations
95
The conclusions from this section are that:
>
Chemotherapy is likely to be cost-effective for
patients with NSCLC. The cost-effectiveness
would improve with regimens that can be
administered on an outpatient basis and have
lower toxicity. Cost-effectiveness might also
improve when the drugs come off patent and
face generic competition. (Level 1+).
>
Patients with a better performance status
respond better to chemotherapy (Level 1+).
>
Chemotherapy involving platinum or third
generation regimens increases survival and
disease control compared to active supportive
care (Level 1+). However, complete or partial
response does not necessarily translate into
improved survival or quality of life
>
>
Chemotherapy for advanced NSCLC should be a
combination of a single third generation drug
(docetaxel, gemcitabine, paclitaxel or vinorelbine)
plus a platinum drug. Either carboplatin or cisplatin
may be administered, taking account of their
toxicities, efficacy and convenience. [D(GPP)]
Patients who are unable to tolerate a platinum
combination may be offered single-agent
chemotherapy with a third-generation drug. [A]
Docetaxel monotherapy should be considered if
second-line treatment is appropriate for patients with
locally advanced or metastatic NSCLC in whom
relapse has occurred after previous chemotherapy. [A]
There is some evidence that Carboplatin and
Cisplatin are similar in terms of response and
improved survival; nevertheless they have
contrasting toxicity profiles (Level 1+).
There is insufficient evidence that any one
particular combination of third generation drug
plus platinum is superior to another
>
There is insufficient evidence to determine whether
regimens with two or three agents are superior
>
There is currently insufficient evidence to
determine whether third generation agents,
alone or in combination, should be used with or
without platinum
>
There is insufficient evidence to identify the
optimum duration of chemotherapy
>
Chemotherapy should be offered to patients with stage
III or IV NSCLC and good performance status (WHO 0,
1 or a Karnofsky score of 80–100), to improve survival,
disease control and quality of life. [A]
There is inadequate evidence to identify optimal
dosages.
8.14.2
Research Recommendations
Further research is needed into whether
chemotherapy or active supportive care result in
better symptom control, quality of life and survival
for patients with advanced NSCLC of performance
status 2.
Further trials should invesigate the optimum timing,
combination, dosage and duration of chemotherapy
for patients with NSCLC who are candidates for
chemotherapy. These should include assessment of
quality of life and survival.
9 Combination Treatment for
Non Small Cell Lung Cancer
9.1
Introduction
Although NSCLC patients may benefit from treatment
with surgery or radiotherapy alone, the cure rate
remains disappointingly low. Data from other tumour
types suggests that improved survival may be gained
from combinations of these modalities.
Adjuvant treatment (chemotherapy or radiotherapy)
is given after curative-intent surgery or radiotherapy,
in an attempt to improve the cure rate. It has been
shown to be effective in a number of other common
solid tumours such as breast and colorectal cancer.
It is important to distinguish neoadjuvant treatment
(usually chemotherapy) and combined
chemoradiotherapy from primary chemotherapy.
Neoadjuvant chemotherapy is given before planned
curative-intent surgery or radiotherapy in patients
with curable disease at presentation. Combined
chemoradiotherapy is given to patients eligible for
radical radiotherapy and the treatments are either
given sequentially or concurrently. In both these
settings, neoadjuvant and combined, the aim of
adding chemotherapy is to improve the cure rate
obtained with surgery or radiotherapy alone.
In contrast, primary chemotherapy is given to
patients unsuitable for surgery or radical
radiotherapy at presentation in the hope that
downstaging their tumour might enable them to
proceed to curative surgery or radical radiotherapy.
The response rates and survival are much lower in
this setting.
Induction chemotherapy is used as a general term to
include neoadjuvant treatment and primary
chemotherapy as defined above.
There is variation in the definitions and
interpretation of the terms resectable and
unresectable in regard to pre and postoperative
treatment. It may refer to a primary tumour in the
chest being technically unresectable at the time of
surgery or biologically unresectable because nodes
or metastases in other organs must be left behind,
meaning that removal of the tumour does not affect
the course of the patient’s disease. Furthermore, it is
often unclear whether categorization of patients as
resectable or unresectable refers to the patient’s
status at the time of presentation or after
neoadjuvant chemotherapy. Thus, the terms
resectable and unresectable should be used with
respect to a surgeon’s ability to remove all the
tumour tissue in its entirety. Operability or
inoperability should refer to the decision based on
resectability and all other factors for example lung
function, that eventually determines whether a
surgeon proceeds to operate or not.
One of the difficulties in reviewing studies of
combination therapy is various methods are used for
patient selection. While some studies have used
surgical (pathological) staging with mediastinoscopy
in addition to radiological (clinical) staging with CT,
this is not applicable to all. Another issue relates to
the substantial heterogeneity in clinical status and
prognosis of patients.
In this chapter, we investigate the evidence for
combined treatment of NSCLC patients with two or
more of these modalities. Various combinations and
orders of treatment have been included. Treatments
by surgery, radiotherapy or chemotherapy in isolation
are dealt with separately in the previous chapters.
96
9.2
LUNG C ANCER
COMBINATION TREATMENT FOR NON SMALL CELL LUNG C ANCER
Techniques included in this review
undergoing preoperative (primary) cisplatin-based
chemotherapy with or without radiotherapy. The
systematic review on which the guideline400 is based,
reports results from two full paper RCTs, which are
reported together with an additional RCT retrieved in
Table 107. The results of the guideline showed that
preoperative chemotherapy significantly reduced
mortality at 2 years compared with no chemotherapy
in patients with stage IIIA disease (OR 0.18 (95% CI
0,06 to 0.51) (Level 2+). However, there are
difficulties in interpretation of the two completed
RCTs. For example, both studies included
postoperative radiotherapy for some patients in both
treatment arms, there were small numbers of
patients in the treatment arms of the trials, stage
IIIA is heterogeneous and different chemotherapy
regimens and doses were used in the two trials.
We included the following combinations of
treatment:
9.3
>
preoperative chemotherapy
>
postoperative chemotherapy
>
preoperative radiotherapy
>
postoperative radiotherapy
>
postoperative chemoradiotherapy
>
sequential and concurrent chemoradiotherapy
Methodology
In our initial search, we retrieved a number of
systematic reviews published in 2001396-398, in
addition to a number of reviews from the Cochrane
Database of Systematic Reviews321,399 and a
guideline400. The NCC-AC team undertook additional
searches to update these reviews.
The RCT401 which updated this review in Table 107
included patients with stage IB - IIIA NSCLC and so,
did not distinguish between the effects of adjuvant
and neoadjuvant chemotherapy. The response rate to
chemotherapy was 64%, but the trial reported no
statistical difference in median, 3-year and 4-year
survival between preoperative chemotherapy plus
surgery and surgery alone. There was however a
significant prolongation of disease-free survival in the
chemotherapy group (13 months versus 27 months, p
= 0.03) and a trend towards improved survival with
preoperative chemotherapy, for the whole group
showing a median survival of 37months (95% CI, 26.7
to 48.3) versus 26 months (95% CI, 19.8 to 33.6),
where P=0.15. A subset analysis suggested a positive
effect of preoperative chemotherapy on survival in
stage I and II NSCLC patients (Level 1+).
The search strategy is shown in appendix six.
9.4
Preoperative Chemotherapy
The role of preoperative chemotherapy has been
examined in two categories of disease burden. Most
studies have involved patients with stage IIIA and IIIB,
while a few trials have considered stage I and II disease.
This section reviews preoperative chemotherapy for
patients with stage I-III NSCLC as compared to
surgery alone, and includes both neoadjuvant and
primary chemotherapy. There was no available
evidence on patient selection for treatment.
9.4.2
9.4.1
Effectiveness
A systematic review396 reported tumour response to
preoperative (primary) chemotherapy from six
prospective phase II trials in patients with stage IIIA
or IIIB NSCLC (Table 106). The review reported a
non-weighted average effect size for radiological
response rate of 64%, a disease progression of 4%
and for histological complete response of 24% of
patients396 (Level 2++).
A recent guideline400 reports survival outcomes for
technically resectable stage IIIA NSCLC patients
was the most common problem noted in the CCOPGI
guideline400 reporting 80% of patients developing
severe neutropenia after the first course and four
patients (15%) requiring hospitalisation for the
treatment of neutropenic fever in one RCT reviewed
(Level 1+)400. Other toxicities reported included
nausea and vomiting (generally mild), diarrhoea,
oesophagitis (rare in patients treated with
chemotherapy alone), hypomagnesemia and alopecia
(Level 1+). There is no definite evidence of a
difference in surgical morbidity or mortality
following chemotherapy compared to surgery alone,
but further information is required to confirm the
safety and efficacy of preoperative chemotherapy.
For example, the additional RCT401 retrieved reported
higher postoperative mortality with chemotherapy
(6.7% versus 4.5%) although this was not
significant (p-0.37) (Table 108).
9.4.3
9.5.2
9.5
Postoperative Chemotherapy
The use of postoperative chemotherapy is based on
the premise that following resection of the lung
cancer in early NSCLC recurrence can be both
systemic as well as local.
Effectiveness
One systematic review on the effectiveness of
postoperative chemotherapy was retrieved321 (Table
110). Regimens including long-term alkylating
agents and cisplatin-based regimens were considered
separately. Two additional RCTs which used cisplatinbased regimens were retrieved.
The systematic review321 reported from 5 trials
(N=1250) that used long-term alkylating agents, all
of which favoured surgery alone with a 15% higher
risk of mortality (HR 1.15; 95%CI 1.04, 1.27,
p=0.005) (Level 1+).
Conclusion
Several studies have demonstrated an improvement
in survival of stage IIIA patients treated with
preoperative chemotherapy and surgery compared to
surgery alone, with a median survival of about 3
years. However, at present the evidence base is not
sufficient to recommend preoperative chemotherapy
for these patients. The forthcoming results of the
Medical Research Council (MRC) LU22 study may
provide further useful data on the effects of
preoperative (neoadjuvant) chemotherapy in the UK
and continental practice.
Patient Eligibility
The majority of patients who survive surgery are fit
for chemotherapy. One Cochrane systematic review
was retrieved on eligibility for postoperative
chemotherapy (Table 109). The review reported that
age and gender did not seem to influence the results
(the effect was homogenous). There were too few
people with poor performance to reach valid
conclusions regarding this variable.
In conclusion, preoperative chemotherapy can produce
complete radiological and pathological responses.
There is no definite evidence so far that surgical
morbidity and mortality are significantly increased
however, a few stage I or II patients have been
included in trials and although one large prospective
study suggested a trend toward a greater survival
benefit for this group, there is currently little evidence
that preoperative chemotherapy prior to resection
provides improves survival in early stage NSCLC.
Toxicity
A number of phase II studies have uniformly shown
that the treatment is well tolerated and are reported
in Table 108. One systematic review396 of 17 phase II
trials of induction chemotherapy showed that the
non-weighted average mortality rate during
induction treatment alone is 2% regardless of
induction regimen. Furthermore, the non-weighted
average treatment-related mortality occurring at any
time during the induction, operative or postoperative
recovery period is 4% (Level 2++). In terms of
morbidity, grade 3 or 4 neutropenia (WHO scale)
9.5.1
97
However, the review321 also reported from 8 RCTs402-409
that cisplatin-based regimens were associated with a
15% reduction in risk of death (HR 0.87; 95%CI,
0.74, 1.02, p=0.08) (Level 1+). We combined these
results with the 2 additional RCTs410,411 in a metaanalysis using the logarithm of the hazard ratio and
its standard error calculated from the original reports.
We found no evidence of significant heterogeneity
among the studies and therefore a fixed effect model
was used to combine the results.
The results of the meta-analysis (see appendix 5)
gave a pooled estimate of 0.87 (95% CI 0.76 - 0.99)
(p=0.048) in favour of postoperative chemotherapy
(Level 1+).
9.5.3
Conclusion
In summary, recently accumulated data, shows that
cisplatin-based adjuvant chemotherapy may produce
a small but statistically significant survival benefit.
The Guideline Development Group recommends
postoperative chemotherapy should be discussed
with patients who have had surgery, with particular
attention to possible benefits and toxicity.
98
9.6
LUNG C ANCER
COMBINATION TREATMENT FOR NON SMALL CELL LUNG C ANCER
Preoperative Radiotherapy
update this evidence (Table 112). There were 2,000
patients in 12 trials. The results were very similar to
the PORT meta-analysis, which found worse survival
overall after postoperative radiotherapy and that the
adverse effect of post operative radiotherapy was
greater for patients with stage I/II N0-N1 disease
and less obvious for stage III, N2 disease.
It was thought at one time that preoperative
radiotherapy would make resection of the primary
tumour easier, as well as controlling occult residual
disease. However, the area has not received much
attention since the 1980s396.
A systematic review 396 identified two large trials
published in the 1970s but no subsequent
additional randomised trials of pre-op radiotherapy
involving at least 100 patients were retrieved (Table
111). These two trials recruited 331 and 568
operable patients who were randomised to either 40
or 50Gy of pre-op radiotherapy then surgery or
surgery alone. The survival curves were almost
identical, with 5-year survival rates of 7% and 14%
for the preoperative radiotherapy, compared to 12%
and 16% for surgery alone (no statistically
significant difference) (Level 1+). There was no
difference in the rate of complete resection or in the
recurrence rate. The studies however, had some
limitations. They relied on the staging and
radiotherapy techniques available at the time. They
also included 10% to 15% of patients with small
cell lung cancer. Many of the patients may have had
undiagnosed systemic disease because 40% - 50%
of both arms died within 6 months.
However, a number of criticisms can be made of
studies included in the PORT meta-analysis. Seven of
the nine studies included in the meta-analysis used
60
Co machines rather than linear accelerators
(LINACs). This is likely to have implications in the
accuracy of targeting the treatment volume and
increasing the lung dose. In addition, the doses used
were sometimes lower than would be used in
modern treatment plans and thus potentially less
effective. For these reasons the results of this metaanalysis for patients with stage III should be treated
with some caution.
The additional RCT414 retrieved reported more
favourable results with the addition of radiotherapy
in stage I NSCLC patients (Table 112). Statistically
significant improved outcomes were reported for 5year disease-free survival (71% versus 60% in
control group (p=0.039)) and overall survival (67%
versus 58% in control group (p=0.048)). There were
no treatment related deaths reported (Level 1+).
Postoperative Radiotherapy
Postoperative radiotherapy has been examined with
the hypothesis that cure rates should be improved by
reducing local recurrence.
9.7.1
In summary, despite these results from a recent
RCT414, the meta analyses have shown that there is
still no strong evidence to recommend routine
postoperative radiotherapy. However, for patients
with stage III NSCLC, modern radiotherapy may
possibly afford benefits in term of local control
without the toxicity seen with earlier treatments;
further randomised trials are need in this area.
Complete resection
The patients included in this review are those with
NSCLC that have undergone complete surgical
resection of the primary tumour.
The Cancer Care Ontario Practice Guidelines
Initiative have published evidence based guidance412
for patients with completely resected stages II and
IIIA NSCLC, which incorporates and updates a metaanalysis413 by the Postoperative Radiotherapy Trialists
Group (PORT). One additional RCT414 was retrieved to
9.7.2
Incomplete resection
Intuitively, postoperative radiotherapy where there
has been incomplete resection of the primary tumour
9.9
9.9.1
9.8
Individual trials in the systematic review found that
performance status was a major independent
prognostic factor (see appendix 2, Figure 4 for
comparison of Karnofsky and WHO/ Zubrod
performance status scales). The review also found
inconsistent evidence to identify weight loss as an
independent prognostic factor6 (Level1+).
Effectiveness
A recent review321 provides the best available
evidence for the clinical effectiveness of
postoperative chemoradiotherapy versus
postoperative radiotherapy. One additional RCT418
was retrieved. The results are presented in Table 114.
The review321 of seven trials (807 patients in total)
reported that the overall hazard ratio of 0.98
(p=0.76) was marginally in favour of
chemoradiotherapy although the result was not
statistically significant (Level 1+). However, it should
be noted that the authors were not able to
distinguish between those studies that included
patients with complete resection only, incomplete
resections only, and those that had a mixture of
both. Keller et al418 reported results from 488 stage
II and IIIA patients who had undergone complete
resection and were randomised to either
postoperative radiotherapy or postoperative
chemoradiotherapy. There was no statistically
significant difference in median survival (38 months
versus 39 months). There was a high incidence of
side effects in the chemoradiotherapy arm, although
the two arms had similar mortality (Level 1+).
In conclusion, there is not sufficient evidence at
present to recommend the routine use of
postoperative chemo radiotherapy.
Patient Eligibility
One systematic review was retrieved which looked at
patient eligibility for chemoradiotherapy419,420. The
results of the systematic review are presented in
Table 115.
Postoperative Chemoradiotherapy
Postoperative chemoradiotherapy has been used in
clinical trials for patients in with stage II and III NSCLC.
It is envisaged that the addition of chemotherapy
might enhance the effects of radiotherapy.
9.8.1
Primary Chemoradiotherapy for
inoperable Non Small Cell Lung Cancer
This section focuses on the use of combination of
chemotherapy and radiotherapy for the treatment of
stage IIIA, b NSCLC patients (although it is likely
that a small proportion of patients within some of
the trials had stage I or stage II disease).
Chemoradiotherapy can be scheduled either
concurrently or sequentially, usually involving
chemotherapy first. This section discusses both of
these techniques and compares the two approaches.
A systematic review398,415, found only two studies416,417
prior to 2000, each of which included around 30
patients with incomplete resection (Table 113). These
two studies were not controlled, but reported
encouraging five-year survival figures of 78% and 23%
for N0 patients with positive resection margin. (Level 3)
Our literature search uncovered no studies since 2000.
Therefore, there is weak evidence that postoperative
radiotherapy in patients with incompletely resected
NSCLC may improve local control.
The CCOPGI review found significantly lower
recurrence in the group randomised to postoperative
radiation (p<0.01)412. Quality of life was not reported.
Radiation related toxicity events were regarded as at
an acceptable level. There were no treatment related
deaths (Level 1+).
In summary, we only identified two randomised
trials, which do not suggest any benefit of routine
preoperative radiotherapy.
9.7
should be helpful in NSCLC patients. However, there
is very little evidence in this area.
99
9.9.2
Sequential Chemoradiotherapy
9.9.2.1 Effectiveness
Table 116 illustrates the retrieved results for
effectiveness of non-cisplatin-based
chemoradiotherapy (3 trials292,421,422 , 431 patients).
There were no significant differences in the objective
response rates in the chemoradiotherapy arms when
compared with radiotherapy alone (Level 1+).
However, in patients treated with cisplatin based
chemotherapy (7 trials288,423-428 , 1857 patients) a
trend toward better response rates was seen (Table
117) (Level1+).
Non-cisplatin based chemoradiotherapy does not
improve survival compared with radiotherapy alone
(Table 116). However, sequential cisplatin based
chemoradiotherapy does (Table 117) (Level 1+). The
rate of local control is not altered by use of
sequential chemoradiotherapy (Level 1+).
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COMBINATION TREATMENT FOR NON SMALL CELL LUNG C ANCER
0.93, p=0.01) and improved two-year locoregional
progression-free survival (relative risk 0.84, p=0.03)
and progression free survival at any site (relative risk
0.90, p=0.005) (Table 118) (Level 1+). The
improvement of survival was more convincingly
demonstrated in those receiving once daily
radiotherapy or higher total doses of chemotherapy
(Level 1+).
9.9.2.2 Adverse effects
Treatment-related mortality with chemoradiotherapy
is rare, averaging about 1% to 3% of all patients
and does not appear to differ between treatment
strategies Table 116 and Table 117 (Level 1+). Acute
haematological toxicity is more common with
chemoradiotherapy but is generally well tolerated.
The toxicity rates vary depending on the
chemotherapy agents and doses, but there is no
clear difference based on treatment strategy in
making comparisons across studies. Addition of
chemotherapy to radiotherapy has not resulted in
significantly increased toxicity compared with
radiotherapy alone, with the exception of
haematological toxicity, nausea and vomiting, which
is variable depending on the agents used. Only one
study427 reported that there was more oesophagitis
in the chemoradiotherapy arm. It is not known
whether adding another treatment modality reduces
the dose-intensity of the primary modality.
9.9.3.3 Adverse Effects
There were more adverse effects in the combination
arm, especially oesophagitis. The incidence of
treatment-related deaths (less than 1% overall),
radiation pneumonitis, pulmonary fibrosis and late
oesophageal damage were not increased by
concurrent treatment. Anaemia of any grade was
more common in the concurrent arm of the 3 trials
in which this was reported. However, it should be
emphasised that the RCTs included in this review
only had limited adverse event reporting in terms of
the incidence of late effects.
9.9.2.3 Quality of life
The NCC-AC did not find any evidence on quality of life.
No quality of life data are available on sequential
chemoradiotherapy.
9.9.4
9.9.2.4 Conclusion
These data suggest that sequential chemoradiation
offers a survival advantage over radiotherapy alone
for inoperable stage I to IIIB patients with NSCLC.
However, the optimal dose and fractionation of the
radiation remains under investigation.
9.9.3
Primary Concurrent Chemoradiotherapy for
Inoperable Non Small Cell Lung Cancer
9.9.3.1 Identified evidence
When considering concurrent chemoradiotherapy, all
interventions that had a planned overlap in
treatment modalities were considered. A recent
Cochrane review was retrieved399. There were no
additional studies identified.
9.9.3.2 Effectiveness
A systematic review and meta-analysis of 14 RCTs,
(2393 patients)399 comparing concurrent
chemoradiotherapy and radiotherapy alone reported
a reduced risk of death at two-years (relative risk
Comparison of sequential versus concurrent
chemoradiotherapy
A Cochrane review399 compared concurrent and
sequential chemoradiotherapy.
9.9.4.1 Effectiveness
A meta-analysis of three trials of concurrent versus
sequential treatment was performed as part of the
systematic review399. All three trials used cisplatinbased regimens and once daily radiotherapy to doses
of 60-66Gy (Table 119). This indicated a significant
improvement in two-year survival with concurrent as
compared to sequential treatment (relative risk 0.86;
95% C.I. 0.78-0.95, p=0.003). Caution must be
exercised in the interpretation of these data as these
trials are as yet published only in abstract form.
9.9.4.2 Adverse effects
There were more deaths in the concurrent arms (approx
3% overall) but the difference did not reach statistical
significance. Acute oesophagitis was more frequent in
the concurrent arm. Again, there was limited adverse
event reporting for example, for some aspects of
toxicity, conclusions were based on only one or two of
the three trials (Table 119) (Level 1+).
101
inoperable” frequently mean that they would also be
considered insufficiently fit to receive chemotherapy.
No evidence covering quality of life was found.
9.9.4.4 Future Considerations
Future research is needed to explore the potential of
drugs other than cisplatin in concurrent regimens
and to explore the optimal frequency of
administration of cisplatin and other drugs. Quality
of life data is essential for the complete evaluation
of concurrent regimens. Trials investigating
concurrent chemoradiotherapy with alternative
fractionation schedules eg 55Gy in 20 fractions or
CHART should be supported. Essential features of
these trials would include detailed recording of the
impact of quality of life and toxicity, particularly
anaemia which may have a confounding effect.
9.9.4.3 Conclusion
There is good evidence from a meta-analysis399 that
primary concurrent cisplatin-based
chemoradiotherapy for inoperable stage III NSCLC
increases survival compared to radiotherapy alone.
However, this may be accompanied by an increased
risk of adverse effects, particularly oesophagitis.
(Level 1+). Treatment-related mortality is not
increased but the effects on quality of life are
unknown. It is unclear how this result relates to
accelerated treatments such as CHART which is
completed in 2 weeks. There is no clear evidence to
recommend a particular chemotherapy regimen or
frequency of administration.
From comparisons of sequential versus concurrent
regimens for chemoradiotherapy, there is evidence of
improved survival at two years with concurrent
treatment, but this maybe at the expense of added
toxicity. However the short follow-up in these studies
means that the magnitude of benefit should still be
regarded as uncertain. The limited conclusions
regarding toxicity and the possible increase in
treatment-related mortality mean that concurrent
chemoradiotherapy cannot be recommended for
routine use at the present time. As the three trials
used conventionally fractionated radiotherapy to 6066Gy, it is unclear how this related to alternative
fractionation schedules, such as the 55Gy in 20
fraction regimen in widespread use in the UK or to
CHART. (Level 1+).
Future developments in radiotherapy planning and
treatment delivery may offset the added toxicity of
concurrent chemoradiotherapy and still permit
exploration of higher total radiotherapy doses.
9.10
Tumours arising in the apex of the chest with chest
wall or brachial plexus invasion are known as Pancoast
tumours. Over 90% of patients with Pancoast
syndrome have non-small cell lung cancer397. The
treatment of these tumours has been influenced by a
report published in 1961 in which neo-adjuvant
radiation was used in combination with surgery397.
9.10.1
Patient Eligibility
One systematic review was retrieved which reported
prognostic factors for combination radiotherapy and
surgery for pancoast tumours specifically397 (Table
115). The results reported that vertebral body
invasion, subclavian artery invasion, rib involvement
and N2, N3 node involvement and Horner’s
syndrome are poor prognostic factors (Level 3).
For the present, the standard of care for patients with
stage III NSCLC and good performance status (PS 0-1)
is sequential chemoradiotherapy. Patients declining or
considered fit enough for radiotherapy but not
chemotherapy, may be offered radical radiotherapy
alone, preferably CHART (see section 7).
9.10.2
There is insufficient evidence to recommend
chemoradiotherapy for patients with stage I/II NSCLC,
as very few (£5%) early stage patients were included
in studies in the meta-analysis. The reasons for
patients in this group being considered “medically
Pancoast Tumours
Effectiveness
One systematic review397 was retrieved by the NCCAC search that reported only survival-related
outcomes from studies of combination treatment for
Pancoast tumours (Table 121). Our search identified
no additional evidence to update this review.
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LUNG C ANCER
Radiotherapy and surgery results in a five-year survival
of 27% (15%-40%). Five-year survival for completely
resected patients is 34% (25-44%) (Level 3).
9.10.3
9.11
COMBINATION TREATMENT FOR NON SMALL CELL LUNG C ANCER
3. Accelerated radiotherapy + chemotherapy (IV
Carboplatin 70mg/m2/day on 1 to 5 days)
Conclusion
4. Hyperfractionated (nonaccelerated) radiotherapy
(the use of two or more fractions daily of smaller
than conventional fraction size)
In conclusion, there is great variation in the survival
figures for combination treatment for Pancoast
tumours. There is an absence of randomised
controlled trials of treatment policies in this
condition. It is recommended that treatment be
guided by stage and performance status as in other
cases of NSCLC.
5. Hyperfractionated radiotherapy + chemotherapy
(cisplatin 20mg, fluorouracil 300mg, VP-16
50mg dys 1-5 and repeated at 4th week of
radiotherapy. After radiotherapy, cisplatin 25mg,
etoposide 120mg, ifosfamide 2g, uromitexan
3x400mg dy 1-3, all at 6x at 4wk intervals).
Economics of Combination Treatment for
Non Small Cell Lung Cancer
The combined modality interventions in treatment of
NSCLC are often associated with improved outcomes
for some patients but increased overall cost, which
necessitates the assessment of incremental costeffectiveness429.
The four economic analyses on combination
treatment for NSCLC (including one abstract) were
summarised in Table 122 and Table 123. The
included studies compared standard radiotherapy
alone with various forms of combined treatment.
Radiotherapy versus different non-conventional
radiotherapy with/ without chemotherapy
The only UK study had evaluated the costeffectiveness of different non-conventional
radiotherapy regimens with or without
chemotherapy, in comparison to standard
radiotherapy315. The regimens under consideration
were as follows:
1. Standard radiotherapy (60Gy in 30 fractions,
5 per week for 6 weeks).
2. Accelerated radiotherapy (the use of two or more
fractions of standard fraction size daily to the
same conventional total dose as standard
radiotherapy. 60Gy in 30 fractions, 10 per week
for 3 weeks).
The literature search identified one abstract that
presented the cost effectiveness of concurrent versus
sequential chemotherapy and radiotherapy for locally
advanced NSCLC patients 430
The analysis was based on an RCT designed to
compare:
>
>
6. Split-course (splitting the total dose into at least
two separate courses with an interruption of 10
to 14 days) + hyperfractionated radiotherapy
+chemotherapy (cisplatin 30mg/m2 , days 1-3
and 28-30 and etoposide 100mg/m2 , days 1-3
and 28-30, or alternatively, cisplatin 60mg,
adramycin 40 mg, for ac only + mitomycin 10mg
or Epipodophyllotoxin etopside 100mg).
7. CHART (Continuous Hyperfractionated
Accelerated Radiotherapy) (the use of many
small fractions given over a reduced time. Total
radiation is 54 Gy, 1.5Gy fractionshyperfractionated and 3 fractions given per day
for 12 days-accelerated)
The number of LYs gained from each intervention
was obtained from seven different trials varying from
36 to 563 patients at various stages of NSCLC.
Among the seven different modalities, two
procedures, split-course hyperfractionated
radiotherapy with chemotherapy and CHART had a
statistically significant survival advantage relative to
standard radiotherapy. There was a gain of 1.05 lifeyears with the split-course hyperfractionated
radiotherapy with chemotherapy and 0.27 LY gained
with CHART relative to standard radiotherapy alone.
The cost per LY gained was £2,311 for split-course
hyperfractionated radiotherapy with chemotherapy
and £11,227 for CHART, and these two modalities
were determined to be cost-effective relative to their
comparators (for our own estimate of the costeffectiveness of CHART see Chapter 7 on radical
radiotherapy alone for the treatment of NSCLC).
arm A: the induction treatment by platinum
(120mg/m2 day 1, 29 and 57) and vinorelbine
(30mg/m2/week, day 1 to day 78) followed by
a thoracic radiation (66Gy); with
arm B: thoracic radiation (66gy) with two
concurrent chemotherapy cycles (platin
20mg/m2 – etoposide 50mg/m2, day 1 to 5)
followed by two cycles (platinum-vinorelbine).
Direct hospital costs of chemotherapy, radiotherapy,
side effects, follow-up, relapse treatments and
terminal care until death were calculated. Concurrent
chemoradiotherapy resulted in improved life
expectancy with a lower cost.
Standard radiotherapy versus induction
chemotherapy and radiotherapy
Dillman et al424 aimed to find out whether
chemotherapy before high-dose radiation therapy
would have a beneficial effect compared with
radiation alone for stage III NSCLC patients in the
USA and Canada. The study was non-blinded
randomised controlled trial. The duration of followup of the treatment cohort was three years.
Patients in the intervention group received cisplatin
(100mg/m2 ,days 1 and 29) and vinblastine (5mg/
m2 , days 1, 8, 15, 22 and 29) and then began
radiotherapy on day 50 (60 Gy over a 6-week
period). Patients in the control group received the
same radiation therapy immediately. Direct costs of
chemotherapy and radiotherapy were obtained from
a private metropolitan hospital.
The results showed that induction chemotherapy
with cisplatin and vinblastine before radiation
significantly improved life expectancy (0.49 LY
gained) and was found to be cost-effective
($7,143/LY gained).
103
Evans et al431 evaluated the cost-effectiveness of the
standard treatment of radiotherapy alone versus preand postoperative chemotherapy with and without
postoperative radiotherapy, and chemotherapy and
radiotherapy. LY gained for each type of combined
treatments were obtained from retrospective data for
stage IIIA patients and from randomised trials for
stage IIIB patients.
In order to estimate costs, it was assumed that all
patients received two cycles of preoperative
mitomycin-vindecine-cisplatin (MVP) (mitomycin
8mg/ m2 on day 1; vindesine 3mg/ m2 on days 1,
8, and 22; and cisplatin 120mg/ m2 on day 1-MVP).
Patients who responded to the chemotherapy
underwent thoracotomy for surgical resection
followed by two further cycles of postoperative MVP
for the first modality.
For the second regimen, it was assumed that all
patients received three preoperative MVP and that
70% of those patients went on to surgery (complete
resection). All patients who underwent surgery
received two cycles postoperative MVP and
postoperative mediastinal irradiation.
The third intervention for stage IIIB NSCLC patients
involved two cycles of vinblastine-cisplatin and then
radiotherapy (cisplatin 100mg/ m2, on 1 and 29
and vinblastine 5mg/ m2 on days 1, 8, 15, 22, and
29). Then, radiation was given on day 50, 60 Gy
over a 6 week period.
All forms of combination therapies in this study
improved life expectancy (1.26 LY gained for stage
IIIA patients and 1.14 LY gained for stage IIIB
patients) relative to radiotherapy alone. The cost per
LY gained was Can$9,348 (£4,172) for pre- and
postoperative chemotherapy, Can$14,958 (£6,674)
for chemotherapy+ surgery +postoperative
radiotherapy and Can$3,348 (£1,494) for
chemotherapy + radiotherapy.
The sensitivity analysis reducing survival gains from
each intervention by 25% and 50%. Although the
cost-effectiveness ratio for all interventions
increased, they stayed below the Can$20,000 cost
effectiveness threshold adopted by this study, except
for the second intervention with 50% reduced
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LUNG C ANCER
survival gain. The second sensitivity analysis was
conducted by increasing per diem rates by 10%,
20% and 30%. The impact of different costs of
hospitalisation on the cost-effectiveness ratios for all
interventions was quite modest. Hence, the costeffectiveness estimates were robust.
9.11.1
ENDOBRONCHIAL TREATMENT AS RADIC AL TREATMENT FOR NON SMALL CELL LUNG C ANCER
9.12
Recommendations
9.12.1
Clinical Practice Recommendations
Patients with stage I, II or IIIA NSCLC who are
suitable for resection should not be offered
preoperative chemotherapy unless it is part of a
clinical trial. [B]
Conclusions and Discussions
10.1
Postoperative radiotherapy is not recommended for
patients with NSCLC after complete resection. [A]
Adjuvant chemotherapy should be offered to NSCLC
patients who have had a complete resection, with
discussion of the risks and benefits. [A]
Patients who are pathologically staged as II and III
NSCLC following resection should not receive
postoperative chemoradiotherapy unless it is within
a clinical trial. [B]
The diagnosis and treatment of in situ carcinomas is
outside the scope of this guideline, thus papers have
been excluded if they only include patients with in
situ carcinoma. However, many of the studies do
include a proportion of patients with in situ
carcinoma. This may have affected the survival
figures measured as these patients are likely to have
longer survival untreated than other patients.
Patients with stage III NSCLC who are not suitable
for surgery but are eligible for radical radiotherapy
should be offered sequential chemoradiotherapy. [A]
9.12.2
Introduction
In this chapter we examine the use of endobronchial
techniques in the treatment of early stage non- small
cell lung cancer (NSCLC). This section describes the
use of these techniques as treatment with curative
intent in patients who are unsuitable for treatment
with other modalities. Most commonly this is due to
comorbidity, particularly poor respiratory reserve.
Endobronchial methods are also used commonly in
palliative treatment and these will be discussed in
the chapter 12 on palliative interventions and
Supportive and Palliative Care.
Postoperative radiotherapy should be considered after
incomplete resection of the primary tumour for patients
with NSCLC, with the aim of improving local control. [D]
Conversely, if the quality of life worsens with
combination therapies due to toxicity, then the cost per
QALY gained would be greater than those estimates
presented and could exceed £30,000, in which case
they are unlikely to be considered cost-effective.
The reviewed studies were comparing only standard
radiotherapy with other forms of combination
therapies. Further studies are needed to compare
different forms of combination therapies e.g. CHART
+ chemotherapy versus CHART.
10 Endobronchial Treatment as Radical
Treatment for Non Small Cell Lung Cancer
Preoperative radiotherapy is not recommended for
patients with NSCLC who are able to have surgery. [A]
The cost-effectiveness studies showed, for specific
forms of combination therapy, improvements in life
expectancy, and a cost per LY gained that seems fairly
low. However, we do not know the overall impact on
quality of life associated with these therapies. If we
were to assume that there was no overall difference in
quality of life and that the average quality of life score
is say 0.6 (see NSCLC chemotherapy chapter 8), then
the cost per QALY gained would be below £30,000.
Alternatively, if the quality of life actually improved
with combination therapy, then these therapies are
even more cost-effective.
A clearer conclusion can be drawn from the
Vergnenegre study430 since concurrent therapy was
both less costly and more effective. However, since
this study was reported from an abstract it is difficult
to fully assess the validity and limitations of the
results. Furthermore, as this was conducted overseas
(in France), the resource implications observed may
not be applicable to the UK NHS.
105
Research Recommendations
Research is needed to compare concurrent
chemoradiotherapy with alternative fractionation
schedules (such as 55 Gy in 20 fractions or CHART) with
sequential chemoradiotherapy for patients with NSCLC.
Outcomes measured should include detailed recording
of the impact on quality of life and on toxicity.
Further large-scale prospective trials should be
conducted into the effect on survival and quality of
life of postoperative radiotherapy compared to
surgery alone in the treatment of completely
resected stage III NSCLC patients.
Prospective randomised controlled trials should be
conducted into the effect on survival and quality of
life of treatment with preoperative radiotherapy and
chemotherapy in the treatment of patients with
Pancoast tumours compared to surgery alone.
10.2
Techniques included in this review
This chapter considers photodynamic therapy (PDT),
brachytherapy, electrocautery, cryotherapy and
Neodymium-Yttrium Aluminum Garnet (Nd-YAG)
laser ablation. This review has looked at endobronchial
therapies used for curative intent only.
10.3
Methodology
A systematic review by Cancer Care Ontario Practice
Guidelines Initiative432 was found which examined
the use of photodynamic therapy in the treatment of
early stage NSCLC.
The full search strategy can be found in appendix six.
10.4
Photodynamic Therapy
10.4.1
Technique
Photodynamic therapy (PDT) is based on the
interaction of tumour- selective photo sensitizer
(mainly porfimer sodium and haematoporphyrin
derivative) and laser light of a particular wavelength
(around 630nm for porfimer sodium).
There are many applications of the technique in
cancer (particularly skin) and other areas. The
majority of data in lung cancer is from patients
deemed non-surgical candidates or as a palliative
intervention. There has, however, been some work
looking at treatment of early stage bronchoscopically
accessible tumours with curative intent.
10.4.2 Quality and amount of evidence
A total of 49 papers were identified. This included
33 reviews, one RCT, 10 prospective cohort studies,
two case series and three other papers. The majority
of the papers pertained to use of PDT in late stage
NSCLC for palliation. In total 41 papers were
discarded for this reason, for non-systematic
methods, or because the evidence had been included
in a more recent paper or systematic review. Two
systematic reviews were identified the most recent
being that by the Cancer Care Ontario Practice
Guidelines Initiative432 on photodynamic therapy.
Papers included in these reviews were mainly noncontrolled observational studies. No randomised
controlled trials were found.
10.4.3 Patient eligibility
Papers reporting on PDT for curative treatment
included patients with early stage 0 and stage 1
disease. Patients generally were unsuitable for or
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LUNG C ANCER
ENDOBRONCHIAL TREATMENT AS RADIC AL TREATMENT FOR NON SMALL CELL LUNG C ANCER
refused surgery. Papers looking at palliative
treatment and assessment of technique were not
included in this section. Two studies included a
proportion of patients with in situ carcinoma.
papers were discarded for either covering palliative
interventions rather than curative treatment, for nonsystematic methods or because the evidence had
been included in a more recent paper. Two noncontrolled observational studies were included433,434.
No randomised controlled trials were found.
10.4.4 Evidence of effectiveness
The systematic review by the Cancer Care Ontario
Practice Guidelines Initiative432 included evidence
from 10 non-controlled observational studies and
one summary paper. The results are presented in
Table 124. A total of 444 patients were included in
the trials. Overall, these methodologically weak
studies found a 5 year survival ranging from 4472% and a complete response rate ranging from 3185%. Eight out of 10 studies reported toxicity and
the most common adverse effect was
photosensitivity, most commonly sunburn. The most
serious adverse effects reported were respiratory
failure and haemoptysis. (Level 3)
Papers reporting on brachytherapy for curative
treatment included patients with early stage 0 and
stage 1 disease that were unsuitable for treatment
with other modalities. Papers looking at palliative
treatment and assessment of technique were not
included in this section.
Brachytherapy
10.5.1
Technique
Brachytherapy is the use of a radioactive source
within or near an endobronchial malignancy to
deliver local irradiation. Iridium-192 is the most
commonly used source. It is placed bronchoscopically
through a catheter.
10.5.2 Quality and amount of evidence
A total of 51 papers were identified. This included
19 reviews, one RCT, 20 prospective cohort studies,
five case series and six other papers. In total 49
10.6.3 Patient eligibility
Papers reporting on electrocautery for curative
treatment included patients with early stage 0 and
stage 1 disease. Papers looking at palliative
treatment and assessment of technique were not
included in this section.
10.5.4 Evidence of effectiveness
The evidence is summarised in Table 125. Two noncontrolled studies were found with low patient
numbers433,434. Local control was found to be 75% at
one year434 and 85% at 2 years433. Two year survival
was found to range from 58%434 to 78%433 (Level
3).There was no evidence that compared the use of
brachytherapy to no treatment or to other treatment
options for this patient group.
10.4.5 Conclusions
10.5
A total of 20 papers were identified. This included
11 reviews, one RCT, four prospective cohort studies,
one case series and three other papers. In total 18
papers were discarded for non-systematic methods or
because the evidence had been included in a more
recent paper. One non-controlled study was included
in the review435.
10.5.3 Patient eligibility
No data was found that compared PDT with other
techniques, or no treatment.
PDT appears to be effective in managing small
superficial squamous cell carcinoma. (Level 3) However,
there is no evidence from randomised controlled trials
and no comparisons with active supportive care or
other treatment options. There is therefore insufficient
evidence to recommend photodynamic therapy as a
course of treatment in preference to other treatment
options at the present time.
10.6.2 Quality and amount of evidence
10.6.4 Evidence of effectiveness
There is very little evidence of its effectiveness as a
curative therapy for lung cancer. Only one small
study, by Van Boxem et al, with 13 patients435 was
found. The study found a complete response in 80%
of lesions. (Level 3). Please see Table 126 for details.
10.6.5 Conclusions
There is very little evidence for the use of
electrocautery in the treatment of early stage NSCLC
for curative intent and the technique cannot at
present be recommended in favour of alternative
treatment modalities.
10.5.5 Conclusions
The two small non-controlled trials appear to show that
treatment with brachytherapy can produce good
response and survival results (Level 3), however this
evidence is weakened by the low patient numbers
involved. There was also no evidence that compared
this treatment to other treatment options and therefore
brachytherapy cannot be recommended as a first
choice of treatment in early stage NSCLC patients.
10.6
10.7
Cryotherapy involves destroying tissue by freezing. No
studies on cryotherapy for curative treatment of
invasive NSCLC were found from the literature search.
Electrocautery
10.8
10.6.1
Cryotherapy
Technique
This technique uses high frequency electrical current,
which produces heat from tissue resistance and then
destroys tumour cells.
Nd YAG Laser ablation
We searched for studies on the use of a Nd YAG
laser to cause direct thermal ablation
bronchoscopically for attempted curative treatment.
No evidence was found that examined the long term
outcomes of patients treated this way. This technique
has been more extensively used as a palliative
intervention (see Chapter 12).
10.9
107
Economics of Endobronchial Therapy for
Non Small Cell Lung Cancer
No studies met the criteria for inclusion. Studies were
rejected which only included patients with in situ
carcinoma. Other studies were rejected on the basis
of relevance and quality.
10.10 Recommendations
10.10.1 Research Recommendations
Further randomised trials should be conducted on the
effect on survival and quality of life of endobronchial
techniques (photodynamic therapy, brachytherapy,
cryotherapy, electrocautery, Nd-YAG laser ablation)
used as curative treatment in patients with early-stage
NSCLC not suitable for conventional treatment.
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109
11 Treatment of Small Cell Lung Cancer
11.1
Introduction
Approximately 20% of all lung cancers are
diagnosed as small cell lung cancer (SCLC). Around
40% of cases are classed as limited stage while the
remainder are extensive stage436 (see Staging
chapter 5). Over the years, there have been different
definitions of limited stage. Most now follow the
IASLC definition of limited stage as disease confined
to one hemi thorax (including pleural effusion) plus
bilateral hilar or supraclavicular lymphadenopathy.
Extensive disease is anything outside of these areas.
While this may suggest that the two stages are
distinct in terms of the type of treatment offered,
there are subsets of patients with extensive disease
who may benefit from the same treatment as limited
disease. As survival is usually not affected by small
differences in the degree of loco regional tumour
involvement, selecting the most appropriate
treatment is a matter of good or poor prognosis,
instead of limited disease (LD) and extensive disease
(ED) groups436.
Evidence on the natural history of SCLC is only
available from a small number of historical studies
conducted prior to the availability of computed
tomography. The results therefore, should be treated
with caution as a number of patients considered to
have limited stage disease may have been understaged436. A recently published Cochrane review on
chemotherapy versus best supportive care in SCLC
patients with extensive disease437 reports results
from two trials by Kokron (1977 and 1982) in which
patients received chemotherapy with symptomatic
treatment (antibiotics and analgesics in the first
study and infusion of Ringers solution 3 times/
week in the second study) (Table 128). The trials
report that with symptomatic treatment only, survival
of SCLC patients ranges between 56 and 93 days.
11.2
Treatment techniques included
in this review
This review is confined to chemotherapy, chemoradiotherapy (both thoracic radiotherapy and
prophylactic cranial irradiation- PCI) and the addition
of surgery to these treatments.
11.3
Methodology
SIGN reviewed the evidence included in this chapter.
The methods are described in section 2.1.2. The
search strategy can be found in appendix six.
11.4
Patient Eligibility
One systematic review was identified that examined
factors affecting the prognosis of SCLC patients438
(Table 127). Although such evidence can provide
some tentative conclusions on the eligibility of
patients for treatment, it does not clearly define how
to select patients for treatment. Among the most
significant factors consistently associated with
poorer survival are poor performance status (WHO >
or = 2, - see Appendix 2, Figure 4 for comparison of
Karnofsky and WHO/ Zubrod performance status
scales) and elevated lactate dehydrogenase levels
(LDH) (Level 3). Other prognostic factors of
moderate importance are the presence of extensive
disease and being of the male sex. Multiple
metastatic sites were also reported to be of
moderate prognostic significance although too few
studies included number of metastatic sites to be
confident about this438. The significance of raised
alkaline phosphate levels, low serum sodium and
older age of patients is less well defined (Level 3).
In the UK, treatment decisions are not made on the
basis of a single prognostic factor, such as disease
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better results. One systematic review436 including
data from three randomised trials reports the
evidence on single agent versus multiple agent
regimens (Table 129). No additional RCTs were
retrieved that update this review.
extent but on the number of adverse features. For
example SCLC patients with 3-5 adverse features
have a substantially worse prognosis than those with
0-2439. Prolonged survival is restricted to patients
with 0-1 adverse features and these patients are
offered more intensive treatments, whereas patients
with multiple adverse features have minimal chance
of prolonged survival and are offered less toxic
treatments with palliative intent. It is important to
explain to patients the rationale for recommending
different treatments.
Lowenbraun et al440 randomised 68 patients (a
majority of whom had extensive disease) to single or
combination therapy and reported a statistically
significant difference in response rate (12% vs. 59%
p< 0.005) and median survival time (18 weeks vs.
31 weeks, p= 0.01)440 (Level 1+). Girling 441 found
similar results from a randomised trial in SCLC
patients with poor PS. Statistically significant
results again favoured the combination
chemotherapy treatment arm in terms of overall
response (45 vs. 51%), median survival time (4
months vs. 6months) and 6-month survival (35% vs.
49%) (Level 1+). Souhami et al442 also
demonstrated that oral etoposide was inferior to
intravenous combination chemotherapy in patients
with poor performance status and extensive disease.
Survival was significantly in favour of those receiving
IV therapy (5.9 vs. 4.8 months; 1 year survival 19%
vs. 10%, p=0.05) and all aspects of symptom control
and quality of life (except acute nausea and
vomiting) were the same or worse in the single drug
(etoposide) arm of the trial.
In conclusion, while patients with adverse prognostic
features do not achieve the same degree of survival
benefit as patients with a good performance status
and/or normal LDH levels (Level 3), chemotherapy is
likely to extend their life expectancy markedly (see
11.5), and these patients can gain excellent symptom
palliation with treatment. However, the toxicity of
treatment does appear to be higher in poor
performance status patients, making patient selection
for treatment a matter of clinical judgement.
11.5
Chemotherapy
As SCLC metastasises early, a systemic approach is
appropriate for the majority of patients.
Chemotherapy remains the mainstay of treating
patients with SCLC and its effectiveness is well
documented436.
A recently published Cochrane review437 on the
effectiveness of chemotherapy for patients with
extensive SCLC reported that the treatment prolongs
survival in comparison with placebo in patients with
advanced SCLC (Level 1++) (Table 128). For patients
with poor prognosis, the risks and benefits are more
finely balanced but the majority of patients will
achieve subjective and objective responses, with an
overall survival benefit (Level 1++). It can be inferred
from the evidence discussed in 11.4 and in the
following sections that for patients with limited
SCLC, chemotherapy can also prolong survival and
produce a response.
11.5.1 Single agent versus multiple agents
Although there are few randomised trials comparing
combination and single agent chemotherapy, there is
little doubt that combination therapy produces
disease reported that the response rate for patients
in the non-platinum based arm was 62%, while for
those patients receiving cisplatin, it was increased to
69% (p<0.0001), with an odds ratio of 1.35 (95%CI
1.18-1.55), p<10-5 ) (Level 1+). In terms of survival,
the risk of death at 6 and 12 months for patients
were lower in the platinum based arm; OR 0.87
(0.75-0.98, p=0.03) and OR 0.80 (0.69-0.93,
p=0.002), respectively. While this meta-analysis
however, included limited and extensive disease
patients, it did not include studies of carboplatin, so
these results cannot be extrapolated to treatment
with carboplatin-based regimens. A single RCT 444
was published after the review was retrieved.
Sundström et al444 (2002) randomised 440 patients
(approximately half of whom were patients with
limited disease) to etoposide and cisplatin or
epirubicin, cyclophosphamide and vincristine and
concluded that overall the platinum regimen was
statistically superior (p<0.0005) both in terms of 2year survival (14% vs. 6%) and 5-year survival (5%
vs. 2%) (Level 1++).
In conclusion, platinum based treatment is more
effective for 1st line treatment of SCLC than nonplatinum containing treatment regimens (Level 1+).
It should also be noted that platinum combinations
are associated with less mucosal toxicity, less
myelosuppression and are easier to combine with
radiotherapy than anthracycline-based regimens.
We can conclude that results from the use of multiagent chemotherapy yield better responses than use
of single agent treatment (Level 1+).
11.5.3
11.5.2
A systematic review438 compared the efficacy of
carboplatin versus cisplatin (Table 131). Clinical
practice currently resides with using cisplatin where
survival is the primary aim and carboplatin where
palliation is the primary aim. While the trials
purport to show equivalence, they are either
underpowered or the statistical significance of the
difference is unclear (Level 1+).
Platinum versus non-platinum
containing regimens
While the evidence for combination chemotherapy is
clear, the most effective multiple agent
chemotherapy regimen is still a matter of debate.
Anthracycline-based regimens (e.g. doxorubicin,
epirubicin) have often been preferred to platinumbased regimens because they are easier and cheaper
to give in the outpatient setting.
11.5.4
Early studies suggested that such regimens were
equipotent, but SIGN retrieved a meta-analysis443and
a RCT444 to update this evidence (Table 130). The
meta-analysis443 of cisplatin vs. non-cisplatin
containing regimens retrieved 19 trials on 4054 lung
cancer patients with both extensive and limited
Cisplatin versus Carboplatin
Duration of treatment
There is evidence from a review reporting the results
from several RCTs on the optimum number of cycles
of chemotherapy for patients with limited disease
SCLC, comparing 3 vs. 6, 4 vs. 8 and 5 or 6 vs.
12445,446. This evidence suggests that there is a
small survival advantage for longer treatment but it
111
is usually outweighed by the toxicity and burden of
prolonged treatment (Level 1+). The compromise to
quality of life that additional cycles of treatment
can cause means that careful patient selection must
take place before advocating more than four to six
cycles of treatment. One RCT447 which updates this
review, reported that despite some encouraging
results for maintenance therapy in extensive disease
patients previously treated with etoposide,
ifosfamide plus cisplatin, the significance of these
results was not clear.
11.5.5
Dose Intensity
Dose intensity refers to the amount of drug delivered
in a given period of time, which is usually
standardised to body surface area (mg/m2/day). It
has been demonstrated that increasing the dose
intensity results in improved outcomes in studies of
some other ‘chemo sensitive’ cancers. There is a
range of methods to achieve an increase in dose
intensity. This review was restricted to increasing the
dose or decreasing the interval of standard
chemotherapy and excludes studies of high dose
therapy with haemopoietic stem cell transplantation.
11.5.5.1 Standard Dose Intensity
A systematic review436,438 was retrieved by SIGN
reporting results of conventional methods of dose
intensification for patients with limited and
extensive disease (Table 133). One meta-analysis448
within this review reported a retrospective analysis of
the results of the intended dose of 60 studies, using
a variety of different chemotherapeutic regimens and
so, is of very limited value. No statistically
significant results were found in relation to objective
response, complete response or median survival time
(Level 1+). Several more recent studies have
prospectively evaluated the effects of increasing
cytotoxic dose intensity in RCTs. An RCT449 also
within the review, evaluated and reported the effect
of the delivered dose intensity in limited disease
patients (300mg/m2 cyclo days 1-4 and 100mg/m2
cis) vs. 225 mg/m2 cyclo days 1-4 and 80 mg/m2
cisplatin, in conjunction with same doses of
doxorubicin, etoposide and radiation in both arms)
with more favourable results although, this study
examined the effect of higher doses for the first
treatment cycle only. At 6 months, the complete
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response rate and the median duration of this
response significantly favoured the dose-escalated
arm. Overall survival was improved at 30 months
and 2- year disease free survival was also superior,
although there was increased toxicity within this arm
(Level 1+). These results for increasing dose intensity
are reflected in a later trial on patients with good
prognostic factors450. None of the additional four
phase three trials451-454 on patients with extensive
disease within the review438 showed a survival
advantage in the dose intensive arm and this arm
often resulted in greater toxicity. An additional
RCT455, retrieved by the SIGN literature search,
reported results of both limited and extensive stage
patients. There was no significant difference in
terms of survival, response and toxicity between the
high-dose platinum arm compared to the carboplatin
alone arm (Level 1+).
cycles of ACE either every 3 weeks (control [C]
group) or every 2 weeks with G-CSF (G group),
standard dose of-intensity of ACE was increased by
50% in group G. The results concluded that
increasing the dose-intensity of ACE with G-CSF
support improved survival while maintaining
acceptable toxicity. In the final trial retrieved459.
patients were randomised to either standard CDE
(cyclophosphamide 1,000 mg/m2 and doxorubicin
45mg/m2 on day 1 and etoposide 100mg/m2 on
days 1 to 3 every 3 weeks for 5 cycles) or intensified
CDE (cyclophosphamide 1,250mg/m2 and
doxorubicin 55mg/m2 on day 1, and etoposide
125mg/m2 on days1 to 3 with G-CSF 5µg/Kg/d on
days 4 to 13 every 2 weeks for 4 cycles). The
authors reported that the dose intensity arm did not
produce improved outcomes in SCLC patients.
Although some differences in effectiveness were
seen in the regimens used and the duration of
treatment, there is insufficient evidence to
recommend alternating chemotherapy (Level 1+).
11.5.7
11.5.6
Relapse of disease can be treated by chemotherapy
but second line treatment response rates are poorer
and the balance of benefit and toxicity should be
discussed with the individual patient. Those who
responded well to first line treatment and who had a
disease free interval respond best.
11.6
Multi-drug regimens may be administered in two
ways; either concurrently or alternately to maximise
their potential for tumour eradication. The
alternation of drugs acting through different (“noncross resistant”) mechanisms was postulated to
reduce the opportunity for drug resistance to
develop, and expected to improve outcomes 464. This
section will review the evidence for this in SCLC.
In conclusion, the response rates and response
duration that can be expected of second line
treatment are generally poorer than those seen with
1st line treatment (Level 1+). As always, the burden
of treatment on the patient should be considered
when the magnitude of benefit is uncertain. Second
line chemotherapy should be offered to patients who
have achieved a response to first line treatment and
discussed on an individual basis.
11.5.8
Conclusion
Chemotherapy is the initial treatment of choice for
small cell lung cancer and can increase survival even
in poor performance status patients. IV multi-drug
regimens and regimens containing platinum are
superior. Initial chemotherapy should comprise 4-6
Radiotherapy
Small cell lung cancer is a radiosensitive tumour and
thus radiotherapy plays an important role in its
treatment. Radiotherapy given as part of the initial
treatment program has the potential to increase
disease control in irradiated sites and as relapse may
sometimes be limited to the chest or brain, there is
also the potential for radiotherapy to improve
survival. Here we consider consolidation thoracic
irradiation and prophylactic cranial irradiation. Lower
dose palliative radiotherapy given for the relief of
symptoms is covered in chapter 12.
Second Line Chemotherapy
A systematic review438 was retrieved on the
effectiveness of second line chemotherapy and no
trials were retrieved to update this review.
Gillenwater et al438 reviewed a number of single and
combination regimens and reported that the overall
response rates range from 6-46% for single agents
and 18-72 for combination regimens436 (Table 136)
(Level 1+). It should be noted that these response
rates are at least as good as those for 1st line
chemotherapy in advanced NSCLC.
Alternating versus sequential
treatment strategies
One systematic review retrieved by the SIGN
literature review reported outcomes relating to the
appropriate timing and delivery of chemotherapy
(Table 135). The ten RCTs within the systematic
review436 analysed, together report that alternating
chemotherapy regimens do not have a major effect
on survival in limited stage patients (Level 1+). A
sub-group analysis of the trials that used either CAV
(Cyclophosphamide, Doxorubicin and Vincristine) or
EP (Etoposide and Cisplatin) within the review
produced mixed results (Table 135). While two of
cycles of treatment as maintenance therapy has not
consistently been shown to improve overall survival.
It is generally believed that second line
chemotherapy will only be of benefit to patients if a
good response is achieved by first line treatment. In
addition, the best results are obtained in patients
who have at least 3 months between the best
response achieved and progression436.
Although some of these results seem encouraging,
the evidence is neither clear nor sufficient to
confidently recommend dose intensification.
However, it is recognised that delays or dose
reductions resulting in a lower cytotoxic dose
intensity are likely to reduce the potential benefits of
chemotherapy treatment.
11.5.5.2 Dose Intensity with the Addition of
Growth Factors
A systematic review438 and four RCTs456-459 were
retrieved on the effectiveness of dose intensification
with the addition of growth factors (Table 134).
Several RCTs460-462 within the review, with the
exception of Steward et al463 failed to demonstrate
improved survival with more dose intensive support
(Level 1+). Sculier et al457 reported that there was
no evidence that patient outcomes improved when
patients were randomised to either standard
chemotherapy with 6 courses of EVI (epirubicin 60
mg/m2, vindesine 3 mg/m2, ifosfamide 5 g/m2)
given on day 1 repeated every 3 weeks versus
accelerated chemotherapy with EVI administered
every 2 weeks and GM-CSF support versus
accelerated chemotherapy with EVI and oral
antibiotics (cotrimoxazole) (Level 1++). Mavroudis et
al456 randomised patients to either TEP (paclitaxel
175 mg/m2 i.v. three-hour infusion on day 1,
cisplatin 80 mg/m2 i.v. on day 2 and etoposide 80
mg/m2 i.v. on days 2-4 with G-CSF support (5
mcg/kg s.c. days 5-15) versus standard EP (cisplatin
80 mg/m2 i.v. on day 1 and etoposide 120 mg/m2
i.v. on days 1-3) in cycles every twenty-eight days
but it was reported that TEP option was too toxic for
routine use and the study was terminated early due
to excessive toxicity and mortality in this arm.
Thatcher et al458, randomised patients to receive six
the trials, Fukuoka et al465 and Feld et al466, reported
that improved response and survival rates were seen
with the alternating regimens, only one of the trials
reported that these reached statistical significance.
Goodman et al467 and Woll et al462 on the other
hand, reported that no difference in outcomes were
seen in the alternating arm (Level 1+).
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11.6.1
Thoracic irradiation
One recent systematic review436 was retrieved on the
effectiveness of thoracic radiotherapy. This review
included seven randomised studies with over 100
limited disease patients (Table 137). While there is
some heterogeneity in the results of these trials,
they suggest a median survival benefit of
approximately 1 month and a 6% improvement in
2-year survival with the addition of radiotherapy
(chemotherapy alone: 13% vs. the addition of
radiation: 19%) (Level 1+). In addition, a
statistically significant improvement in local control
was reported in all the studies although the manner
in which each trial reported these results differed
(Level 1+). Two earlier meta-analyses468,469 that
were not limited to RCTs randomising over 100
patients have supported these findings (Table 137).
The meta-analysis of 13 RCTs by Pignon et al469
showed that the addition of radiotherapy reduced
the risk of death by 14% equivalent to a 5.4%
increase in absolute 3-year survival. A similar
improvement was shown in the meta-analysis of 11
studies by Warde and Payne 468 (Level 1+).
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In terms of intrathoracic control, in a meta-analysis
of nine RCTs, Warde and Payne468 demonstrated an
absolute improvement of 25% with the addition of
radiotherapy, an improvement that was associated
with a 1.2% absolute increase in the risk of
treatment related mortality (Level 1+).
In a randomised study of thoracic irradiation in 210
patients with extensive stage SCLC achieving a
complete response at distant sites and complete or
partial response in the chest (mostly CT-based), the
addition of thoracic irradiation increased 5-year
survival from 3.7% to 9.1%470.
The majority of RCTs from which evidence of the
effectiveness of thoracic irradiation is derived were
carried out in the 1970s and 1980s when the
standard method of response assessment was the
chest x-ray. Most patients were eligible for these
studies if they were deemed to have had a complete
response to chemotherapy. CT is now recognised as
being vastly superior to assessment by chest x-ray
alone and will identify variable amounts of disease
not apparent on chest x-ray. Indeed some patients
included in these studies of limited disease may have
had more widespread disease, which would have
been defined as extensive by CT.
The situation is further complicated by the variety of
ways in which thoracic irradiation can be delivered.
Options include giving thoracic irradiation following
completion of chemotherapy or with the final cycle
of chemotherapy (i.e. “late”) or earlier in the
treatment programme, commonly concurrently with
the first or second cycle of chemotherapy (“early”).
There is also uncertainty regarding the optimal dose
and fractionation of radiotherapy.
Patients with limited disease require discussion with
a clinical oncologist prior to commencement of
chemotherapy to assess the feasibility of subsequent
thoracic irradiation. Disease should not be so bulky
as to result in an unacceptable high risk of lung
damage. As poorer survival has been observed in
patients with SCLC who have treatment interruptions
during radiotherapy471 or who smoke during
radiotherapy472, every effort should be made avoid
these factors (see Table 139). Smoking during and
after treatment is also discussed in chapter 13.
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Patients with limited disease SCLC (and some with
extensive disease SCLC) should therefore be
considered for thoracic consolidation therapy if they
have a CT based complete or a good partial response
to chemotherapy.
11.6.1.1 Radiation dose and fractionation
oncologists recommend a dose in the range of 40Gy/
15 fractions over 3 weeks to 50Gy/ 25 fractions over
5 weeks. This dose has been used in an RCT of early
versus late radiotherapy476 see Table 138.
115
following completion of chemotherapy if there has
been at least a good partial response within the
thorax (Level 1++). While the optimal dose and
fractionation of radiotherapy remains unclear, most
clinical oncologists recommend a dose in the range
of 40Gy/ 15 fractions over 3 weeks to 50Gy/ 25
fractions over 5 weeks.
11.6.1.2 Timing and sequencing of chemotherapy
and radiotherapy
A systematic review436 retrieved only one RCT473 that
examined whether there is a dose response
relationship for the addition of radiotherapy (Table
138) and one RCT comparing hyperfractionated with
conventional radiotherapy474 (Table 139).
The optimum timing in the delivery of radiotherapy
and chemotherapy remains uncertain. A systematic
review436 included the results from five trials, in
addition to two RCTs477,478 retrieved with more recent
data (Table 141).
For patients with extensive disease, thoracic
irradiation may be considered following
chemotherapy if there has been a complete response
at distant sites and at least a good partial resonse
within the thorax (Level 1+).
Coy et al473 randomised 168 patients who had either
a complete response or partial response to
chemotherapy to either 25Gy in 10 fractions over 2
weeks or 37.5Gy in 15 fractions over 3 weeks.
Although there was no difference between the two
arms in terms of complete response rate or overall
survival, the higher dose arm did demonstrate an
improvement in median local disease-free
progression (11 months vs. 9 months, p=0.03) and in
2-year local disease-free progression survival (80%
vs. 69%, p=0.03)473 (Level 1+).
A single trial of alternating chemoradiotherapy with
sequential treatment showed no significant
difference between arms479. The remaining trials
compared early versus late radiotherapy using a
range of radiotherapy doses and fractionation. In the
“early” trials, radiotherapy was given concurrently
with the first or second cycle of chemotherapy. In the
remaining trial480 radiotherapy was delivered prior to
commencement of chemotherapy. “Late”
radiotherapy was given concurrently with the fourth
to sixth cycle of chemotherapy except in two trials
when it was given following completion of
chemotherapy477,480. Two trials indicated a benefit for
early radiotherapy476,481. Two trials updated this
review. While Skarlos et al478 reported that the
sample was small and there were no significant
difference in findings, Takada et al477 reported that
while there were no significant difference in median
survival or PFS, there was a trend in trend in favour
of the concurrent arm.
Radiotherapy should be delivered without
interruption and patients should be actively
encouraged to stop smoking prior to therapy.
Turrisi et al474 randomised 417 patients to receive
either 45Gy of twice-daily radiation (1.5Gy fractions)
over a period of 3 weeks or daily radiation over 5
weeks (in fractions of 1.8Gy) with concurrent
cisplatin and etoposide (Table 140). While a
statistically significant difference in survival was
reported in favour of the more intensive (i.e.
hyperfractionated) arm, it is not clear whether this
was due either to a higher biologically effective dose
in the hyperfractionated arm, or the
hyperfractionation or scheduling itself474. The
incidence of oesophagitis was also higher in the
hyperfractionated arm.
A third RCT475 randomised 262 patients receiving 3
cycles of etoposide plus cisplatin to either once daily
thoracic radiation (50.4Gy in 28 fractions) or twice
daily 48Gy on 32 fractions). The authors also
reported that there was no improvement with twice
daily irradtiation although it was not clear if the trial
was powered to detect a difference.
While the optimal dose and fractionation of
radiotherapy remains unclear, most clinical
Since conducting this review a recent Cochrane
review482 (unpublished at the time of writing) has
found that there was no statistically significant
difference between early and late radiotherapy and
between concurrent and sequential
chemoradiotherapy for SCLC. A conclusion cannot
therefore be made specifying the optimal timing and
sequencing of chemotherapy and radiotherapy for
SCLC patients.
11.6.1.3 Conclusion
In limited stage SCLC, thoracic irradiation may
therefore be given to patients concurrently with the
first or second cycle of chemotherapy or to patients
11.6.2
Prophylactic Cranial Irradiation
The central nervous system is a recognised sanctuary
site for micrometastases and cytotoxic drugs
penetrate the blood-brain barrier poorly. Isolated
brain metastases are a significant cause of failure in
those who have had a complete response to initial
therapy. Prophylactic cranial irradiation (PCI)
attempts to eradicate microscopic disease in patients
without symptoms of brain metastasis. The aim is to
treat the group with highest risk of the brain being
the sole site of metastasis, as they are the ones who
could benefit from PCI. PCI is therefore usually
considered for patients with limited disease who
have had a complete or good partial response to
primary treatment.
There is less evidence pertaining to the effectiveness
of PCI in patients with extensive disease.
11.6.2.1 Effectiveness
Studies conducted during the 1970s and 1980s on
the effectiveness of PCI provide limited data due to
the lack of statistical power of the randomised data.
In addition, these studies were based on patients
with complete response judged by chest x-ray. A
systematic review483 was retrieved and there were no
RCTs to update this evidence (Table 142). This metaanalysis of 987 patients randomised in 7 RCTs
concluded that while PCI reduces the risk of brain
metastasis by 54%, the risk of death is reduced by
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TREATMENT OF SMALL CELL LUNG C ANCER
16% (P=0.01) contributing to an increase in 3-year
survival of 5.4% (20.7% vs. 15.3%) (Level 1++).
The meta-analysis reported that there was no
evidence of differential benefit with age or radiation
dose, although there was a trend to lower rates of
brain metastases with higher radiation doses. (Level
1++). In addition, the benefit of PCI appeared
independent of disease extent, although only 14%
of patients in the analysis had extensive disease and
therefore the magnitude of benefit in patients with
extensive disease should still be regarded as
uncertain. There were no significant differences in
neurocognitive function in an RCT479 comparing PCI
with no PCI. Although doses used in trials reported
in the meta-analysis by Auperin483 were most
commonly 24-30Gy in 8-10 daily fractions, the
regimen in most frequent use currently is 25Gy in 10
daily fractions. Further trials are examining the
benefits of higher doses of PCI.
examination of the operative specimen the disease
may appear to be SCLC or planned treatment may
very occasionally be offered to patients with stage I
SCLC usually after neo-adjuvant chemotherapy.
Surgery has been used as a salvage treatment for
those patients who have either relapsed or failed to
respond to primary treatment involving
chemotherapy and radiotherapy.
11.6.2.2 Conclusions
There is insufficient evidence to recommend a
definite dose schedule.
11.7
Surgery for patients with SCLC
The majority of patients with SCLC present with
systemic disease precluding surgery with curative
intent. The role of surgery in SCLC is limited and to
very specific groups of patients. Patients may
undergo a surgical procedure and only on
The objective of Doyle et al’s488 study was to identify
whether the use of etoposide phosphate with
cisplatin due to its ease of administration resulted in
cost-savings compared to etoposide with cisplatin.
The analysis was based on clinical data obtained
from a randomised controlled trial of cisplatin plus
either etoposide phosphate or etoposide 489. The use
of etoposide phosphate saved $737 per patient.
When the time savings of ease of administration of
etoposide phosphate were added into the model, use
of etoposide phosphate reduced the cost per patient
by $2,897.
Table 143 shows three further observational
studies485-487. Although the results of the trials
reporting results on patients undergoing
postoperative chemotherapy were favourable in
terms of survival time, they were also conducted on
small groups of atypical patients with less advanced
disease (Level 2++).
In summary, there is insufficient evidence to
recommend surgery for this group of patients.
11.8
Economics of the treatment of SCLC
Four studies were selected for tabulation (Table 144
and Table 145). Since the treatment of side-effects of
chemotherapy is out of the scope of this guideline,
we excluded studies on haematopoietic growth
factors which were being used for treatment of
chemotherapy side effects (reducing infections and
neutropenic fever). Most of the remaining evidence
was limited in terms of the treatments compared and
was mainly concerned with chemotherapy.
11.8.2
Can$4,500 (£1808) with alternating chemotherapy.
The cost effectiveness of alternating chemotherapy
was favourable when compared with standard
chemotherapy. However, the clinical evidence did
not show clear overall results in favour of alternating
chemotherapy (see section 11.5.6).
Single agent / multiple agent Chemotherapy
Khan et al387 conducted a cost analysis on the use of
carboplatin versus cisplatin in treatment of patients
with NSCLC, SCLC and ovarian cancer to determine
which treatment has potential cost savings. The
results showed that chemotherapy with cisplatin was
less costly ($203) than carboplatin for limited and
extensive stage of SCLC patients. Hospitalisation
costs ($574± 1,197 with carboplatin, $475± 858
with cisplatin) and costs for chemotherapy agents
($7,280 ± 2,685 for carboplatin, 5,507 ± 3,725 for
cisplatin) were higher with carboplatin treatment
than treatment with cisplatin. Costs of growth
factors ($992 ± 2,596 with carboplatin, $1,448 ±
3,266 for cisplatin) were higher for cisplatin. The
results should be treated with caution due to high
standard errors reported associated with each cost
category and small number of patients in the study.
The applicability of the results to the UK practice is
uncertain: carboplatin is given as an outpatient basis
in the UK and growth factors are not typically used.
SIGN retrieved one RCT and three observational
trials that reported results on the addition of
chemotherapy to surgery. Lad et al484 reports results
from an RCT on the addition of surgical resection of
the primary tumour following a complete or partial
response to chemotherapy (see Table 143). As the
authors point out, the 146 patients randomised were
an unusually favourable population (82% of patients
were PS 9+ on the Karnofsky scale, 92% had lost £
10% body weight), this is reflected in the overall
survival rate of 20% (Level 1++). Comparing the two
treatment groups, pulmonary resection did not
influence the pattern of relapse and survival actually
favoured the non-surgical group by three months
(Level 1++).
PCI is generally given following completion of
chemotherapy and may be delivered at the same
time as thoracic irradiation if this is also being given
following chemotherapy. The meta-analysis by
Auperin483 also showed that PCI was more effective
if commenced sooner (less than 4 months) rather
than later after randomisation, indicating that PCI
should not be unduly delayed following completion
of chemotherapy (Level 1++).
In conclusion, limited disease SCLC patients should
be considered for PCI if they have a CT based
complete or a good partial response to primary
treatment. Benefit is unclear for patients with
extensive disease and the guideline development
group recommended that these patients should be
entered into clinical trials.
11.8.1
Alternating versus sequential
chemotherapy treatment
A cost-effectiveness analysis on sequential versus
alternating chemotherapy was conducted alongside
a two year randomised controlled trial of
cyclophosphamide, doxorubicin and vincristine alone
or alternating with etoposide and cisplatin for the
treatment of patients with extensive SCLC 490. The
use of alternating chemotherapy was associated with
increased survival (0.13 years) and improved quality
of life (0.10 QALY) with Can$450 (£190) additional
cost. The additional cost per LY gained was
Can$3,370 (£1,354) and cost per QALY gained was
117
11.8.3
Platinum versus non-platinum containing
regimens: an original cost-effectiveness
analysis
The literature search identified no economic studies
that compared platinum based drugs regimens with
non-platinum based drugs for SCLC. Therefore we
conducted a simple cost-effectiveness analysis based
on a well-conducted RCT as follows.
Sundstrom et al444 reported a Norwegian RCT with
five-year follow-up. The data were analysed
separately for limited and extensive disease. The
regimens compared were:
>
Etoposide and cisplatin (EP) (up to 5 courses):
Day 1 IV – etoposide 100mg/m2 & cisplatin
75mg/m2; Days 2&4 oral – etoposide
200mg/m2
>
Cyclophosphamide etoposide vincristine (CEV)
(up to 5 courses): Day 1 IV – epirubicin
50mg/m2, cyclophosphamide 1000 mg/m2,
vincristine 2 mg/m2
Most patients had the full five cycles and the main
reason for failure to complete was death. For patients
with limited disease the trial reported significantly
longer survival for EP. There was no significant
between-arm difference in quality of life or in use of
radiotherapy or prophylactic cranial irradiation.
Drug costs were taken from the British National
Formulary491 (assuming body surface area =1.8m2) –
see Table 146. The other assumptions are listed in
Table 147.
Platinum-based drug regimens appear to be costeffective for patients with both limited and extensive
SCLC (compared with a threshold of £30,000 per
QALY gained) – see Table 148 and Table 149. The
sensitivity analysis (Table 150) suggests that the
results for patients with limited disease are robust to
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changes in the model parameters. The results for
extensive disease would be much more sensitive due
to the lack of significance in the treatment effect.
These results may be imprecise because actual
hospital utilization was not measured. Also,
although there were no significant differences in
either radiotherapy or prophylactic cranial irradiation
there may have been other differences not recorded
by the trial, e.g. additional costs associated with
treating side-effects, additional services during
extended years of life or perhaps patient costs. The
trial was not conducted on a UK population but
there is no reason to assume that treatment effect
would be markedly different.
11.8.4
Prophylactic Cranial Irradiation (PCI)
The clinical and cost-effectiveness of PCI was
investigated using ten year retrospective data of
patients with limited SCLC who had achieved a
complete remission492. The mean overall survival
improved by 13.5 months (11.2 months qualityadjusted) when PCI was used in conjunction with
chemotherapy and radiotherapy. This strategy was
cost-effective; the cost per LY gained was Can$840
(£350) and cost per QALY was Can$1,020 (£423).
These results must be treated with caution because
the improvement in survival from this small study
(13.5 months) was much greater than the
improvement implied by the Cochrane review (4
months using the DEALE method313,314). This would
still be cost-effective compared with a cost per lifeyear threshold of say £20,000 as long as the
incremental cost of PCI is below £6,000.
11.8.5
Conclusions and discussion
The economic evidence indicated that:
>
platinum-based drug regimens can be costeffective, especially for patients with limited
disease
>
cisplatin was found to be slightly less costly than
carboplatin in one US study
>
the use of PCI in conjunction with chemotherapy
and radiotherapy appears to be cost-effective
The results should be interpreted cautiously because
they were based on trials conducted outside the UK
NHS. Hence treatment effects, resource outcomes
and especially prices may not strictly be applicable.
Furthermore, most of the studies did not report the
clinical outcomes separately for the stage of disease.
11.9
Recommendations
11.9.1
Clinical Practice Recommendations
Patients with SCLC should be offered an assessment
that includes evaluation of the major prognostic
factors: performance status, serum lactate
dehydrogenase, liver function tests, serum sodium,
and stage. [D]
All patients with SCLC should be offered:
>
platinum-based chemotherapy [A]
>
multidrug regimens, because they are more
effective and have a lower toxicity than singleagent regimens. [A]
Four to six cycles of chemotherapy should be offered
to patients whose disease responds. Maintenance
treatment is not recommended. [A]
Patients with limited-stage SCLC should be offered
thoracic irradiation concurrently with the first or
second cycle of chemotherapy or following
completion of chemotherapy if there has been at
least a good partial response within the thorax. For
patients with extensive disease, thoracic irradiation
should be considered following chemotherapy if
there has been a complete response at distant sites
and at least a good partial response within the
thorax [A]
Patients undergoing consolidation thoracic
irradiation should receive a dose in the range of 40
Gy in 15 fractions over 3 weeks to 50 Gy in 25
fractions over 5 weeks. [D(GPP)]
Patients with limited disease and complete or good
partial response after primary treatment should be
offered prophylactic cranial irradiation. [A]
Second-line chemotherapy should be offered to
patients at relapse only if their disease responded to
first-line chemotherapy. The benefits are less than
those of first-line chemotherapy. [D(GPP)]
11.9.2
Research Recommendations
Clinical trials should be conducted to determine to
benefit of prophylactic cranial irradiation compared
to no prophylactic treatment in terms of survival and
quality or life for patients with extensive disease
SCLC and a complete response at distant metastatic
sites and a complete or good partial response within
the thorax after treatment.
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12 Palliative Interventions and
Supportive and Palliative Care
12.1
Introduction
This chapter focuses on palliative interventions and
supportive and palliative care specifically for patients
with lung cancer. This is a priority because most
patients diagnosed with lung cancer have incurable
disease and while effective treatment is often
available, symptoms are often poorly evaluated and
managed493. It is essential therefore, that the impact
of lung cancer and its symptoms on the patient’s
psychological, social and physical state including
activities of daily living are identified early and that
patients are referred to the appropriate specialist for
further assessment, if required. In this chapter we
have reviewed the evidence on palliative
interventions and palliative care specific to lung
cancer patients. This chapter will also highlight
supportive care services, including communication, in
relation to patients with lung cancer which are
important throughout the patient’s journey.
12.1.1
Improving Supportive and Palliative Care for
Adults with Cancer
The National Institute of Clinical Excellence (NICE)
has recently published guidance and
recommendations to improve supportive and
palliative care for adults with cancer494. This
guidance should be used alongside this document.
The guidance provides an evidence base for how
services should be organised and delivered using
cancer networks to improve the care of patients with
cancer. The guidance encompasses co-ordination of
care, user involvement, face-to-face communication,
information, psychological support services, social
support services, spiritual support services, general
palliative care services (including the care of dying
patients), specialist palliative care services,
rehabilitation services, complementary therapy
services, services for families and carers (including
bereavement care) and workforce development. It is
based on the following principles of both supportive
and palliative care:
Palliative care is:
and a range of expertise provided by:
‘…the active holistic care of patients with advanced
progressive illness. Management of pain and other
symptoms and provision of psychological, social and
spiritual support is paramount. The goal of palliative
care is achievement of the best quality of life for
patients and their families. Many aspects of
palliative care are also applicable earlier in the
course of the illness in conjunction with other
treatments.’494
>
physiotherapists
>
occupational therapists
>
dietitians
>
pharmacists
>
social workers
>
chaplains/spiritual care givers
>
professionals able to deliver psychological
support as defined by the NICE guideline on
Supportive and Palliative Care494
Palliative care is based on the following principles:
>
To provide relief from pain and other distressing
symptoms
>
Integrate the psychological and spiritual aspects
of patient care
Supportive care:
‘…helps the patient and their family to cope with
cancer and treatment of it – from pre-diagnosis,
through the process of diagnosis and treatment, to
cure, continuing illness or death and into
bereavement. It helps the patient to maximise the
benefits of treatment and to live as well as possible
with the effects of the disease. It is given equal
priority alongside diagnosis and treatment.’ 494
>
>
It covers a range of issues relevant to people with
cancer and their carers, including:
>
self help and support
>
user involvement
>
information giving
>
psychological support
>
symptom control
>
social support
>
rehabilitation e.g. appliance officers, dietitians.
complementary therapies
>
spiritual support
>
palliative care
>
end-of-life and bereavement care.
The Guideline Development Group strongly supports
this guidance494, in particular, the emphasis on:
Offer a support system to help patients to live as
actively as possible until death and to help the
family cope during the patent’s illness and in
their own bereavement
Be applied early in the course of illness in
conjunction with other therapes to prolong life
(such as chemotherapy and radiotherapy),
including investigations to better understand
and manage distressing clinical complications
The professions involved in providing these services
and aims, fall into 2 distinct categories:
>
>
Those providing day-to-day care to patients and
carers in the community or in hospitals.
Those who specialize in palliative care
(consultants in palliative medicine and clinical
nurse specialists in palliative care for example),
some of whom are accredited specialists.
Specialist palliative care teams require:
>
121
>
palliative medicine consultants
>
palliative care nurse specialists
>
a team secretary/administrator
12.1.2
>
The responsibility of all professionals to provide
high quality ‘general’ supportive and palliative
care
>
The need for a multidisciplinary approach
>
The importance of good communication
>
The timely involvement of specialist services
when patients supportive and palliative care
needs are not being met.
Common symptoms of lung cancer
Common symptoms of lung cancer include fatigue,
loss of appetite, weight loss, breathlessness, cough,
haemoptysis, hoarseness, chest pain, bone pain,
spinal cord compression, brain metastases and
superior vena cava obstruction. Thoracic symptoms
have been subdivided into management of dyspnoea
(breathlessness), including malignant pleural
effusion, non-obstructive airway symptoms (cough,
haemoptysis, hoarseness and chest pain) and
superior vena cava obstruction. Neurological
symptoms include those arising from brain
metastases and spinal cord compression. The
treatment of bone pain and pathological fractures is
covered under a section on bone metastases. No
specific evidence on the treatment of pain has been
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PALLIATIVE INTERVENTIONS AND SUPPORTIVE AND PALLIATIVE C ARE
reviewed as this is a general symptom of cancer and
not specific to lung cancer which is outside the
scope of this chapter. Nevertheless, the management
of pain is recognised by the Guideline Development
Group to be of particular importance and the Group
places great emphasis on the prompt evaluation and
effective treatment of pain.
Many of these symptoms can be very debilitating
and considerably reduce quality of life. Others are
life-threatening conditions requiring immediate
treatment. Some palliative treatments, in addition to
relieving symptoms and improving quality of life may
increase survival; this is particularly so when the
underlying cause is life threatening (e.g. superior
vena cava obstruction, hypercalcaemia of
malignancy). We have examined the various
symptoms encountered and assessed the evidence of
the effectiveness of interventions to improve
symptoms. The symptoms’ underlying causal
mechanisms and the stage and performance status
of the patient also determine the treatment given.
Although we identified studies that review palliative
interventions, surprisingly few include measures of
quality of life.
The GDG are aware that the methodology followed
has highlighted a lack of specific evidence relating
to the management of many of the common
symptoms experienced by patients with lung
cancer. Subsequently this section may appear to
ignore a number of approaches in common use, e.g.
opioids for breathlessness. As a result the GDG
would like to stress:
>
>
>
this section can not be nor was intended to be a
comprehensive or textbook account of the
management of physical, psychological, other
symptoms or problems encountered by patients
with lung cancer
The guideline development group felt they should
highlight the importance of prompt referral and
treatment for specialist palliative care services and
made the following good practice point:
>
12.2
12.3
Many techniques are included in this review,
reflecting the diversity of symptoms, underlying
causes and treatments available:
>
Communication with patients with lung cancer
>
Management of dyspnoea (breathlessness):
bronchoscopy, laser treatment, photodynamic
therapy, stents, treatments for breathlessness
caused by malignant pleural effusion (pleural
drainage, thoracentesis and pleurodesis by
sclerotherapy agents), cryotherapy,
brachytherapy, external beam radiotherapy and
non-drug methods (e.g. psychosocial support,
breathing control methods, coping strategies)
>
Management of cough: palliative radiotherapy for
cough and haemoptysis, antitussive therapy
(opioids), treatment for cough caused by malignant
pleural effusion (pleural drainage, thoracentesis
and pleurodesis by sclerotherapy agents)
>
Management of hoarseness: surgery
>
Management of chest pain: palliative
radiotherapy and treatment for chest pain
caused by pleural disease
>
Management of superior vena cava obstruction:
chemotherapy or radiotherapy or both; stents,
steroids
>
Management of neurological symptoms (brain
metastases): corticosteroids, whole brain
radiotherapy, surgery and chemotherapy
>
Management of pain caused by spinal cord
compression: corticosteroids and radiotherapy;
and surgery
Management of pain caused by bone metastases
>
Management of other symptoms (weight loss,
loss of appetite, depression and difficulty with
swallowing).
Information can be given in oral, audio taped, video
taped, or written format, depending on patient
preference, and availability of literature. The NHS
Cancer Plan (2000)495 states:
“All NHS Trusts and cancer Networks are being
required to make high quality information available
to all cancer patients. Information must be culturally
sensitive and specific to local provision of services as
well as information about the type of cancer and
treatment option”
Methodology
The search for evidence of the effectiveness of
palliative interventions was undertaken by NCC-AC
and is in appendix six. The search for palliative care
and communication was carried out by SIGN, and is
in appendix six.
Tools included in this review
that an absence of this level of evidence does
not imply that nothing can be done to help
the important role of the supportive and
palliative care multidisciplinary team, in
particular specialist palliative care teams in
symptom control
Patients who may benefit from specialist
palliative care services should be identified and
referred without delay
>
It is important for health care professionals not to
assume what the patient knows, and to check out
level and extent of knowledge. Facts may not always
be remembered in the way they were given. Studies
show that some patients only remember a tenth of
what they were told during a consultation495.
Effective communication between health care
professionals across the primary/secondary interface
is essential and should include:
The search for the evidence referred to in this
chapter was restricted to patients with lung cancer.
The Guideline Development Group’s collaborators,
SIGN, found no research evidence assessing the
effectiveness of different treatments for symptoms
such as weight loss, loss of appetite, difficulty with
swallowing and depression, specific to lung cancer
patients but the GDG wanted to make good practice
points as specific treatments are available for lung
cancer patients which are detailed in section 12.13.
12.4
Communication
No evidence regarding the information needs of lung
cancer patients specifically was retrieved by the SIGN
literature search. In the light of recommendations
from sources based on other patient groups however,
the guideline development group wanted to make
good practice points. The group also felt that
communication was such an important issue that the
recommendations made should appear early on in
the guideline and as such, they can be found in the
Access to Services chapter (3.6).
Government guidelines state that patients and their
carers should be offered accurate, clear, full and
prompt information that is culturally sensitive in
both verbal and other means accessible to the
patient, at every stage of the care pathway495-498.
Good communication and adequate information can
help reduce anger and anxiety, and improve patient
confidence499,500. Information needs will vary
depending on the particular patient, their age and
individual knowledge base, carer, stage of disease,
and performance status.
123
>
Patient problems
>
What the patient was told
>
What the patient understood (where possible)
>
Management plan
>
Involvement of other agencies
>
That patients should not be given bad news by
letter and only by phone in exceptional
circumstances
The Nursing Contribution to Cancer Care (2002)501
states that for site-specific cancers in a cancer unit or
cancer centre, a clinical nurse specialist should be
provided to support patients and carers.
12.4.1
Discussions at diagnosis:
Ideally the patient’s partner or family member
should be present, unless the patient specifically
requests otherwise, in addition to a nurse or another
healthcare professional. Information, both verbal
and written (supported by any other format the
patient prefers), should include, whenever possible,
details of the stage of disease, treatment options
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PALLIATIVE INTERVENTIONS AND SUPPORTIVE AND PALLIATIVE C ARE
(including no treatment) and aims of treatment
(which will include chances of cure and
prognosis)502,503 and information on supportive care
e.g. diet. Patients should be given time to ask
questions. The nurse (specialist nurse, when
available) plays a vital role. For example, she/he
provides support to the patient and relative(s) and
can reiterate or clarify information.
USEFUL LUNG CANCER PATIENT INFORMATION
AND SUPPORT RESOURCES
There are many ways of finding out more about lung cancer. There are many booklets and internet sites available.
Below are a few examples:
1.
12.4.2 Discussions regarding treatment options:
12.4.3 Discussions regarding relapsed disease:
Cancer BACUP
Freephone 0808 800 1234
Booklets –
"Understanding Cancer of the Lung" and other booklets on many aspects of cancer treatment and care, including
Complimentary Therapies, Fatigue, Hair Loss and Diet.
Patients should have the opportunity to be
accompanied by a carer. Informing a patient of
relapsed disease should be seen as breaking bad
news, and approached as such. It is important that
patients have the opportunity to ask questions,
discuss treatment options and aims of treatment,
which will include prognosis when desired by the
patient and whenever possible. A realistic
discussion of how the aims of a person’s treatment
can change and a re-evaluation of individual
prognosis may be appropriate.
British Lung Foundation
Leaflet –
"Living with Lung cancer. The facts (Nov 2002) This leaflet explains what lung cancer is, and provides information
on diagnostic tests and treatment. Copy free with an SAE to the British lung foundation, 73-75 Goswell Road,
London, EC1V 7ER. www.lunguk.org/index)
2.
USEFUL BOOKLETS ON SYMPTOM CONTROL AND PALLIATIVE CARE
Cancer BACUP
Freephone 0808 800 1234
A number of booklets specifically for symptom control such as "Controlling symptoms of cancer" and "Controlling
pain" and "Dying with Cancer" looking at practical and emotional issues that surround dying with cancer. Also,
"Coping at home- caring for someone with advanced cancer" which is about services that can be accessed in the
community. Also see the "Q&A" section that covers different questions on lung cancer. www.bacup.org.uk
12.4.4 Discussions regarding end of life care:
For more detailed recommendations regarding
communication and provision of information, see the
NICE Supportive and Palliative Care Guidance497.
USEFUL INFORMATION BOOKLETS ON LUNG CANCER
The Roy Castle Lung Cancer Foundation
Freephone 0800 358 7200
Booklets –
"So You Have Just Been Told You Have Lung Cancer" (Personal thoughts from lung cancer patients and carers
designed to address initial questions after diagnosis)
"Lung Cancer – Answering Your Questions" (A 50 page booklet answering most of the commonly asked questions
relating to lung cancer)
Patients may require clarification of treatment options,
and time to consider these and to discuss with
whomever they feel appropriate as well as further
information in order to give informed consent.
This is a sensitive issue and may or may not involve
the palliative care team. Patients should be given a
choice about their end of life care and discussion
about this issue should happen early in the course of
their palliative treatment. Aims of treatment and
care should be discussed with full involvement of the
carer and other health care professionals as
appropriate.
125
3.
USEFUL INFORMATION ON BREATHLESSNESS
Cancer BACUP
Freephone 0808 800 1234
Factsheet– "Management of Breathlessness".
The Roy Castle Lung Cancer Foundation
Freephone 0800 358 7200
Booklet – "A Practical Guide To Breathlessness"; Video – "Take A Breather"
126
4.
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PALLIATIVE INTERVENTIONS AND SUPPORTIVE AND PALLIATIVE C ARE
It is difficult to monitor the quality of information on a website. If in doubt, patients should ask their nurse or doctor
for further clarification on good quality websites that might be appropriate for their situation.
www.bacup.org.uk
www.nhsdirect.nhs.uk
www.alcase.org
www.macmillan.org.uk
5.
12.5
Management of Dyspnoea
(Breathlessness)
12.5.1
Introduction
SOME USEFUL WEBSITES
www.roycastle.org
www.cancerresearchuk.org
www.patient.co.uk
www.mariecurie.org.uk
www.lungcanceronline.org
www.graylab.ac.uk
www.dipex.org
ADDITIONAL LUNG CANCER PATIENT SUPPORT
There are many different organisations which work with the NHS to provide support and information for lung cancer
patients. Listed below are a few such organisations:
The Roy Castle Lung Cancer Foundation
Network of monthly Lung Cancer Patient Support Groups. Through its Information Line, provides contact details for
local lung cancer nurses throughout the UK.
Freephone Helpline 0800 358 7200.
Benefit Enquiry Line
Provides information and advice about social security benefit entitlement
Freephone 0800 88 22 00
Cancer BACUP
Helps patients, their families and friends, to live with cancer. For information and support from cancer nurses,
freephone 0808 800 1234.
Macmillan Cancer Relief
Services include Macmillan Nurses, doctors, cancer care and information units. Also, financial help for individuals,
through patient grants.
Information Line 0845 601 6161.
The Macmillan CancerLine is open Mon-Fri 9am-6pm on 0808 8082020.
Marie Curie Cancer Care
Runs hospice centres throughout the UK, and a community nursing service to support cancer patients and their
carers in their homes.
Telephone 0207 599 7777
The British Lung Foundation
Runs a network of Breathe Easy Patient Support Groups for patients with all types of lung disease.
Telephone 020 7688 5555
The NHS Smoking Helpline
Offers down to earth help and advice to people who want to stop smoking.
Freephone 0800 358 7200
Three-quarters of lung cancer patients experience
dyspnoea at some time and this rises to around 90%
in their last month of life504. It has a number of
causes and is a distressing and sometimes life
threatening symptom, the palliation of which can be
of major benefit to the patient505. Each treatment is
appropriate for a slightly different group of patients
and is discussed independently. The effectiveness of
non-drug interventions is assessed alongside medical
treatments. The effectiveness of surgery is not
reviewed as no evidence was retrieved.
Where malignant pleural effusion is the underlying
cause it should be treated as described in section
12.5.6 below.
12.5.2 Physical De-bulking via the
Rigid Bronchoscopy
Although rigid bronchoscopy (including the
mechanical removal of the tumour) has been
undertaken for several decades, there is relatively
little published data reporting detailed outcomes.
A single, recent systematic review505 was retrieved,
which described one case series of rigid
bronchoscopy for lung cancer patients (see Table
151). Of the 56 patients, 62% were treated
electively and 86% had mostly endoluminal tumours
involving the trachea, carina, or main stem bronchi.
The study reported a success rate of 91%, measured
by both symptomatic assessment and bronchoscopy.
The palliation of symptoms however, does depend on
the location of the tumour. In patients with lobar
obstruction for example, there was a 38% success
rate compared with over 90% in patients with
tracheal or main stem bronchial lesions (Level 3).
Complications occurred in 20% of patients. The
patient group was unusual in that 28% went on to
have open surgical resection. Median survival of the
remainder was six months (Level 3).
12.5.3 Laser Treatment
Historically the CO2 laser was first used to treat
airway lesions. This method suffers from a limited
127
ability to coagulate bleeding and can only be
transmitted in a straight line. Most of the published
data involves the use of the Nd-YAG laser, which can
be transmitted through a flexible or rigid
bronchoscope.
Our search identified a single, recent systematic
review505 reporting four case series (which total more
than 2,500 patients) achieving palliation of
dyspnoea in 80% of patients (see Table 152).
Success was influenced by the location of the
tumour: 70-95% of patients with central lesions, 4060% of patients with lobar obstruction and 57% of
patients with complete occlusion of the airway (Level
3). Almost all patients had endoluminal tumours
while patients with extrinsic compression were
generally excluded. Symptom relief was measured
using a combination of symptomatic assessment and
bronchoscopy. This procedure was reported to have a
mortality of 0.4%-3% and complications, including
haemorrhage, in 3% of cases505. Between 50-60% of
patients were retreated 3-4 months later; median
survival was 6 months505(Level 3).
12.5.4 Photodynamic Therapy
Photodynamic therapy (PDT) involves the
administration of a photosensitiser, which is taken
up by tumour cells. Subsequent exposure to light of
a particular wavelength induces cell death. Light
from PDT is reported to penetrate to a depth of 510mm, making tracheobronchial tumours well suited
to this treatment. Routine bronchoscopic
debridement typically follows treatment.
Our search identified two systematic reviews505; 506
and a recent case series. The first systematic review
identified two case series meeting its inclusion
criteria of having more than fifty patients505. The
second review506 incorporated 12 case series506 with
a total of 636 patients (see Table 153). One large
study (175 patients) was included in both reviews.
The first review found that photodynamic therapy
temporarily palliated breathlessness in 60% of
patients although palliation is much higher (80%) in
patients with strictly endoluminal tumours (Level 3).
There is a 4% one month mortality rate and 2% risk
of major haemorrhage505 (Level 3). The second
review506 reported skin photosensitivity (sunburn) in
5%-28%, haemoptysis in up to 18% in addition to
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post-treatment cough, expectation of necrotic debris
and dyspnoea which were noted by many authors.
Nevertheless it concluded that almost all patients
had relief of dyspnoea and cough along with an
improvement in lung function. The recent study, a
prospective case series of 40 patients, used PDT with
hyperbaric oxygen and reported improved dyspnoea
in all but one patient and improved haemoptysis in
10 of the 12 patients experiencing this507 (Level 3).
12.5.5 Stents
A number of airway stents are available for the
palliation of dyspnoea. These include silastic stents
for the trachea or main stem bronchi, silastic Y stents
for use at the carinal level and expandable metal
stents that can be used in the trachea and the main
bronchi. Stents are commonly used in patients with
endoluminal obstruction and extrinsic compression.
Our search identified a recent systematic review
(describing three case series) and a further two case
series508,509 (see Table 154). The systematic review505
reported the success rate of endoluminal stents in
three case series (413 patients) to be 90%. The
majority of patients had central tumours and severe
obstruction (Level 3). Stents placed at lobar level are
often not as successful as those placed for central
lesions505. The mortality of the procedure is reported
as 0% to 7% with complications such as stent
migration and mucus retention occurring in 10-20%
of patients (Level 3).
These high levels of relief have also been observed in
later case series of 34 and 14 patients with the most
severe levels of breathlessness (for example as an
emergency procedure)160,508 (Table 154).
12.5.6 Pleural Effusion
Breathlessness due to pleural effusion may be
relieved by needle aspiration or more completely by
drainage with a tube left indwelling for a period of
time. Recurrence in days or weeks is common, so
symptomatic relief is usually temporary. Any
symptomatic benefit gained may be extended by
pleurodesis. Our review of the literature found no
data on the use of pleural drainage or pleurodesis
that was specific to lung cancer. However, we
identified one guideline510and two systematic
PALLIATIVE INTERVENTIONS AND SUPPORTIVE AND PALLIATIVE C ARE
reviews511,512 that examined pleural effusion in mixed
populations (Table 155).
>
Recent guidelines by the British Thoracic
Society510covered the management of malignant
pleural effusions resulting from various primary
tumours. Based on the evidence from their literature
search and the experience of the expert group they
found that chest tube drainage via an intercostal
tube should be considered as the first line of
treatment followed by chemical pleurodesis, for
patients where a chest x-ray shows that there is
complete lung re-expansion510 (Level 1+). Our
guideline development group considered that this
result, based on a general population of patients
with malignant pleural effusion, could be applied to
lung cancer patients. However, lung cancer patients
are more likely to have a collapsed or obstructed and
therefore non-functioning lung and drainage of fluid
may not lead to an improvement in breathlessness.
The grade of the recommendation has therefore
been extrapolated to a Grade B to reflect this.
No data specific to lung cancer were found; most
studies included a mixture of patients and did not
break down the results by disease. Both reviews
found that talc was the most effective agent. Again,
the Guideline Development Group considered that it
was reasonable to apply this finding to lung cancer
patients although the recommendation would be
downgraded to a grade B to reflect the fact that the
target population of the studies was not specifically
lung cancer patients.
A recent Cochrane systematic review511 examined the
results from 36 RCTs on pleurodesis and a systematic
review by Tan et al512 examined 227 papers
(including 45 RCTs and 98 observational studies) on
pleurodesis. The Cochrane review511 concluded that
there was evidence for three statements (Level 1++):
>
A sclerosant instilled into the pleural space is more
effective than placebo or tube drainage alone.
>
Talc was associated with less recurrence than any
other agent
>
Thoracoscopic pleurodesis was more effective than
bedside tube pleurodesis where talc was used
The systematic review by Tan et al512 concluded
similarly on these questions but was a more
exhaustive review of the details of implementation
and provides further details (Level 1+):
>
Protracted tube drainage is not more effective
than earlier tube removal.
>
Rolling and tipping the patient does not confer
advantage.
Tube size is not important. Smaller tubes are as
effective as larger ones
12.5.7 Cryotherapy
Cryotherapy is the rapid freezing of tissue, which
destroys tumour cells then debrided over several
bronchoscopic procedures. Our search identified a
recent systematic review505 that described three case
series (411 patients) (See Table 156). Palliation was
65-68%, with greater palliation in patients with
central lesions compared to those with peripheral
lesions (60% vs. 35% respectively). There is currently
no data on the durability of results505 (Level 3).
12.5.8 Brachytherapy
Brachytherapy is the delivery of radiation from an
endobronchial source. A catheter is placed across
the lesion, loaded with the appropriate radiation
source, and this remains in place until the prescribed
dose has been delivered.
Our search identified three RCTs493,513,514 on the
effectiveness of endobronchial brachytherapy alone
(see Table 157), although one was underpowered to
detect any differences in the treatments compared.
Stout et al493 randomised patients to either
endobronchial brachytherapy or external
radiotherapy and reported that both treatments
produced good levels of symptomatic relief although
they were better for external radiotherapy at the
expense of more acute morbidity. While late side
effects were similar, improved survival was recorded
in the radiotherapy arm, which was statistically
significant (Level 1+). One other trial was retrieved
which combined endobronchial brachytherapy with
radiotherapy. Langendijk et al515 reported that the
combination of techniques provides higher rates of
129
expansion of collapsed lung resulting in transient
lower levels of dyspnoea and importantly, there is no
significant increased risk of fatal haemoptysis .
12.5.9 External Beam Radiotherapy
External beam radiotherapy is the most common
palliative treatment modality, received by between
20-30% of patients with lung cancer516. Our search
identified two systematic reviews516,517 and one RCT518
(See Table 158). The first, a Cochrane systematic
review516 of ten randomised controlled trials
compared different radiotherapy regimens (See Table
158). This found that symptoms improved under all
regimens. There was no strong evidence that higher
dosages gave greater palliation overall (lack of
consistent reporting and assessment in the
individual trials prohibit greater detail) although
there was evidence of greater toxicity with higher
doses. Recommended dosages are 10 Gy in one
fraction or 16-17 Gy in 2 fractions although there is
some evidence that higher doses produce a modest
survival benefit in patients with good performance
staus (Level 1++). The more recent review517 did not
identify any additional studies. A recent randomised
controlled trial518 of 230 patients comparing 10Gy in
a single fraction or 20Gy in five fractions found
similar levels of symptom relief (Level 1+).
12.5.10 Non-drug treatment
SIGN identified one recent UK RCT519 assessing the
effectiveness of a nurse-led clinic for the palliation
of breathlessness that offered breathing control,
activity pacing, relaxation techniques and
psychosocial support (see Table 159). The weekly
clinic was compared with best supportive care over
an 8 week period. Performance status and
symptoms universally deteriorated in the control
group but were generally maintained in the
intervention group. This was statistically
significant for five of the11 outcome measures;
breathlessness at best (Visual Analogue Scale
(VAS) scale), performance status, depression
(Hospital Anxiety and Depression (HAD) scale),
physical symptoms (Rotterdam symptom checklist)
and an activity subscale (Rotterdam symptom
checklist). The research group considered the
mechanism may be the emphasis on teaching more
effective ways of coping with breathlessness and
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PALLIATIVE INTERVENTIONS AND SUPPORTIVE AND PALLIATIVE C ARE
the opportunity to talk about difficult feelings and
concerns. Such non-drug approaches appear to be
of benefit to patients with dyspnoea (Level 1+).
recent systematic review505 described above
concluded the following issues should be considered
(Level 4):
The Guideline Development Group considers that
such non-drug treatments should be delivered by a
multidisciplinary team, facilitated or co-ordinated by
a professional with an interest in breathlessness and
the necessary expertise in the techniques (e.g. nurse,
physiotherapist, occupational therapist or other).
Although it may be provided within a breathlessness
clinic, patients should have access to such support
wherever they are. In addition, there is scope to
improve the efficacy of non-drug treatments and this
is an area that requires further research.
>
12.5.11 Summary of management of dyspnoea
Comparison between the treatments is not
straightforward because evidence is typically from
non-randomised retrospective studies, outcomes
are not measured systematically and many patients
receive more than one type of intervention.
Unfortunately a MRC randomised trial designed to
answer this question failed to recruit sufficient
patients514. The authors of the systematic
review505,520 that identified the most evidence on
each intervention concluded that the acute
mortality and morbidity for all the interventions
for obstructive airway management are similar505
(Level 3). Our search identified a single
randomised trial comparing endobronchial
brachytherapy with external radiation for the relief
of breathlessness, cough and haemoptysis493 (see
Table 160). This found that both treatments
relieved symptoms of cough, haemoptysis and
breathlessness (59%, 85% and 78% for
endobronchial brachytherapy, and 59%, 90% and
66% for external radiotherapy respectively).
Median survival was higher with external
radiotherapy (287 vs. 250 days). Interestingly,
28% of those receiving external radiotherapy went
on to have endobronchial treatment (at a median
304 days) whereas 51% of those in the
endobronchial group subsequently had external
radiotherapy (at a median 125 days) (Level 1+).
In deciding the best course of treatment for a
patient presenting with dyspnoea the authors of the
>
Nature of obstruction: endoluminal, mixed,
extrinsic
>
Urgency
>
Technical issues: ease for patient, durability of
relief, availability of equipment and expertise,
depth of penetration into tissue.
Our search identified a systematic review on the
management of cough521 and a later double-blind,
randomised controlled trial (see Table 161).
Each randomised, double-blind, placebo controlled
trial within the systematic review had 79 patients
and compared codeine and dextromethorphan to
placebo. Both found cough reduced significantly
(Level 1++). The later randomised controlled trial522
of 140 lung cancer patients with a documented
history of non-productive cough (at least 5 coughs
per hour) compared the effectiveness of a non-opioid
(although levodropropizine is not available in the
UK) to an opioid antitussive (Level 1+). Cough
severity scores (graded by both the patient and
assessor) showed a significant decrease with
treatment but no significant difference between the
drugs. Opioid and non-opioid anti-tussives are
effective in the treatment of cough (Level 1+). In
UK clinical practice, generally codeine is used, and if
ineffective, substituted for morphine.
Whether or not the above interventions are
undertaken, non-drug approaches appear to benefit
patients with dyspnoea.
12.6
Management of Cough
Four in five lung cancer patients (79%) experience
cough and a third (35%) experience haemoptysis504,520.
12.6.1
12.6.3 Pleural drainage, thoracentesis and
pleurodesis for malignant pleural effusion
Palliative radiotherapy for cough and
haemoptysis
Our search identified a Cochrane systematic review
(described above) and a later randomised controlled
trial. The Cochrane systematic review516(see section
Table 158) reported the effectiveness of low dose
radiotherapy in palliating a range of thoracic
symptoms, including cough and haemoptysis (the
outcomes for each symptom were combined in the
results)(Level 1+). The first of the later RCTs (Table
158) found no difference in outcome with
immediate treatment or delaying treatment until
required for symptom relief for patients with
previously untreated NSCLC that is locally too
advanced for resection or radical radiotherapy with
curative intent, minimal thoracic symptoms and no
indication for immediate thoracic radiotherapy (Level
1+). The other RCT518 favoured a fractionated
regimen over a single dose (Level 1+).
Development Group observed hoarseness due to left
recurrent laryngeal nerve involvement very rarely
responds to external beam radiotherapy and
recommends that cases should be referred to an ear
nose and throat specialist for assessment.
12.6.2 Antitussive therapy for cough
Location of obstruction: trachea; main stem
bronchus, bronchus intermedius; lobar,
segmental
Cough may also be a symptom of malignant pleural
effusion. The effectiveness of treatment for this is
discussed in section 12.5.6 above.
12.6.4 Summary of management of cough
Cough and haemoptysis (among a group of
undifferentiated symptoms) are improved by
palliative radiotherapy, both external and
endoluminal. There is no strong evidence that higher
doses of radiotherapy are associated with better or
longer lasting palliation516. Cough is also reduced by
opioid and non-opioid anti-tussives521,522. Cough
caused by malignant pleural effusion can be treated
as discussed in section 12.5.6.
12.7
Management of Hoarseness
About one in ten patients experience some
hoarseness of their voice (11%)504. Our search
identified only one, uncontrolled, trial of a surgical
treatment (vocal cord medialisation for unilateral
paralysis) which improved symptoms of hoarseness523
(Level 3) (see Table 165). The Guideline
131
12.8
Chest pain
A third of patients (37%) experience chest pain
during their last 12 months of life, rising to
approximately half during the last month504. Pain
should be evaluated carefully in order to identify
the underlying cause and provide the most
appropriate treatment. Management includes
explanation of the symptom to the patient (also
addressing their concerns), treating the underlying
cause when possible, (e.g. radiotherapy) non-drug
and drug approaches. If pain is not progressively
improving over a 1-2 week period (less if severe),
advice should be obtained from specialists in
palliative care or pain.
12.9
Superior Vena Cava Obstruction
12.9.1
Introduction
Superior Vena Cava Obstruction (SVCO) is due
either to a tumour arising in the right main or
upper lobe bronchus or by the presence of bulky
mediastinal lymph nodes typically arising from the
right paratracheal or pre-carinal stations. It causes
oedema of the face, neck and arms. Distended
veins over the chest are also usually apparent.
SVCO is present at diagnosis in 10% of patients
with SCLC and 1.7% of patients with NSCLC524.
Traditional management of SVCO includes systemic
corticosteroids (e.g. dexamethasone) and either
radiotherapy (more commonly used for NSCLC) or
chemotherapy (generally for SCLC). More recently,
with the development of endovascular stenting, an
expandable stent placed percutaneously in the SVC
to relieve compression and restore blood flow, has
been increasingly used. Our search identified a
recent Cochrane systematic review524 (see Table
162) on the treatment of SVCO by steroids,
radiotherapy, chemotherapy and stents which drew
on two randomised trials and 44 non-randomised
studies, most of which were retrospective.
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12.9.2 Chemotherapy and/ or Radiotherapy
The Cochrane review identified two relevant
randomised trials. Based predominantly on nonrandomised trials the review found that
chemotherapy and/or radiotherapy relieved SVCO in
77% of patients with SCLC. Of those treated, 17%
had a recurrence of SVCO. In NSCLC, chemotherapy
and/or radiotherapy relieved SVCO in 60%, with
19% of those treated having a recurrence. In
addition, the review noted that rates of relief of
SVCO were very similar for chemotherapy and for
radiotherapy in both cell types; 77% and 78%
respectively for SCLC and 59% and 63% in NSCLC.
Effectiveness was not clearly related to any particular
radiotherapy fractionation schedule or chemotherapy
regimen (Level 2++)
12.9.3 Stents
The Cochrane review524 described fewer, smaller (15
patients or fewer) non-randomised studies of
patients treated with stenting (Table 162). The
review found that insertion of an SVC stent relieved
SVCO in 95%, with 11% of patients developing
recurrent SVCO. However, recanalisation was often
achievable with a resulting long-term patency of
92%. The use of anticoagulation during and after
insertion varied between studies, with most using
heparin during placement, and some reporting use
of warfarin following insertion. The systematic review
could not conclude whether a particular policy of
subsequent anticoagulation resulted in fewer stent
thromboses, though morbidity following stent
insertion was greater if thrombolytics were used
(Level 2++).
12.9.4 Corticosteroids
Although corticosteroids are often used in high
doses and short courses to treat SVCO along with
radiotherapy, neither the Cochrane review524 nor our
search identified studies that examined the
effectiveness of corticosteroids in SVCO.
12.9.5 Summary of the management of SVCO
Although largely based on retrospective and nonrandomised studies the Cochrane review524
concluded that chemotherapy and radiotherapy are
PALLIATIVE INTERVENTIONS AND SUPPORTIVE AND PALLIATIVE C ARE
effective in relieving SVCO and that stent insertion
appears to provide relief in more patients more
rapidly. The effectiveness of corticosteroids
remains uncertain.
12.10 Management of Brain Metastases
12.10.1 Introduction
Brain metastases occur frequently in patients with
lung cancer, especially SCLC, and have a profound
effect on both quality of life and survival. Headaches
(40%), motor deficits (36%), seizures (27%),
disorientation (24%) and lethargy (16%) account for
the vast majority of presenting symptoms505.
Treatment is generally palliative, although
occasionally it may be given with curative intent.
Aggressive treatment of the metastasis is by
resection; treatments with a palliative intent include
corticosteroids and whole brain radiotherapy (WBRT).
Our search identified one systematic review520 and
two guidelines525,526 relevant to this topic. Many of
the studies of brain metastases involve patients with
a variety of types of cancer, but lung cancer accounts
for the majority (see Table 163).
12.10.2 Corticosteroids
Corticosteroids reduce symptoms caused by cerebral
metastases (including headache, focal or generalised
seizures and motor or sensory deficits) by reducing
cerebral oedema. A recent systematic review520 and
a guideline525 found corticosteroids palliate
symptoms in the short term for most patients525
although complications arise in approximately
30%520 (longer term side effects were not reported).
The median survival of patients with brain
metastases is one or two months when treated with
corticosteroids alone520 (Level 3) (see Table 163).
12.10.3 Radiotherapy
Palliative whole brain radiotherapy (WBRT) may be
offered to improve symptoms. Improvement in
neurological symptoms can be seen in half of
patients after 2 weeks and three-quarters after 4
weeks505. A recent systematic review examined seven
randomised trials (4,104 evaluable patients)505.
Dosage ranged between 12 Gy to 54 Gy, with
between 1.6 and 6 Gy fractions. Many of the studies
included some patients who had primary cancers at
sites other than the lung. Median survival is
approximately four months (range 2.5 to 5.3
months)505 (Level 3) (See Table 163). Nevertheless,
progressive brain disease remains the cause of death
in approximately 40% of patients receiving WBRT520.
A previous guideline states that corticosteroids and
radiotherapy could be considered for headache due
to cerebral metastases526(Level 4).
12.10.4 Surgery
Resection of a solitary brain metastasis is currently
sometimes considered for NSCLC patients who have
undergone complete resection for the primary
tumour and who have no other sites of metastases.
Without treatment survival is very short505.
Ten case series involving 565 patients were retrieved
by a systematic review which reported median
survival of 11 months (2 year survival 28%)520.
Where a complete resection was achieved median
survival increased to 20 months and two year
survival increased to 41% (226 patients)520 (see
Table 163).
12.10.5 Chemotherapy
Although it has been assumed that chemotherapy
drugs pass the blood-brain barrier poorly, a recent
systematic review520 commented that small scale
series of NSCLC and SCLC patients had responses
similar to those with tumours located elsewhere
(Level 3). A previous guideline states that
chemotherapy is effective at reducing pain caused by
cerebral metastases in SCLC patients525 (Level 4).
133
12.11 Spinal Cord Compression
12.11.1 Introduction
Compression of the spinal cord, typically by
metastatic epidural tumours, can lead to
neurological impairment and paraplegia. At the time
of diagnosis the most common symptom is pain,
followed by weakness, autonomic dysfunction or
sensory loss 527. Many types of cancer metastasise to
the spinal column, but in relation to lung cancer the
commonest cause is SCLC, with the majority of
epidural metastases found in the thoracic region 528.
12.11.2 Corticosteroids, radiotherapy and surgery
Our search identified a systematic review505 reporting
one (underpowered) randomised controlled trial529
and three case series528,530,531 and two later case
series532,533 (see Table 164). The retrospective studies
describe the combined outcomes of corticosteroids,
radiotherapy and surgery. These include improved
symptoms533 and regaining (22%528) or retaining
ambulatory status (Level 3). These studies concluded
that any treatment of spinal cord compression
should be initiated rapidly; treatment within 12
hours is associated with functional recovery532;
conversely the studies observe a lack of recovery of
functions of patients presenting with the severest
symptoms (e.g. paraplegia)528,530,533 (Level 3).
Although not based on analysis of prognostic factors
the systematic review505 suggests surgery should be
considered in certain contexts: patients who have
received previous irradiation to the area; patients
who experience progressive neurological
deterioration while receiving radiation; and for
patients with symptomatic spinal instability or bone
fragments causing compression505 (Level 4).
12.10.6 Summary of management of brain metastases
The results from a systematic review520 and
guidelines525,526 indicate that corticosteroids and
whole brain radiotherapy are effective in palliation
of lung cancer patients with a single brain
metastasis. There is some evidence that
chemotherapy also reduces pain caused by cerebral
metastasis520,525.
12.11.3 Summary of management of
spinal cord compression
Radiotherapy remains the mainstay of managing
patients with spinal cord compression, with some
evidence of its effectiveness in palliating pain and
improving or at least preserving neurological function.
Although there are no comparative studies surgery
continues to be a largely supportive treatment in
managing patients with specific symptoms (Level 3).
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Patients with spinal cord compression should have
treatment within 24 hours. Corticosteroids,
radiotherapy and surgery where appropriate, should
be administered. Patients with spinal cord
compression should also have early referral to the
physiotherapist and occupational therapist for
assessment, treatment and rehabilitation. Referral to
the occupational therapist should be made for
wheelchair assessment, assessment of activities of
daily living and home assessment (GPP).
12.12 Hypercalcaemia, Bone Pain and
Pathological Fractures
As one of the most frequent sites of metastasis in
lung cancer patients, bone metastases present either
as painful lesions or as pathological fractures. An
HTA report has been published on treatments for
hypercalaemia534. Methods of treating bone
metastases include radiotherapy, bisphosphonates
and nerve blocks. After sifting and appraisal, there
were no studies retrieved from our search to evaluate
the effectiveness of these treatments that were
confined to lung cancer patients only. A small
number of RCTs on patients with a combination of
primary sites however, did provide sufficient
breakdown for lung cancer patients, although the
results are extremely limited, both in terms of the
numbers of patients and the outcomes reported, as
they are sub-analysis of papers. To supplement this
type of data, where appropriate, we extrapolated
using the results of systematic reviews of RCTs of
mixed primaries. Such reviews were primarily made
up of patients with breast and prostate cancer and it
is envisaged that bone metastases resulting from
different primaries will respond in a similar way
to interventions.
12.12.1 Radiotherapy
12.12.1.1 Effectiveness
Results on the effectiveness of radiotherapy on pain
from bone metastasis were obtained from a
Cochrane review535 and an RCT536, both of which
reported results of cancer patients with a
combination of primary sites (Table 166). Within the
Cochrane review, radiotherapy was compared to an
assumed rate of one in 100 patients having naturally
PALLIATIVE INTERVENTIONS AND SUPPORTIVE AND PALLIATIVE C ARE
resolving pain and the authors found that
radiotherapy produced complete pain relief at one
month in 25% of patients and at least 50% pain
relief in 41% of patients at some time during the
trial (Level 1++). In addition to these results, Salazar
et al 536 reported that a total of 91% of patients
responded to therapy, 45% achieving complete pain
relief (Level 1+). In terms of adverse events, the
Cochrane review535 reported no obvious difference
between the fractionation schedules in the incidence
of nausea and vomiting, diarrhoea or pathological
fractures although they acknowledged that the
reporting of adverse effects was poor in the studies
included (Level 1++).
12.12.1.2 Time to and Duration of Relief
The Cochrane review535 also reported results on the
time to pain relief. SIGN’s literature review retrieved
one additional RCT536 which reported results on the
time taken to maximum pain relief from three
different radiotherapy treatment plans; A) 3Gy’s
fractions for 5 days, B) 2 fractions (6-8hrs apart) of
4Gy each in a single day, and C) 3Gy twice daily (68hrs apart) on two consecutive days (Table 167).
The RCT reported that while the average time to any
pain relief was three days, there was no statistical
difference between any of the arms in terms of
average time to maximum pain relief (range 6-9
days) or percentage of patients achieving net pain
relief (Level 1+). The Cochrane review535 reported
that half of patients who achieved complete relief
took more than 4 weeks and that median duration
of relief was 12 weeks (Level 1++).
12.12.1.3 Single versus Multiple Fractions
The Cochrane review535 and two RCTs537,538 reported
results on single vs. multiple radiotherapy fractions
(Table 168). Steenland et al538 examined the
effectiveness of a single fraction of radiotherapy
against a total dose of 24Gy given in six fractions of
radiotherapy on almost 300 patients with lung
cancer. The single dose arm produced favourable
results, both in terms of complete response (28% vs.
19%) and percentage of patients with progression
(55% vs. 46%) although the statistical significance
of these results was not reported. In terms of the
percentage of retreatments needed however, the arm
of the trial undergoing multiple fractions of
radiotherapy had many less (5% vs. 32%) although,
again the significance of this result is not clear (Level
1+). The Cochrane review535 and Sarkar et al537,538
also reported that no difference was seen in terms of
single fraction vs. multiple fractionation schedules
(Level 1++) and so single fractions are appropriate in
most circumstances.
12.12.2 Bisphosphonates
No RCTs were retrieved for lung cancer patients or
which included a breakdown of results for lung
cancer patients only. We identified two systematic
reviews539,540 on the effectiveness of bisphosphonates
for the relief of pain and skeletal morbidity from
bone metastases from a combination of primary
sites. However, the GDG felt that such evidence
could not be extrapolated to lung cancer
patients539,540. The findings of Ross et al539
suggested that benefit was apparent only after 6
months of treatment; this raises the question of their
usefulness in patients with a shorter prognosis. The
second review, Wong and Wiffen540, reported that
although there was some evidence for the
effectiveness of bisphosphonates (Table 169), there
was not enough to recommend them for first line
treatment and their relative effectiveness for
different neoplasms was inconclusive. Further
research is required.
12.12.3 Conclusion
In conclusion, guidance exists (e.g. SIGN pain
guidelines526) for standard treatments such as
analgesics for the relief of symptoms from bone
metastasis from all types of cancer which is not
reviewed here. These standard treatments should be
administered as first line treatment before more
invasive treatment. If such interventions are
insufficient, single fraction radiotherapy should
be administered.
12.13 Other symptoms: weight loss, loss of
appetite, difficulty swallowing, fatigue
and depression
Other symptoms experienced by large numbers of
patients that require palliative treatment and care
include fatigue, weight loss, loss of appetite,
difficulty with swallowing and depression. The
135
Guideline Development Group’s collaborators, SIGN,
found no research evidence assessing the
effectiveness of different treatments for these
symptoms specific to lung cancer patients.
The Group recommends that for all symptoms there
should be a multidisciplinary approach. This
multidisciplinary group will include occupational
therapists, physiotherapists and dieticians whose
particular roles are outlined below. If the patient
has unmet physical, psychological, social or
spiritual needs despite this general palliative care
approach, referral should be made to a specialist
palliative care service, which will include access to
counselling provision494.
12.13.1 Occupational Therapists,Physiotherapists and
Dieticians
The importance of a multidisciplinary approach in
general and for rehabilitation in particular for
patients with cancer has been highlighted in the
NICE Supportive and Palliative Care Guidance494.
Occupational therapists treat people with physical and
mental health problems through the use of specific
activities, to enable patients to reach their optimum
level of function and independence in all aspects of
their daily lives. Occupational therapists can assist with
managing fatigue, breathlessness, pain, pressure care,
weight loss, cognitive problems, bone metastases,
anxiety, panic management and depression.
Interventions such as energy conservation –
emphasising the importance of planning, prioritising
and pacing daily occupations – can have a beneficial
effect on patients’ self-esteem and well-being.
Physiotherapists treat physical conditions through
specific treatment modalities such as electrotherapy,
manipulation, tissue mobilisation, exercise,
rehabilitation etc. Patients with lung cancer should
be referred to a physiotherapist for advice on
breathing techniques, positioning, life style changes,
and relaxation and coping strategies. Exercise
including progressive walking and stepping regimens
to improve muscle strength as well as their exercise
tolerance. Such exercise should be carefully
prescribed within their disease limitations. One to
one treatment also provides psychological support
for the patient and the carer.
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In addition to the above, the Guideline Group
recognises the particular contribution that
occupational therapists and physiotherapists make
to patients with lung cancer and brain metastases
or spinal cord compression, for example all aspects
of rehabilitation including pressure care advice
and management.
Dieticians provide specialist nutritional advice.
Patients with lung cancer should have access to a
registered dietician. Dieticians can advise on specific
problems such as anorexia, weight loss, swallowing
difficulties and fatigue.
12.14 Economics of Palliative Interventions
Two studies were selected for tabulation (Table 170
and Table 171). Four economic evaluations of
chemotherapy versus best supportive care (BSC)
are reported in Chapter 8 Chemotherapy for
NSCLC369,371,374,376.
Given that there is no evidence specifically for lung
cancer patients in the treatment of malignant pleural
effusion, evidence was sought regardless of cancer
site and four economic analyses were selected for
tabulation (Table 170 and Table 171).
12.14.1 Palliative Radiotherapy versus Best
Supportive Care (BSC)
The objective of Coy et al541 was to compare high
dose palliative radiotherapy with BSC in terms of
cost per LY gained and cost per QALY gained. Given
that the study is comparing essentially palliative
treatments, the use of un-adjusted life-years is
clearly inadequate
High dose radiotherapy in addition to BSC resulted
in slight improvements in survival (by 79 days) and
QALY (by 0.15) that were statistically significant
with an incremental cost of CAD$2,001 (£816)
(clinical perspective) and CAD$ 2,652 (£1,081)
(societal perspective) per patient. When the
incremental costs and effectiveness (LY gained and
QALY gained) were compared, the incremental costeffectiveness ratio of radiotherapy + BSC over BSC
alone was equal to CAD$ 12,836 (£5,235) per
QALY gained from a clinical perspective. From a
societal perspective the incremental cost-
PALLIATIVE INTERVENTIONS AND SUPPORTIVE AND PALLIATIVE C ARE
effectiveness ratio of radiotherapy + BSC over
BSC was equal to CAD$17,012 (£6,938) per
QALY gained.
The sensitivity analysis identified the best scenarios
(upper bound of the approximate 95% confidence
interval for LY/QALY gained, 80% of average cost)
and the worst scenarios (the lower bound of the
approximate 95% confidence interval for LY/QALY
gained, 120% of average cost) for high dose
palliative radiotherapy + BSC in comparison with
BSC. The cost-effectiveness of high dose palliative
radiotherapy + BSC over BSC ranged from £3,261
to £16,806 per QALY gained from the clinic
perspective and, from £4,322 to £22,274 from the
societal perspective.
According to the results of the analysis, the
incremental cost-effectiveness ratio for high dose
palliative radiotherapy combined with BSC lies
below the threshold of £30,000/QALY gained,
which is commonly used to select medical
interventions. Hence, palliative radiotherapy
combined with BSC was found to be a cost-effective
strategy in comparison with BSC for advanced
NSCLC. However, as the patients who received only
BSC had already refused high dose radiotherapy, the
potential for bias is high.
12.14.2 Nd-YAG Laser versus Bronchoscopic
Electrocautery
Van Boxem542 evaluated the costs and clinical
outcomes of Nd-YAG laser versus electrocautery for
palliation of patients with symptomatic tumour
obstruction due to inoperable NSCLC. The rate of
symptom improvement (dyspnoea relief), occurrence
of complications, mean survival, and the length of
hospital stay were observed as health outcomes.
The perspective of the economic analysis was the
health insurance company in the Netherlands.
It was observed that symptom improvements were
achieved in about 70% of patients in both study
groups and no treatment complication was recorded.
The mean survival was 8.0± 2.5 months in the NdYAG laser group and 11.5± 3.5 months in the
electrocautery group. The mean survival months
were reported as LYs in Table 171.
The average costs of treatment per patient were
£3,326 in the Nd-YAG laser group and £2,678 in
electrocautery group. The cost difference was mainly
due to longer hospital stay in the laser group (8.4
days) than in the electrocautery group (6.7 days);
the number of treatment sessions was the same in
each groups.
The comparison of costs of treatment per patient
and LYs gained for both group showed that
electrocautery was a dominant strategy. Life
expectancy was slightly improved with electrocautery
at lower cost.
12.14.3 Talc versus Bleomycin in the treatment of
malignant pleural effusion
Zimmer et al543 assessed the cost-effectiveness of
talc slurry compared with bleomycin. No significant
difference was found between the groups in terms of
improvement in pain and dyspnoea scores (Table
171). There was a significant cost advantage with
using talc to control symptomatic malignant pleural
effusions. The cost of medication was $12.36 for
talc and $955.83 for bleomycin treatment. The
results of this study should be treated with some
caution as it was restricted with small sample size
and lack of detailed analysis on costs.
Diacon et al544 result was similar to that of Zimmer
et al. Their analysis included all relevant direct costs
and effectiveness results were based on a
randomised controlled trial. Thoracoscopic talc
poudrage was a dominant strategy over bleomycin
instillation with lower recurrence rate of effusion
(13% vs. 41%) and lower costs (3,893 vs. 4,169 in
Swiss francs).
The retrospective analysis of Read et al545 found
shorter length of stay associated with thoracoscopy
with talc pleurodesis (4.6 ± 3.3 days) compared to
the tube thoracostomy (13.9 ± 5.9 days).
Belani et al546 found talc to be the most effective
pleurodesis agent, however unlike the other studies
it found talc to be more costly than bleomycin,
mainly due to the need for operating theatre and
anaesthesiology. The additional 15 symptom-free
days associated with talc were at a cost of $308
per day.
137
All of the studies compared talc administered
surgically with bleomycin administered by bedside
thoracotomy. Hence it is not possible to separate
the effects of the sclerosing agent from those
pertaining to the type of procedure.
12.14.4 Chronic indwelling pleural catheter versus
chest tube and sclerosis in the treatment of
malignant pleural effusion
The management of malignant pleural effusions by
indwelling pleural catheter was compared with chest
tube and sclerosis 547. When patients were treated
with outpatient pleural catheter, the mean charge
was lower ($3,391±$1,753) than the inpatient
charges for patients treated with chest tube and
sclerosis ($7,830±4,497) (p<0.001). The difference
occurred due to seven days higher mean length of
stay with the treatment of chest tube and sclerosis.
There was no difference in survival between both
treatment groups (see Table 171). However, if pleural
catheter was placed in an inpatient basis, the
charges would be higher ($11,188±7,964) than that
for chest tube and sclerosis.
12.14.5 Conclusions and Discussions
The economic evidence found from the literature review
for the management of malignant pleural effusions was
not specific to lung cancer patients. No economic
evidence based on the UK health system was found.
Three economic analyses (two cost-effectiveness and
one resource use) concluded that talc was a dominant
strategy over bleomycin for the management of
malignant pleural effusions and a fourth study
indicated that talc was more costly but may be costeffective. Outpatient pleural catheter could be costsaving. However, this retrospective study measured
hospital charges, which do not reflect the true costs.
The other reviewed studies were conducted in
different health settings (Canada and the
Netherlands) and these technologies may not be
applicable to the UK NHS practice. They were
restricted in their sample size. The studies were not
randomised and patients were self-selecting, which
may be a cause of bias. Further trials and economic
evaluations are needed to compare different forms of
palliative treatments of lung cancer patients that are
more commonly available in UK healthcare context.
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12.15 Recommendations
12.15.1 Clinical Practice Recommendations
Supportive and palliative care of the patient should
be provided by general and specialist palliative care
providers in accordance with the NICE guidance
‘Improving supportive and palliative care for adults
with cancer’. [D(GPP)]
Patients who may benefit from specialist palliative
care services should be identified and referred
without delay. [D(GPP)]
External beam radiotherapy should be considered for
the relief of breathlessness, cough, haemoptysis or
chest pain. [A]
Opioids, such as codeine or morphine, should be
considered to reduce cough. [A]
Debulking bronchoscopic procedures should be
considered for the relief of distressing large-airway
obstruction or bleeding due to an endobronchial
tumour within a large airway. [D]
Patients with endobronchial symptoms that are not
palliated by other means may be considered for
endobronchial therapy. [D]
Patients with extrinsic compression may be
considered for treatment with stents. [D]
Non-drug interventions based on psychosocial
support, breathing control and coping strategies
should be considered for patients with
breathlessness. [A]
Non-drug interventions for breathlessness should be
delivered by a multidisciplinary group, co-ordinated
by a professional with an interest in breathlessness
and expertise in the techniques (for example, a
nurse, physiotherapist or occupational therapist).
Although this support may be provided in a
breathlessness clinic, patients should have access to
it in all care settings. [D(GPP)]
Patients with troublesome hoarseness due to
recurrent laryngeal nerve palsy should be referred to
an ear, nose and throat specialist for advice.
[D(GPP)]
PALLIATIVE INTERVENTIONS AND SUPPORTIVE AND PALLIATIVE C ARE
Patients who present with superior vena cava
obstruction should be offered chemotherapy and
radiotherapy according to the stage of disease and
performance status. [A]
Stent insertion should be considered for the
immediate relief of severe symptoms of superior
vena caval obstruction or following failure of earlier
treatment. [B]
Corticosteroids and radiotherapy should be
considered for symptomatic treatment of cerebral
metastases in lung cancer. [D]
Other symptoms, including weight loss, loss of
appetite, depression and difficulty swallowing,
should be managed by multidisciplinary groups that
include supportive and palliative care professionals.
[D(GPP)]
Pleural aspiration or drainage should be performed
in an attempt to relieve the symptoms of a pleural
effusion. [B]
Patients who benefit symptomatically from aspiration
or drainage of fluid should be offered talc
pleurodesis for longer-term benefit. [B]
For patients with bone metastasis requiring
palliation and for whom standard analgesic
treatments are inadequate, single-fraction
radiotherapy should be administered. [B]
Spinal cord compression is a medical emergency and
immediate treatment (within 24 hours), with
corticosteroids, radiotherapy and surgery where
appropriate, is recommended. [D]
Patients with spinal cord compression should have
an early referral to an oncology physiotherapist and
an occupational therapist for assessment, treatment
and rehabilitation. [D(GPP)]
12.15.2 Research Recommendations
The management of common symptoms such as
cachexia, anorexia, fatigue and breathlessness
experienced by patients with lung cancer needs
further research. Specifically, research is required into
clinically meaningful outcome measures for the
treatment of the cachexia-anorexia syndrome. For
example, does the level of physical activity as
measured by an activity meter relate to performance
status, quality of life and use of health and social
care services?
Further research is required to determine the benefit
of non-drug treatments for breathlessness, compared
to no treatment or other drug based treatments, in
terms of symptom relief and performance status for
patients with lung cancer.
The effect of bisphosphonates in the relief of pain
and skeletal morbidity from bone metastasis in lung
cancer needs further research.
139
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SERVICE ORGANISATION
care physicians, clinical and medical oncologists,
thoracic surgeons, geriatricians, cellular pathologists,
radiologists, radiographers, occupational therapists,
specialist nurses, physiotherapists, dieticians,
pharmacists and clinical psychologists.
13 Service Organisation
13.1
Introduction
13.2
These guidelines are concerned with evidence based,
best practice recommendations for the diagnosis and
treatment of lung cancer. The logistics of how to
organise the service to best provide these
interventions is outside of this document’s remit.
Details on service issues can be found in the Manual
of Cancer Service Standards498 and the NHS Cancer
Plan549. There is however, some evidence reviewed in
this chapter relating to specific organisational issues
affecting the outcomes of patients with lung cancer.
These are: the effects of using a multi-disciplinary
team structure, one or two-stop clinics for the
diagnosis of the disease, the involvement of specialist
nursing staff in the care pathway and the effect of
delays on treatment outcomes. We have also assessed
the effectiveness of different follow up strategies.
The most important change in the care of lung
cancer patients in the last decade has been the
development of integrated multi-disciplinary teams
(MDTs) to facilitate their diagnosis and management
(Calman-Hine Report548). Patients require a
combination of a rapid diagnosis, empathetic
handling and the confidence that their treatment is
of a high quality. These objectives can be realised by
optimising local service arrangements.
Before the Calman-Hine reforms, a regional
randomised stratified analysis of the management
pathways of 400 patients with an eventual diagnosis
of lung cancer, found 80 such pathways19. More than
50% of patients did not present to hospital with a
chest x-ray suspicious of lung cancer. There were
substantial delays between diagnosis and treatment
and many patients never saw a lung cancer
specialist. This study illustrated that by utilising
organised pathways, a better standard of care may
be provided. The new pathways should ensure that
all patients see a lung cancer specialist (usually a
chest physician), that delays - especially to
bronchoscopy, fine needle aspiration (FNA) or
computerised tomography (CT) - are minimised and
to ensure that all patients have a management plan
as a result of input from a chest physician, a
specialist nurse (including those from palliative care),
a radiologist, medical and clinical oncologists and
(usually) a surgeon. Such service changes have not
been subject to randomised controlled trials and
comparative studies pre and post reform are difficult.
Although some evaluation may emerge, there is at
present a professional consensus that patient care
both organised around an MDT and consistent with
the Manual of Cancer Service Standards498, is
superior to conventional non-specialised and
fragmented care.
13.3
Methodology
In this chapter, the NCC-AC and SIGN both carried
out sections of the literature search and appraisal.
The NCC-AC performed searches on rapid access
clinics, specialist nurse support, multidisciplinary
teams, timing of treatment and the patient
perspective. SIGN carried out the search for follow-up.
The search strategies can be found in appendix six.
The methodology used to appraise the papers was
described earlier in section 2.1.2.
13.4
Multi- Disciplinary Teams (MDTs)
As input from many different professionals is
required in the management of patients with lung
cancer, MDT’s are especially appropriate and can
reduce delays caused by cross-referral between
specialists. These teams may include, general
physicians and nurses, chest physicians, palliative
randomised pilot study on the use of two stop
clinics. This study randomised 88 patients with
suspicion of lung cancer to attend a two-stop clinic
or to receive conventional care. The study found
that the time from presentation to treatment was
four weeks shorter (p=0.0025) in the two-stop
clinic arm of the trial552. Although no significant
difference was noted in survival it seems intuitive
that faster treatment would lead to more patients
being suitable for radical treatment and therefore
improvement in survival. No significant difference
was found in the overall quality of life between
the two groups, but a survey of satisfaction found
that patients in the two-stop clinic arm were more
satisfied with the organisation of investigations
(p=0.07) and their personal experience of care
(p=0.09)552(Level 1+). Please see Table 171
for details.
The importance of MDTs has been noted by a
number of previous reports: the Calman- Hine
report548, Improving Outcomes in Lung Cancer (NHS
Executive)496, NHS Cancer Plan549, Clinical Oncology
Information Network guidelines525, British Thoracic
Society recommendations on organising care for lung
cancer patients550 and the American College of Chest
Physicians551 (Level 4). Expert opinion and formal
consensus in the above reports suggests that:
Issues examined in this review
>
>
All patients with a likely diagnosis of lung
cancer should be referred to a member of a
lung cancer multi-disciplinary team (usually a
chest physician).
A survey of 61 lung cancer patients and carers
carried out by the Roy Castle Lung Cancer
Foundation and the National Collaborating Centre
for Acute Care (see section 13.9.1 for details) found
that one of the main opinions of the group was a
desire for speedy access to services (Level 3).
The care of all patients with a working diagnosis
of lung cancer should be discussed at a lung
cancer multi-disciplinary team meeting.
It is important that there is adequate administrative
support for MDTs. We found no studies on the clinical
or cost effectiveness of MDTs in lung cancer with
regard to improvement of survival or quality of life.
13.5
We found no economic evidence in this area.
In conclusion, integrated One-stop or Two-stop
clinics for the investigation of putative lung cancer
patients are associated with a reduction in
diagnostic delay and patient anxiety. They should be
utilised where possible.
Early Diagnosis Clinics
Patients with a putative diagnosis of lung cancer are
often subject to multiple appointments and
potentially considerable delays in the diagnostic
pathway. An initial consultation in an outpatient
clinic may result in separate appointments for a daycase bronchoscopy, a staging CT scan, a CT guided
FNA, full pulmonary function tests, and then a
separate clinic meeting to discuss the results. To
overcome these problems, units have developed
integrated diagnostic days. Patients are seen for the
initial consultation and then may receive subsequent
investigations (CT/ bronchoscopy/ FNA/ lung
function tests) on either the same day (one stop
clinic) or on a second day (two stop clinic).
We found no evidence on the effect of using a
one-stop clinic approach in the treatment of lung
cancer. The literature search retrieved one
141
13.6
Specialist Nurse Support
We did not find any evidence on whether the
involvement of specialist nurse support during
diagnosis or treatment of patients with lung cancer
had an effect on quality of life or survival. The British
Thoracic Society (BTS) recommend that all cancer
units should have a trained nurse who would see
patients at or after diagnosis and then provide
continuing support or establish a link with the
general practitioner or community team550 (Level 4).
A survey of 61 lung cancer patients and carers carried
out by the Roy Castle Lung Cancer Foundation and
the National Collaborating Centre for Acute Care
supports this recommendation. Respondants placed
importance on having access to a lung cancer
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SERVICE ORGANISATION
support nurse throughout the treatment journey (see
section 13.9.1 for details) (Level 3). No economic
evidence was found in this area.
delay before surgery. No studies had a breakdown of
results showing the effect of the delay before
chemotherapy. One study looked at the delay before
treatment of any kind (radiotherapy, surgery or
chemotherapy). Studies tended to use different start
and end points of the time measured and few
measured survival or quality of life.
There is some evidence on the involvement of
nursing support during follow up (see section 13.8).
The guideline development group supports the
findings of the BTS report550 and recommends that:
13.7.2
>
All cancer units/centres should have one or
more trained lung cancer nurse specialists to see
patients before and after diagnosis, to provide
continuing support, and to facilitate
communication between the MDT, secondary
care and the general practitioner and the
community team. Their role includes the
availability for patients to access advice and
support whenever they need it
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
chemotherapy553. Guidence on timing has also been
issued by the Department of Health in the National
Manual of Quality Measures for Cancer554 and the
Welsh Assembly Government in the All Wales
minimum standards for lung cancer555. Patients
should be treated within 31 days of the decision to
treat and within 62 days of their urgent referral. In
this section, we investigated the effect that delays in
diagnosis or treatment might have on survival and
quality of life.
The time for a tumour to double in size has been
estimated from chest radiographs of solitary
pulmonary nodules to be about 100 days for NSCLC
and about 30 days for SCLC32. It seems intuitive that
as the tumour grows, the chances of curative
treatment or prolongation of survival would
decrease. Although there is little definitive evidence
in this area, some observational studies have
reported that this is the case (Table 173).
13.7.1
Time before surgery
Patients not suitable for radical treatment, and not
having symptoms demanding immediate treatment,
were randomised in an RCT to receive immediate
palliative radiotherapy or palliative radiotherapy
delivered symptomatically559. No significant
differences were found in symptom control, quality
of life or survival (Level 1+).
A systematic review that reported observational
results mostly from breast cancer and head and neck
cancer studies found that delays in treatment were
>
Patients who cannot be offered curative
treatment, can be either observed until
symptoms arise and then treated with palliative
radiotherapy or treated with palliative
radiotherapy immediately.
Further research is necessary to determine:
Two studies examined whether patients found to be
at later stages of the disease had experienced longer
delays. One found that there was no significant
relationship562 and the other found that stage III and
IV patients had experienced significantly longer
delays563 (Level 3).
>
13.8
Time before radiotherapy
The study by O’Rourke and Edwards (2000)557 found
that whilst on the waiting list 21% of candidates for
radical radiotherapy had significant disease
progression which meant that the tumour could no
longer be encompassed by the radiation port for
radical treatment. The delay ranged from 18-131
days (median 54 days). Tumour growth ranged from
0-373% in this time although this was not
significantly correlated with delay (Level 3). Another
observational study noted that 95% of patients who
were referred for continuous hyperfractionated
accelerated radiotherapy were found not to be
suitable for inclusion in an RCT which was being
conducted558. The main reasons were poor general
condition (37%), large tumour size (27%) or
extrathoracic metastases (19%). The median delay
between diagnosis and treatment was five weeks
(range 3-9 weeks) (Level 3).
delay, according to Welsh Assembly Government
and Department of Health recommendations
(within 31 days of the decision to treat and
within 62 days of their urgent referral)554,555
Only one study looked at the influence of the delay
until surgery on survival on 1082 patients561. No
significant relationship was found although 34
patients were excluded because their surgery was
>154 days after diagnosis (Level 3).
Time before any treatment
Studies considered for the review
We found three studies that looked at delay before
radiotherapy and three studies that looked at the
13.7.4
One study that examined the influence of treatment
delay on survival did not find a significant
relationship using multivariate analysis556. This study
looked at time from referral to treatment by
radiotherapy, surgery or chemotherapy but did not
examine delay in referral or patient delay, which may
have an effect on survival (Level 3).
13.7.3
13.7
associated with higher five year local recurrence
rates560. Although they found very few studies on
lung cancer, the results may be applicable (Level 3).
143
13.7.5
Summary of impact of waiting times
for treatment
No economic evidence was found in this area.
The guideline development group concluded that:
>
Patients with lung cancer suitable for radical
treatment, chemotherapy or requiring
radiotherapy or ablative treatment for relief of
symptoms, should be treated without undue
Follow Up
This section refers to the surveillance of patients in
remission after treatment. SIGN carried out a search
for literature on strategies for following up patients
(see chapter 2).
The disagreement in the results for all treatment
modalities may well be due to the heterogeneity in
the definitions of ‘delay’ which studies have used.
Delay can arise for many reasons including delay in
referral, patient delay and hospital delay. These
different delays have not been fully addressed by the
past studies in this area for lung cancer. Due to the
high incidence of distant metastases compared with
other cancers, it may be difficult to identify the
impact of waiting times on reduced local control and
subsequent outcomes. This is an area where future
research would be useful.
Although there is a lack of consistent clinical
evidence, in terms of patient preferences and
reduction of anxiety at a difficult time it is important
to reduce the time taken as much as possible.
Patient views are discussed in further detail in the
next section.
The impact of the time between first symptom
(or first detection if asymptomatic) and
treatment, on survival and quality of life of lung
cancer patients.
No systematic reviews were found but one
randomised controlled trial564 on nurse led follow up,
and one cohort study565 on smoking cessation were
identified and are discussed below. The search
identified no evidence on specific follow up
strategies after different types of treatment (surgical,
radiotherapy, chemotherapy or palliative), or whether
certain routine tests should be performed. However
the guideline development group decided to make
some good practice points where no high quality
evidence was retrieved.
13.8.1
General follow-up issues
Follow-up Plan
The guideline development group wished to make a
good practice point that after finishing radical
treatment, a personal follow-up plan should be
discussed and agreed with patients, following
discussion with all healthcare professionals involved
in the patient’s care. GPs should also be informed
of the plan.
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Smoking Cessation
No randomised controlled trials were identified on
the effect of smoking cessation on the outcomes of
treatment. The literature search did identify one
cohort study565 that examined the difference in
outcomes of patients who were and were not
smoking within one month of their surgery (see
Table 174). Those patients who were still smoking
within 1 month of the operation were 2.7 times
more likely to have major pulmonary events 95% CI
1.18 to 6.17 p=0.018 (Level 2++). An additional
cohort study, Nakagawa et al566 reported on the
impact that smoking status had on the incidence of
postoperative pulmonary complications (PPC’s) after
pulmonary surgery. The authors reported that the
cessation of smoking preoperatively has a positive
impact on the incidence of PPC’s. Patients who had
ceased smoking for more than 5 weeks experienced
a decrease in PPC’s although it is unclear if this was
statistically significant (level 2+). However, there is
no data on the effect of smoking cessation on any
other outcome measures such as survival or quality
of life after surgery. Evidence on the effect on
smoking during radiotherapy treatment for SCLC is
discussed in chapter 11.
One consensus report recommended that patients
should stop smoking because there is a higher risk of
a second primary cancer in patients who remain
active smokers after treatment for a first primary
lung cancer567 (Level 4).
The guideline development group decided to
recommend that patients with lung cancer, and
particularly those with a better prognosis should be
encouraged to stop smoking and should be given
information on the NHS stop smoking services. Any
encouragement of cessation of smoking should be
sensitively approached.
Nurse led follow-up
One randomised controlled trial was identified on
nurse led follow up564. This trial recruited patients
thought to have a life expectancy of greater than
three months after primary treatment. One group
of patients was randomised to nurse led follow up
of outpatients, while the other group received
conventional medical follow up (see Table 175).
SERVICE ORGANISATION
Although there was no significant difference in
survival or overall quality of life score, the nurse led
follow up was associated with less severe dyspnoea
at 3 months (p=0.03), better scores for emotional
functioning at 12 months(p=0.03) and less
peripheral neuropathy at 12 months (p=0.05)
(Level 1++).
After completion of their treatment, patients with an
expectation of life greater than three months should
have access to protocol controlled nurse led follow
up as an option.
13.8.2 Follow up after Surgery
No studies were retreieved that looked specifically at
survival and quality of life outcomes for routine
follow up after surgery. However, the guideline
development group felt it was reasonable to follow
up patients for six months after surgery to check for
postoperative complications. A recent consensus
statement567 on follow up suggested that follow up
should take place at a frequency suitable to measure
the adverse effects of the treatment and
recommended that patients receive a chest x-ray at
the follow up visit (Level 4).
The consensus statement567 went on to recommend
that, after the initial visit, patients should be
followed up every three months for the first two
years, and then every six months up to five years
(Level 4). There is no evidence that follow up beyond
five years is beneficial.
There is debate about the merits of using a
symptom led follow up strategy (where imaging is
only performed for patients with new symptoms or
signs) as opposed to having regular appointments
with patients. Evidence in this area is conflicting.
Three cohort studies were identified568-570 in the
NCC-AC economics search, that examined survival
after regular or symptom related follow up (see
Table 176 and Table 177). Two studies found no
significant difference in survival568,570 and one found
better survival in those patients followed up
regularly569. (Level 2+). Quality of life was not
measured by any of the studies and no overall
conclusion can be made about the best strategy for
follow up.
13.8.3 Follow up after Radical Radiotherapy
A recent consensus document567 found that the
interval between end of treatment and follow up
should be related to anticipated toxicity from the
treatment (Level 4). The search identified no further
evidence relating to follow up after radical
radiotherapy. The guideline development group
considered that it was good practice for these
patients to be followed up routinely, with thoracic
imaging, for nine months after the completion of
treatment in order to treat any pneumonitis as
appropriate, identify the need for further
radiotherapy and the prognosis.
There is no evidence that follow up beyond five years is
beneficial for this group of patients. Six monthly follow
up with radiographs in well patients essentially offers a
form of screening for new lesions – particularly likely if
patients continue to smoke. However, there appears to
be no evidence that a policy of regular review is better
than symptom-led review.
13.8.4 Follow up after Palliative Radiotherapy or
Chemotherapy
No evidence on the use of follow up after palliative
radiotherapy or chemotherapy was found. The
guideline development group considered that is was
good practice to follow up patients routinely one
month after the end of treatment. The examination
should include chest x-ray, if clinically indicated. A
recent consensus document567 also suggested that
the interval between end of treatment and follow up
should be related to anticipated toxicity from the
treatment. They also went on to suggest that a chest
x-ray should be carried out and that follow up visits
should continue every 1-2 months for the first six
months (Level 4).
The GDG also wanted to make the following
research recommendation:
>
For patients who have had attempted curative
treatment and have completed their initial follow
up, trials should examine the duration of follow
up and whether regular routine follow up is
better than symptom led follow up in terms of
survival, symptom control and quality of life.
145
13.8.5 Economics of Follow-up after curative surgery
Five studies were selected for tabulation that
analyzed follow-up of NSCLC patients who had
undergone curative resection. There was no evidence
on follow-up after other treatment modalities, e.g.
chemotherapy, radiotherapy, combination or
palliative treatment.
The literature review showed that there is diversity of
follow-up after complete resection for lung cancer. See
Table 176 and Table 177 for the definition of each
follow-up protocol used and details of the studies.
Routine follow-up versus symptom-related follow-up
Three studies assessed the cost effectiveness of
regular follow-up of patients who underwent
resection for NSCLC using retrospective data568-570.
Egermann et al.568 analysed 10-year retrospective
data for 563 NSCLC patients who had operated with
curative intent. It was assumed that follow-up could
provide a chance for a second curative treatment.
Therefore the life-years (LYs) gained was calculated
for those patients (n=23) who underwent further
operation with curative intent during the follow-up
period. The improvement in life expectancy of those
patients was low and not significant (0.05 LYs
gained). They added the costs of re-operations of the
patients into the costs of follow-up procedures. The
cost effectiveness of regular follow-up was SF90,000
(£39,000) which was above the upper limit of
acceptable cost-effectiveness (£30,000). Hence, the
regular follow-up was not cost-effective.
Westeel et al.569 produced contrary results, through
the analysis of 14-year retrospective data for the
similar group of patients in France. The mediandisease free survival (19 months) for the whole study
population was assessed and costs were calculated
for this period. Regular follow-up improved life
expectancy (0.11 LYs gained) and was found to be
cost-effective ($16,154)569.
Younes et al.570 carried out a cost-effectiveness
analysis on strict versus symptom related follow-up.
No significant improvement in survival was obtained
with strict follow-up. Symptom related follow-up was
less costly than strict follow-up. Hence, symptom
related strategy was cost-saving.
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LUNG C ANCER
SERVICE ORGANISATION
Non-intensive versus intensive follow-up
Virgo et al.571 identified specific follow-up strategies
from the literature. By using Medicare hospital
charges, they estimated the cost for a single patient
with lung cancer followed up for five years. They
assumed that there was no improvement in life
expectancy with intensive follow-up. They concluded
that non-intensive follow-up was cost-saving.
Nurse-led telephone follow-up versus
outpatient follow-up
The only study conducted in the UK was Moore et
al.’s analysis that aimed to assess the costs and
effectiveness of nurse-led follow- up versus
conventional follow-up of patients with lung
cancer who had completed their initial
treatment564. According to the results of the
randomised controlled trial, there was no
significant difference between the two groups in
terms of the overall quality of life, median survival
time and cost per patient. However, patients’
satisfaction was higher with nurse-led follow-up. In
addition, the intervention group had significantly
fewer medical consultations with a doctor
(p=0.004) at 3 months, fewer radiographs taken at
3 months (p=0.04) and 6 months (p=0.03). It was
concluded than nurse-led follow-up led to costsavings and higher patient satisfaction.
Discussion and Limitations of Economic studies
The literature indicates that routine follow-up of
patients after curative surgery for NSCLC adds to
overall health service costs. The studies found
that follow-up was associated only with small
improvements in life expectancy. They differed
substantially in terms of the estimated costeffectiveness of follow-up (£16,000-£30,000).
These differences were caused by the approach
taken for the assessment of the clinical
effectiveness and costs of the follow-up in
each study.
568
569
and Westeel et al both
Egermann et al
estimated from their respective cohorts that about
4% of patients benefited from follow-up by being
diagnosed with an operable new lesion. The crucial
difference between the studies was the assumption
about the life-years gained that would be
attributable to the diagnosis of new cancer during
follow-up.
Egermann et al 568 estimated a gain of 9 months by
comparing the life expectancy of those who had a
second resection with those who didn’t. This could
be an under-estimate because patients that did have
a second re-section probably would have had a lower
than average life expectancy in the absence of the
second resection. However, their overall estimate of
effectiveness might be an under-estimate because
included were the patients who were identified due
to symptoms rather than the follow-up procedures.
569
Westeels et al estimated a gain of 3 years because
all seven patients were alive 3 years after their
recurrence – again this is a biased estimate of the
true incremental gain in life expectancy. This does
seem to be an over-estimate, as it is the same as the
estimated life-expectancy of patients after their first
resection142 and also it doesn’t subtract the life
expectancy that they would have had if they had not
had a second re-section. In addition to apparently
under-estimating the effectiveness of follow-up, they
clearly under-estimate the costs substantially by not
including the cost of the additional re-sections (a
crucial omission).
It is not possible to conclude on the costeffectiveness of follow-up of NSCLC patients after
curative surgery because there are no precise
estimates of the improvement in life expectancy
associated with second re-section in asymptomatic
patients. However, the evidence presented overall
does not point to routine follow-up being costeffective, as the only study to show it to be costeffective clearly under-estimated the incremental
cost-effectiveness ratio. Of course cost, effectiveness
and cost-effectiveness are dependent on the nature
of the follow-up protocol and few follow-up
protocols have been evaluated.
One UK study564 based on a randomised controlled
trial concluded that nurse-led follow-up by telephone
was cost saving without affecting the quality of life
or survival of patients when compared with
conventional outpatient follow-up. This might be a
more cost-effective option that outpatient follow-up.
There is diversity of follow-up after complete
resection of lung cancer. The ideal surveillance has
not been defined. Future research based on
randomised controlled trials is needed to compare
the effectiveness and cost-effectiveness of different
follow-up strategies. The studies examined follow-up
of lung cancer patients only after resection. There
was no evidence on follow-up after chemotherapy,
radiotherapy, combination therapy or palliative care.
13.9
people with lung cancer are not only elderly but also
less fit than their contemporaries, often suffering
from smoking-related illnesses, they may be too ill to
attend meetings.
However, certain organisations (such as the Roy
Castle Lung Foundation and Cancer Relief
Macmillan’s CancerVOICES) are involved in patient
advocacy issues for lung cancer patients and
endeavour to harness the spectrum of patient views
with an eye to shaping future cancer services
and research.
The Patient’s Perspective
The 1995 Department of Health publication, A
Policy Framework for Commissioning Cancer
Services548, recommended that services be ‘patient
centred’. This document paved the way for cancer
patient involvement in service provision.
Recently strategies have been produced, setting a
framework to achieve this. In England, the relevant
document is Involving Patients and the Public in
Healthcare (2001)572 and in Wales, Signposts - A
Practical Guide to Public and Patient Involvement in
Wales (2001)573. These strategies underline the
benefits of service user involvement in improving
outcomes of health care, increasing patient
satisfaction and in strengthening public confidence
in the NHS. They provide a framework for patients
and the public to be involved both at a collective /
strategic level and on an individual basis.
Involvement in service provision is, broadly speaking,
achieved in two ways:
>
Patient consultation through surveys and
questionnaires or through patient focus groups.
>
Active partnership with user representatives as
members of committees or working groups.
Though lung cancer is the most common cancer
diagnosis in the UK, there are currently very few
patient representatives involved in service planning
and delivery. There are, inherent within this disease,
a number of barriers to such patient involvement.
With a median survival of four months from
diagnosis, around 80% of patients are dead at one
year, with only around 5% surviving five years3, the
average lung cancer patient may not survive the
length of the working group. Furthermore, as most
147
13.9.1
Lung Cancer Patient Opinions
Within the NHS, the experiences and needs of
patients and families living with a diagnosis of lung
cancer have been collected in the following
initiatives:
Cancer Service Patient Survey574
In July 2002 a survey on cancer services eliciting the
views of more than 65,000 patients (74% of those
approached), was published. 4,000 (6%) of
respondents were lung cancer patients. The survey
showed that, in most cases, patients were receiving
high levels of care - for example, 86% had complete
confidence in their doctors; 79% felt they were
treated with respect and dignity at all times.
However, the survey highlighted variations between
Trusts (Level 3).
The patients surveyed came from 172 NHS Trusts in
England and questions related to care received
between July 1999 and June 2000. As the National
Cancer Plan (2000)549 was published after the
survey was carried out, the findings will act as a
baseline, upon which improvements can be
measured at the individual Trust level.
Of the 65,000 views, only 4000 (6%) were from
lung cancer patients.
Cancer Services Collaborative Patient
Experience Projects
In England, as part of the Cancer Services
Collaborative, a number of projects have measured
how patients rate their care and have monitored the
impact of system changes. A key area has been to
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improve communication between patients and their
clinical team. This has been achieved in a variety of
ways, including written patient information booklets,
patient held records and taped consultations. The
Service Improvement Manuals (produced by the NHS
Modernisation Agency), including the Lung Cancer
Manual, give details of individual projects and how
changes have resulted in improvement.
Patients with lung cancer have reported experiencing
greater levels of unmet psychological, social and
economic needs than other cancer groups575 (Level
3). They have also been less satisfied, than other
people with cancer, with the care received576 (Level
3). A national needs assessment of lung cancer
patients and carers, undertaken on behalf of
Macmillan Cancer Relief, identified a myriad of
deficiencies in the organisation of care delivery and
in areas of information and support20.
As part of this Guideline process, The Roy Castle
Lung Cancer Foundation (RCLCF), in association with
the National Collaborating Centre for Acute Care,
collected experiences and opinions from 61 lung
cancer patients and carers. Full details of this are
available on the RCLCF website (www.roycastle.org).
General themes expressed by this group, on the
organisation of services, included:
>
>
Accessing services – respondents expressed a
desire to have speedy access to specialist
services, with the overwhelming majority
favouring the rapid access diagnostic clinic
approach. Many also reported a willingness to
travel considerable distances to access the most
specialist services.
Respondents also placed emphasis on seeing the
same doctor at every hospital visit.
>
The importance of accessing a lung cancer
support nurse, throughout the treatment journey
>
Continuing care – Few in this group had
accessed community based support services,
those who did rated them highly.
More work is needed to establish the specific
opinions of lung cancer patients and carers, on the
organisation of lung cancer services.
SERVICE ORGANISATION
13.9.2 Monitoring the Effects of Patient Involvement
As with the Cancer Services Collaborative Patient
Experience Projects, there are many individual
examples of patient views being surveyed and the
results contributing to service changes in a number
of settings577 (Level 3). There is, however, no
evidence of such involvement directly improving the
quality of care or the outcome for patients. The
challenge, therefore, as lay involvement continues to
be embedded within health services, is to ensure
that it is appropriate, representative and having its
impact monitored.
The review of NHS Cancer Care in England and
Wales, published in December 2001 and undertaken
by the Commission for Health Improvement (CHI)
and the Audit Commission (AC)22, concluded that
cancer services still have a long way to go before
they are truly “patient focused”. This review, however,
only addressed the progress in implementing
recommendations of the 1995 Calman-Hine report,
A Policy Framework for Commissioning Cancer
Services548. It did not take into account the multiple
policy changes and initiatives, which have taken
place in the intervening years.
At a local level, systems need to be in place to ensure
that the opinions and experiences of lung cancer
patients and carers are collected. Further work is
needed to ensure that such patient involvement is
meaningful and that lung cancer services improve as
a result. The guideline development group made a
good practice point that the opinions and
experiences of lung cancer patients and carers should
be collected and used to improve the delivery of lung
cancer services. Patients should receive feedback on
any action taken as a result of such surveys.
149
All patients with a likely diagnosis of lung cancer
should be referred to a member of a lung cancer
MDT (usually a chest physician). [D]
Patients who have had attempted curative surgery
for NSCLC, or radical radiotherapy should be
followed up routinely by a member of the MDT for
up to 9 months to check for post-treatment
complications. Thoracic imaging should be part of
the review. [D]
The care of all patients with a working diagnosis of
lung cancer should be discussed at a lung cancer
MDT meeting. [D]
For patients who have had attempted curative
surgery for NSCLC, any routine follow-up should not
extend beyond 5 years. [D]
Early diagnosis clinics 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. [A]
Patients who have had palliative radiotherapy or
chemotherapy should be followed up routinely at 1
month after completion of treatment. A chest X-ray
should be part of the review if clinically indicated. [D]
All cancer units/centres should have one or more
trained lung cancer 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. [D]
Patients with lung cancer – in particular those with a
better prognosis – should be encouraged to stop
smoking. [D]
13.10 Recommendations
13.10.1 Clinical Practice 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). [D]
Patients who cannot be offered curative treatment,
and are candidates for palliative radiotherapy, may
either be observed until symptoms arise and then
treated, or be treated with palliative radiotherapy
immediately. [A]
When patients finish their treatment a personal
follow-up plan should be discussed and agreed with
them after discussion with the professionals involved
in the patient’s care. GPs should be informed of the
plan. [D(GPP)]
After completion of their treatment, patients with an
expectation of life of more than 3 months should have
access to protocol-controlled, nurse-led follow-up. [A]
The opinions and experiences of lung cancer patients
and carers should be collected and used to improve
the delivery of lung cancer services. Patients should
receive feedback on any action taken as a result of
such surveys. [D(GPP)]
13.10.2 Research Recommendations
For patients who have had attempted curative
treatment and have completed their initial follow up,
trials should examine the duration of follow-up and
whether regular routine follow-up is better than
symptom-led follow-up in terms of survival, symptom
control and quality of life.
The impact of the time between first symptom (or
first detection if asymptomatic) and the treatment of
lung cancer on patients’ survival and quality of life
should be investigated.
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14 Priority Areas for Audit
A national cancer dataset has been developed by the NHS Information Authority in collaboration with clinicians and the
Department of Health. A data subset for lung cancer has been derived by the Intercollegiate Lung Cancer Group to
support the National Lung Cancer Data Project (LUCADA), a national ongoing audit programme for lung cancer. The
guideline development group notes that many of the recommendations within the complete guideline are auditable
through this dataset. All English Cancer Networks are being encouraged to take part in this programme which began its
national roll-out in July 2004. A copy of this dataset and further details of the LUCADA project can be found at:
http://www.nhsia.nhs.uk/ncasp/pages/audit_topics/cancer.asp?om=m1#lung
or:
http://www.rcplondon.ac.uk/college/ceeu/ceeu_lung_home.htm
PRIORIT Y AREAS FOR AUDIT
Recommendation
Criterion
All patients diagnosed with lung cancer
should be offered information, both verbal
and written, on all aspects of their
diagnosis, treatment and care. This
information should be tailored to the
individual requirements of the patient and
audio and videotaped formats should also
be considered.
Percentage of patients diagnosed with lung
cancer that are offered information, both
verbal and written, on all aspects of their
diagnosis, treatment and care. This
information should be tailored to the
individual requirements of the patient and
audio and videotaped formats should also
be considered.
Urgent referral for a chest X-ray should be
offered when a patient presents with:
Percentage of patients that present to a GP
with the following symptoms and signs who are
offered an urgent referral for a chest X-ray:
151
Definition of terms
> haemoptysis, or
> haemoptysis, or
> any of the following unexplained or
persistent (that is, lasting more than
3 weeks) symptoms or signs:
> any of the following unexplained or
persistent (that is, lasting more than 3
weeks) symptoms or signs:
– cough
The audit criteria highlighted below are based on the recommendations selected as key priorities for implementation. Only
two of these highlighted criteria fall within the LUCADA dataset. We have specified audit criteria, exceptions and
definitions of terms for those recommendations that are not included LUCADA.
– cough
– chest/shoulder pain
– chest/shoulder pain
– dyspnoea
– dyspnoea
– weight loss
– weight loss
– chest signs
– chest signs
– hoarseness
– hoarseness
– finger clubbing
– finger clubbing
– features suggestive of metastasis
from a lung cancer (for example in
brain, bone, liver or skin)
– ervical/supraclavicular
lymphadenopathy
– features suggestive of metastasis from
a lung cancer (for example in brain,
bone, liver or skin)
– ervical/supraclavicular
lymphadenopathy
If a chest x-ray or chest CT suggests lung
cancer (including pleural effusion and slowly
resolving consolidation), patients should be
offered an urgent referral to a member of the
lung cancer multidisciplinary team (MDT)
usually a chest physician.
Percentage of patients with a chest x-ray or
chest CT suggestive of lung cancer (including
pleural effusion and slowly resolving
consolidation) that are offered an urgent referral
to a member of the lung cancer
multidisciplinary team, usually a chest physician.
Every cancer network should have a system
of rapid access to FDG-PET scanning for
eligible patients.
Percentage of eligible patients within the
cancer network that have a FDG-PET scan.
Rapid – rapid enough to
ensure time to diagnosis
and treatment standards are
achieved
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BIBLIOGRAPHY
Recommendation
Criterion
Patients with stage I or II NSCLC who are
medically inoperable, but suitable for
radical radiotherapy should be offered the
continuous hyperfractionated accelerated
radiotherapy (CHART) regimen.
Percentage of medically inoperable patients
with stage I or II NSCLC who are suitable for
radical radiotherapy who are treated using
the continuous hyperfractionated accelerated
radiotherapy (CHART) regimen.
Chemotherapy should be offered to
patients with stages III and IV NSCLC
and good performance status (WHO 0,
1 or a Karnofsky score of 80–100) to
improve survival, disease control and
quality of life.
This is covered by the LUCADA dataset.
Non-drug interventions for breathlessness
should be delivered by a multidisciplinary
group, co-ordinated by a professional with
an interest in breathlessness and
expertise in the techniques (for example,
a nurse, physiotherapist or occupational
therapist). Although this support may be
provided within a breathlessness clinic,
patients should have access to it in all
care settings.
Percentage of patients with lung cancer that
experience breathlessness who have access to
support from a multidisciplinary group with
an interest in breathlessness and expertise in
non-drug interventions (for example, a nurse,
physiotherapist or occupational therapist).
The care of all patients with a working
diagnosis of lung cancer should be
discussed at a lung cancer MDT meeting.
Definition of terms
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Appendices 1-8 are provided in a
separate document (CD-ROM attached)
RUNNING HEAD
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