Exercise intervention for people who are surgically treated for lung cancer: A mixed methods study

by

Katy Crandall RN BSc

Submitted for the degree of Doctor of Philosophy

School of Health Sciences

University of Surrey

May 2016

Katy Crandall 2016

Table of contents

Table of contentsiList of tablesvList of figuresviList of abbreviationsviiAbstractixAcknowledgementsxiiDeclarationxviChapter 1: Introduction11.1 Rationale of thesis11.2 Structure of thesis7Chapter 2: Lung cancer102.1 Introduction102.2 Epidemiology102.2.1 Prevalence/ Incidence102.2.2 Risk factors122.2.3 Presenting Symptoms152.3 Screening and initiatives172.3.1 Screening172.3.2 Initiatives to detect lung cancer early212.4 Management and Treatment222.4.1 Diagnosis and prognosis222.4.2 Staging242.4.3 Treatment252.4.3.1 NCSLC262.4.3.2 SCLC372.4.3.3 Emerging therapies392.5 Patient experience of lung cancer and surgical treatment442.5.1 Burden related to lung cancer452.5.2 Burden and needs related to surgical treatment472.6 Conclusion51Chapter 3: Exercise and cancer533.1 Introduction533.2 Exercise intervention in the context of health543.3 Current evidence base for exercise and cancer563.3.1 During and Post-treatment573.3.1.1 Reduced cardiorespiratory fitness583.3.1.2 Muscle strength reduction623.3.1.3 Fatigue663.3.1.4 Decreased Quality Of Life (QOL)723.3.1.5 Depression783.3.1.6 Body composition833.3.1.7 Summary of during and post-treatment evidence873.3.2 Pre-treatment883.3.3 Safety, feasibility and acceptability903.3.4 Exercise guidelines for people with cancer973.4 Exercise intervention for people treated radically for lung cancer1013.5 Behaviour change theory1103.5.1 Health Belief Model1133.5.2 The Transtheoretical Model1153.5.3 The Theory of Planned Behaviour1173.5.4 The Health Action Process Approach (HAPA)1203.6 Conclusion123Chapter 4: Methodology1254.1 Introduction1254.2 More than a method1264.3 Epistemological position1374.4 Mixed methods methodologies1404.5 Rationale for using an exploratory sequential intervention design1454.6 Conclusion149Chapter 5: Methods1505.1 Introduction1505.2 Study Aim and research questions1505.3 Study design1515.3.1 Phase 11515.3.1.1 Part 11525.3.1.2 Part 21585.3.2 Phase 21865.3.2.1 The intervention1875.3.2.2 Sample1895.3.2.3 Recruitment1915.3.2.4 Setting1935.3.2.5 Data collection1945.3.2.6 Data Analysis1955.4 Conclusion196Chapter 6: Phase 1 results1976.1 Introduction1976.2 Summary of phase 1 part 1 (systematic review) results1976.3 Results from phase 1 part 22006.3.1 Characteristics of the Study Sample2016.3.2 Results of analysis2026.3.3 Findings2036.3.3.1 Attitudes and beliefs2056.3.3.2 External factors2196.3.3.3 Intervention design2256.4 Intervention development2396.4.1 Intervention components2406.4.2 Justification of intervention components2466.4.2.1 Time period2466.4.2.2 Components2486.4.3 Outcomes measured2526.5 Conclusion261Chapter 7 Phase 2 results2627.1 Introduction2627.2 Characteristics of the study sample2627.3 Quantitative results2647.3.1 Primary outcomes2647.3.1.1 Recruitment and response rate2647.3.1.2 Adherence2657.3.1.3 Compliance2687.3.2 Secondary outcomes2697.4 Results of qualitative analysis2717.5 Findings2737.5.1 Intervention design2757.5.1.1 Pulmonary rehabilitation2757.5.1.2 Walking2817.5.1.3 Consultation and telephone calls2837.5.1.4 Suggestions2857.5.2 Behaviour change2937.5.2.1 Motivation to change2957.5.2.2 Benefits2997.5.2.3 Barriers3057.5.2.4 Change talk3077.6 Conclusion310Chapter 8 Discussion3128.1 Introduction3128.2 Strengths and limitations3148.3 Key findings with reference to the wider literature3218.3.1 Research question one3218.3.2 Research question two3338.3.3 Research question three3408.4 General Conclusions3688.5 Recommendations for future work and practice370References375Appendices420Appendix 1 Systematic review publication420Appendix 2 ACSM poster presentation abstract423Appendix 3 Systematic review protocol424Appendix 4 EoSRES-REC 2 Ethical approval447Appendix 5 Focus group/ interview schedule448Appendix 6 Initial analytic framework phase 1450Appendix 7 Snapshot of coded transcript phase 1452Appendix 8 Snapshot of intervention design matrix453Appendix 9 Snapshot of front cover of Macmillan physical activity education booklet454Appendix 10 Weekly telephone guide phase 2455Appendix 11 Patient information sheet phase 2456Appendix 12 Initial analytic framework phase 2463Appendix 13 Snapshot of behaviour change matrix phase 2464Appendix 14 Interview schedule phase 2465

List of tables

TableTitlePage number

Table 2.1Treatment of NSCLC by stage34

Table 5.1 Number of focus groups168

Table 6.1 Characteristics of sample phase 1201

Table 6.2 Final analytic framework phase 1203

Table 6.3 Themes and Subthemes phase 1204

Table 6.4 Intervention design 241

Table 6.5 Outcomes and measures255

Table 7.1Participant demographic data 263

Table 7.2Reasons for not participating265

Table 7.3 Participant walking details267

Table 7.4 Phase 2 results270

Table 7.5Final analytic framework phase 2273

List of figures

FigureTitlePage number

Figure 3.1 HAPA model121

Figure 4.1 Study process148

Figure 5.1 Search string 154

Figure 5.2 Patient variations 169

Figure 5.3 Recruitment process phase 1172

Figure 5.4Recruitment process phase 2193

List of abbreviations

ACSMAmerican College of Sports Medicine

BMIBody Mass Index

BMDBone Mineral Density

BTSBritish Thoracic Society

CNSClinical Nurse Specialist

COPDChronic Obstructive Pulmonary Disease

CRFCancer Related Fatigue

CTComputed Tomography

CVDCardiovascular Disease

CXRChest X-Ray

DOHDepartment Of Health

ECLSEarlyCDT Lung Cancer Scotland

EGRFEpidermal Growth Factor Receptor

HAPAHealth Action Process Approach

HRQOLHealth Related Quality Of Life

MRC Medical Research Council

MWTMinute Walk Test

NCSLSNon-Small Cell Lung Cancer

NCCNNational Comprehensive Cancer Network

NLSTNational Lung Screening Trial

PCIProphylactic Cranial Irradiation

pTNMpathological Tumor-Node-Metastasis

QOL Quality Of Life

RCTRandomised Control Trial

RFARadio Frequency Ablation

SCLCSmall Cell Lung Cancer

SRTStereotactic Radiation Therapy

UKLSUK Lung Screen

VO2Oxygen consumption

WHOWorld Health Organisation

Abstract

Background: This thesis describes a three-year mixed methods study which aimed to develop and test the feasibility of an exercise intervention for people who are surgically treated for lung cancer. The study employed the Health Action Process Approach (HAPA) as an underpinning theoretical framework in order to focus on the behaviour change components necessary for such kind of intervention. It used an inductive approach to aid the development of the intervention using guidance from the Medical Research Council (MRC) on developing and evaluating complex interventions.

Methods: The study was split into two phases with three parts. Phase one part one consisted of a systematic review examining the literature on exercise intervention for people who are surgically treated for lung cancer. Part two comprised a qualitative study examining the attitudes and beliefs of key stakeholders (patients and health professionals) on exercise for the population under study. The results from phase one informed the development of a three week pre-surgical exercise intervention carried out in phase two. Feasibility and acceptability were measured alongside other secondary outcomes to explore the feasibility of implementing the intervention.

Results: The results from the review illustrated the infancy of the field under study and provided evidence for the need for further investigation of key stakeholders attitudes and beliefs. The qualitative study, which included 23 participants, added to the results from the review and indicated that the design of an exercise intervention for this population should be multifaceted, for example including the option for both supervised centre-based group exercise and home-based exercise such as walking. Fourteen participants were recruited to the three week pre-surgical exercise intervention implemented in phase two. The results concerning feasibility of the intervention designed were mixed. Overall recruitment rate was low (33%). However, at one participating site recruitment was much higher (63%) and overall adherence to the programme was acceptable (74%) for those who did attend. The intervention was considered acceptable (measured through individual interviews), participants reported enjoying the programme and wanting to continue with something similar after their surgery. Participants felt the intervention should be part of standard care. Concerning secondary outcomes, the only statistically significant change detected was improvement in exercise capacity measured by 6MWT (p=0.018, median 50 metres) from baseline to post-intervention.

Conclusion: A review of the literature and exploration of key stakeholders attitudes and beliefs towards exercise for people surgically treated for lung cancer provided a strong evidence base for a multifaceted exercise intervention to be designed. The intervention proved to be feasible under certain circumstances (e.g. where there was sufficient time before surgery) and acceptable by people who opted to participate. Future pilot and RCT work is necessary in order to develop the intervention further and test the feasibility, acceptability and effectiveness of implementing it into clinical practice.

Acknowledgements

Firstly I would like to thank God. I do believe that without acknowledging the faith which He has given me that I would be disregarding the most important part of who I am and how I got here. I am grateful for the provision of this PhD, for the people who have made it possible and for those who have supported me through it.

I would like to express my gratitude to the participants, those who so willingly gave of their time and shared their experiences, thoughts and views with me.

To the lung specialist nurses: Lynn McAllister, Gillian Watson, Susan Smyth, John McPhelim, Kirsty Mcmanus and Kirsty Bridges, for facilitating the recruitment of participants and giving me of their time to provide information and discuss ideas.

To my supervisors:

My thanks go to Professor Nora Kearney who from before I had any faith in my abilities gave me the encouragement and support to try. She has supported me in more ways than I can put here and has always been the person to challenge me and believe in me. Her passion to improve care for people going through a cancer journey is inspiring. For the endless opportunities you have made possible, thank you!

To Professor Roma Maguire who with her passion for the lung cancer population and extensive knowledge in the area has kindled in me a desire to always keep learning. It is from her that I have caught the research bug and have grown to love working with the population under study.

To Dr Anna Campbell who has given me so many opportunities in the area of exercise and cancer. It is through her expertise in the area and invaluable networking skills that I have been able to experience and grow in this field. Thank you also for taking me to Florida and giving me many opportunities to grow and teach.

To all three of you, thank you for encouraging me, challenging me and on many occasions allowing it to be fun! Please forgive me for when I have wanted to jump ahead thank you for keeping me grounded!

I would also like to thank: the University of Dundee and the University of Surrey for providing the funding for my studentship. To those who provided training and advice throughout my PhD journey, although too numerous to mention individually, I thank them all for their contributions to my development as a researcher and the many healthcare professionals who so willingly shared their knowledge and views with me, thus helping to guide and shape the research.

Lastly I would like to thank my friends and family! You are all amazing!

In particular, thanks to my trampoline coach, Alastair Stewart. You have been an amazing support and allowed me to keep going with one of my biggest passions. It is because of you and the sport that I was able to keep sane during this time!

To my family!! You are the best!! You have believed in me, laughed with me and allowed me to express every emotion there is! You have always encouraged me.

Thank you Auntie Eileen for taking the time to proof read my thesis and encourage me along the way. I think I now understand where commas go!

To my Dad and sister!! THANK YOU!!!!! You are my greatest encouragers. Thank you for always believing in me, loving me and supporting me beyond belief! This journey would not be possible without you!

And finally to my late mum. What you instilled in me has provided me with the resources to live life and live well! You and Dad taught me to love life and give my best to everything no matter how small. I am ever grateful for the best parents!

Declaration

I declare the work in this thesis to be my own, except where otherwise stated.

Katy Crandall

May 2016

xvi

Chapter 1: Introduction1.1 Rationale of thesis

The ideas for this PhD project were generated from my interest in the area of exercise for people diagnosed with cancer. On a personal level I was driven by my passion for sport and exercise and inspired by my mother who underwent a gruelling battle with cancer over a six year period which during the last three years I was privileged to do my nursing training. In the final year of my undergraduate programme I was able to carry out my dissertation (a literature review) on exercise for women with breast cancer. It was from this time that I started to recognise the importance of this topic and saw the opportunity to research an area with the potential to make a positive impact within clinical practice.

I was encouraged by my now supervisors to look at an area that would be novel and I was inspired by their passion for understudied populations, such as people who are diagnosed with lung cancer. As I read more about this population I discovered few research studies in the field of exercise that included people with lung cancer. This heightened my interest in the area and my enthusiasm grew as I started to work with patients in an exercise setting prior to commencing this PhD project.

With reference to the literature I became aware of the global burden of lung cancer, it being one of the most common forms of cancer and the leading cause of cancer death worldwide (Sugimura et al. 2007, CRUK 2012a). Unfortunately at present it is recognised that the majority of people diagnosed with lung cancer will receive a poor prognosis, with less than 10% of people living beyond five years (CRUK 2012a). This is mainly thought to be due to late symptom presentation and thus more advanced stage disease at diagnosis.

On commencing this PhD I learnt about the many screening programmes that are being trialled in the UK and further afield in order to try and identify the disease at a less advanced stage. This would potentially mean that more people would be able to receive curative treatment such as radical chemo/radio therapy and/or surgery. Due to this potential change in lung cancer care I became interested in exploring the radical treatment pathway.

After consulting both health professionals in the field and patients from a steering group set up at the start of this PhD, I learnt of the burdens people face during and after radical treatment for lung cancer, in particular regarding the current most effective treatment, surgery. Surgical removal remains the best curative option for patients with early stage (stages I and II) lung cancer and for appropriately selected patients with locally advanced disease (stage IIIA) (Peddle et al. 2009). At present approximately 11% of patients diagnosed with lung cancer are eligible for surgical resection (SIGN 2005), owing to the stage of disease, limited functional capacity and/or associated comorbidities (Little et al. 2005). However, with a government focus on the early detection of cancer and lung cancer screening programmes being trialled across the country, it is possible that this may result in an increase in the number of patients detected with early stage disease, thus increasing the number of people eligible for surgery (Scottish Government 2011). However, despite the possibility of a cure, surgical resection is associated with significant morbidity, functional limitations and decreased Quality Of Life (QOL) post-surgery (Handy et al. 2002, Kenny et al. 2008). Therefore, I felt that to conduct research in the area of the surgical pathway would be of considerable benefit to patients with lung cancer and had the potential to make a significant contribution to clinical practice in the future.

With this in mind I started to look at the literature in the area of exercise intervention and lung cancer. My previous experience (undergraduate dissertation) in the area of exercise for people with breast cancer meant that I was aware that exercise intervention is a newly emerging field in the area of cancer and has only become a focus of research in the past two decades. Thus, with lung cancer often being one of the more understudied populations (possibly due to poor prognosis) it did not come as a surprise that there were few research papers with a focus on this area. It was evident that only a very few studies including this population have been published, leaving open many questions regarding the feasibility and acceptability of exercise intervention for people with lung cancer.

Furthermore, and of key importance in this PhD project, the lack of necessary development work such as the views and experiences of key stakeholders (patients and health professionals) unveiled an unexplored area that is deemed one of the necessary steps in intervention development (Craig et al. 2008). I therefore decided that, in light of the significant limitations identified, I would aim to make a novel contribution to knowledge and conduct a study formally exploring the attitudes, beliefs and views of people who are surgically treated for lung cancer on exercise, in order to develop and test an exercise intervention.

Furthermore, fundamental to the study of exercise intervention is the process of behaviour change. Therefore study of the theoretical aspects of behaviour change was pertinent to this PhD study. This is discussed further in chapter three, where the justification for the use of the Health Action Process Approach (Schwarzer 1992) (HAPA) demonstrates the need to examine the factors that affect both ones intention to carry out a behaviour, and also, key to this study, the variables in the process from intention to action.

For the purpose of this study, exercise is defined as any type of physical activity that is repetitive and planned with the objective to improve or maintain physical fitness, whereas physical activity is a general term for any body movement via skeletal muscles that results in energy expenditure.

I decided that the best way to explore this phenomenon was to use a mixed methods approach, as discussed in chapter four, instead of trying to reduce the phenomenon to statistical associations or relying solely on subjective experience. This choice was based on my epistemological stance and belief that knowledge is influenced by the perceptions of the person in the context of their lives and cannot be synonymous with the worlds objective state. This recognises that knowledge is not objective, admitting a degree of subjectivity, and accepting the fallibility of our knowledge.

Having decided on a mixed methods approach, I then explored the different methodologies within mixed methods research. I decided that due to the infancy of the field under study in this PhD, an exploratory design (with an emphasis on the initial qualitative phase) was deemed most appropriate in order to explore how best to develop an exercise intervention for people with lung cancer. The methodology outlined in chapter four has been termed an exploratory sequential intervention mixed methods design. The distinguishing attribute of the sequential design is that the second phase of the study emerges as a result of, or in response to the findings of the first phase (Tashakkori and Teddlie 2003). Therefore mixing occurs between the data analysis of the first phase and data collection of the second phase. This kind of design is common in tool and intervention development (Creswell 2009) where the ideas for the tool/intervention arise from the explorative work carried out with key informants. Therefore an emphasis on the initial qualitative stage reflects the exploratory nature proposed in this PhD.

The methods used in this study further reflect my epistemological position (critical realism) and my desire to inform the intervention from the views of key stakeholders (in this case patients and health professionals). Focus groups and semi-structured interviews with key stakeholders informed the intervention design alongside the literature available in the area and underpinning theoretical framework mentioned above. This was followed by feasibility testing including both qualitative (semi-structured interviews) and quantitative (e.g. recruitment measures) measures.

As will be evident in the following chapters of this thesis, the approach used in this study provides understanding of the views of patients and health professionals in the development and evaluation of an exercise intervention, making an important contribution to this body of knowledge. Having outlined the rationale and approach used in this thesis, I will now provide a brief summary of the structure of this thesis.

1.2 Structure of thesis

The following two chapters (chapters two and three) begin with a review of the literature presenting the problem under study (lung cancer) and the intervention proposed (exercise for people with cancer). The literature in these chapters was identified from various sources, including database searches, PhD theses, conference proceedings and reference lists from key research papers.

Chapter two introduces the topic of lung cancer, its epidemiology, clinical presentation, treatment and in particular the issues surrounding surgical treatment and management. It presents the most up to date literature on the current issues in lung cancer care (e.g. screening) and discusses the burden of lung cancer and its treatment in order to emphasise the importance of investigating intervention work for this population.

Chapter three examines the evidence base regarding exercise intervention for people who are diagnosed with cancer. The chapter begins with a general overview of exercise intervention in the context of health before focusing on the literature in the field of exercise and cancer, covering the pre, during, and post treatment time periods. It further discusses the development of exercise guidelines for people with cancer before specifically covering the evidence in relation to exercise for people diagnosed with lung cancer. Finally, behaviour change theory is discussed in relation to the field of exercise intervention and the underpinning theoretical framework used throughout this thesis is justified.

Chapter four discusses the development of the methodological approach used for the empirical stages of this PhD study. Firstly, the limitations of the predominantly quantitative approached used in the study of exercise intervention research is discussed and a justification for a mixed methods approach is provided. Thereafter the common philosophical assumptions underlying mixed methods research are discussed and my philosophical position is presented. Lastly, this chapter discusses the different strategies used in mixed methods research and provides a rationale for using an exploratory sequential mixed methods intervention design.

Chapter five presents the methods used and includes a discussion of the aims and research questions which governed the study, the study design, the sample of patients recruited, and the data collection and data analysis strategies used in each phase of the study. Chapter six presents the results from phase one of the study, both from the systematic review and qualitative work carried out in order to inform the intervention design. This chapter also presents the justification for each component of the designed intervention and the outcomes measured in phase two. Chapter seven presents the findings from phase two - the feasibility study of the intervention designed.

Finally, in chapter eight, the strengths and limitations of the study are identified and the key findings of this PhD project are discussed in relation to the wider literature. A general conclusion is made before the implications of the study findings for future research and practice are presented.

Chapter 2: Lung cancer2.1 Introduction

This chapter provides an overview on lung cancer, its epidemiology, clinical presentation, treatment and in particular the issues surrounding surgical treatment and management. It presents the most up to date literature on the current issues in lung cancer care (e.g. screening) and critically discusses the burden of lung cancer and its treatment in order to emphasise the importance of and provide the rationale for this study.

2.2 Epidemiology 2.2.1 Prevalence/ Incidence

Lung cancer is the second most common cancer in the UK, the most common cancer in Scotland, and the leading cause of cancer death worldwide (Sugimura et al. 2007, CRUK 2012a). In 2010, there were 42,026 new cases of lung cancer in the UK and in 2011, 35,184 deaths (CRUK 2013d). Incidence rates in Scotland are amongst the highest in the world (Parkin et al. 2005) reflecting the countrys history of high smoking prevalence (CRUK 2014a).

Lung cancer is frequently diagnosed at a late stage and until recently it was believed that this was due to the symptoms of lung cancer occurring late in the disease process (once the cancer had progressed). However, this assumption has been challenged and it has been suggested that subtle health changes and symptoms may occur earlier in the disease course (Tod et al. 2008). For example, Tod et al. (2008) argue that it is possible that patients and health professionals underestimate the seriousness of these symptoms therefore delaying diagnosis and allowing the cancer to progress (thus most often presenting with late stage disease). Lung cancer also tends to occur in older people, who live in deprived areas and have other co-morbidities such as COPD (Loganathan et al. 2006, Ruysscher et al. 2009, Walker et al. 2013), making it one of the most difficult cancers to diagnose or treat (CRUK 2014a).

Lung cancer incidence rates in men have decreased by around 48% since the late 1970s, reflecting the decline in smoking rates in men after World War II (CRUK 2013d). The prevalence of lung cancer has always been greater in men than women. However, now that fewer men smoke, coupled with an increase in the number of women who smoke, this gap is reducing (Blot and McLaughlin 2004). Lung cancer deaths in men have decreased by more than a quarter in the UK (a 27% reduction between 1971 and 2006) (NICE 2011), whilst deaths from lung cancer in women have increased (lung cancer is now the leading cause of cancer death in women in the UK (CRUK 2013a)). The male to female ratio for lung cancer was 39:10 in the mid 1970s but now for every 12 cases in men there are around 10 in women (CRUK 2013d).

Unlike other cancers where mortality rates have dropped and survival of the disease has increased, overall lung cancer mortality rates have not altered dramatically over the last 20 years (CRUK 2013a), most probably reflecting the populations notorious late presentation and thus advanced stage disease on diagnosis (Birring and Peake 2005). Once the cancer has progressed to an advanced stage prognosis is very poor; only 30% of all patients diagnosed with lung cancer survive one year following diagnosis and less than 10% survive beyond five years (approximately only 5.5% of lung cancers are currently cured) (CRUK 2013d). However, early detection initiatives and possible new treatments (discussed in this chapter) may transform lung cancer management in the coming years (Wood et al. 2012, Calvert and Chatterji 2013, Hall et al. 2013).

2.2.2 Risk factors

In the UK, most lung cancer cases (approximately 90%) are caused by tobacco smoking (CRUK 2012a). Other risk factors include: exposure to environmental smoke or radon gas, industrial carcinogens or air pollutants (for example asbestos, diesel, non-ferrous metals, silica, nitrogen oxides and polycyclic hydrocarbons), family history of lung cancer, previous pneumonia, human immunodeficiency virus and previous radiation treatment to the chest (CRUK 2013c).

The evidence of links between lung cancer and diet and physical activity are inconclusive (CRUK 2013c). Interest in the possibility that fruit and vegetable intake may reduce the risk of lung cancer dates back to the 1970s where a small prospective study by Bjelke (1975) suggested people with a low intake of vitamin A were at increased risk for lung cancer, even after allowing for the effect of smoking. In 1997 the World Cancer Research Fund (WCRF) together with the American Institute for Cancer Research (AICR) published an expert statement (WCRF 1997) that stated there was convincing evidence that high intake of fruit and vegetables reduced the risk of some cancers, including lung cancer. However, an updated report in 2007 (WCRF 2007) downgraded the evidence from convincing to probable or limited-suggestive as more recent larger prospective studies (Smith-Warner et al. 2003) with detailed adjustment for smoking did not show convincing association between diet intake and risk for lung cancer.

In relation to physical activity, higher levels of physical activity have been associated with 20-40% reductions in lung cancer risk (Friedenreich et al. 2010) although stronger risk decreases were observed in studies that did not fully control for smoking (a strong confounder of this relation). It seems that the preventative effect is stronger in smokers than non-smokers thus authors suggest that smoking status is a strong moderating variable (Leitzmann et al. 2009, Friedenreich et al. 2010). Furthermore, it appears that vigorous physical exertion, rather than general daily activity, may be required to obtain benefit in this population (Wiggins and Simonavice 2010). However, this area has not been explored extensively and requires further investigation.

A recent meta-analysis by Yang et al. (2013) demonstrated that a number of epidemiological studies have indicated a possible inverse association between Body Mass Index (BMI) and lung cancer risk especially amongst current and former smokers. However, possible confounding by smoking, and reverse causality (weight loss caused by lung cancer) mean this finding should be interpreted with caution. Obesity is a strong risk factor in many cancers, for example, colon, breast, stomach, pancreas, gallbladder, liver, and more (Calle and Kaaks 2004), however, higher lung cancer risk was mostly observed in individuals with lower BMI (Yang et al. 2013). The results are inconclusive and conflicting and other studies have failed to find such an association or the association disappeared when smoking status was taken into account (Henley et al. 2002, Kanashiki et al. 2005).

Although the predominant risk factor for lung cancer is tobacco smoking, globally it is estimated that 15% of lung cancers in men and 53% in women are not attributable to smoking (Parkin et al. 2005). Although there has been no predominant causal factor, the risk factors considered important for people who have never smoked include: second-hand smoke, radon exposure, environmental exposures, such as indoor air pollution, asbestos, and arsenic, history of lung disease, and genetic factors (Yang 2011). Lung cancer in people who have never smoked appears to be a different disease molecularly to that which presents in smokers based on information gained on disease response to treatment (Subramanian and Govindan 2007, Sun et al. 2007, Yang 2011, Yano et al. 2011). However, the aetiology is less clear and no predominant cause has been determined (Moore 2009). Lung cancer in people who have never smoked appears to be driven by a single genetic event, opposed to widespread genetic and epigenetic changes observed in lung cancer in smokers. For example, Lee (2011) explains that genetic changes in several genes such as EGFR, KRAS, P53, and ALK, in people who have never smoked with lung cancer are critically different from those in smokers with lung cancer (Lee et al. 2011).

2.2.3 Presenting Symptoms

The presenting symptoms of lung cancer are typically a cough, shortness of breath, coughing up phlegm, tiredness (fatigue), weight loss and voice changes (Tod et al. 2008, CRUK 2012a). Symptoms may result from local invasion or compression of adjacent thoracic structures (such as compression involving the oesophagus, causing dysphagia) and/or from metastases (NCI 2014b).

The majority of literature suggests that these symptoms occur once the cancer has progressed when curative options are limited and therefore reflect a poor prognosis (Corner et al. 2005). However, as stated earlier in this thesis some (Tod et al. 2008) suggest that a delay in diagnosis due to an underestimation of the seriousness of initial symptoms may contribute to late stage disease at diagnosis.

A cough is found more frequently in early stage disease and haemoptysis and dyspnoea have been found to be present at least six months before diagnosis (Hamilton et al. 2005). These could be symptoms that prompt patients to seek medical help. However, a survey carried out in 2008 (Robb et al. 2009) found that the UK public had little awareness of a persistent cough as a cancer symptom. Poor knowledge of lung cancer symptoms is evident throughout the literature. Tod and Rose (2010) explored the issues that influenced delay in reporting symptoms and found that participants had a tendency to attribute other meanings to symptoms such as smokers cough. Tod and Rose (2010) found that participants tended to self-manage a cough and feared healthcare professionals attitudes towards their way of life. For example, the blame and stigma associated with smoking, thus, people did not seek medical attention (these latter issues are discussed further in section 2.5).

Often symptoms are disregarded as symptoms of other chronic respiratory diseases (e.g. COPD) that may already be known to the patient or may be under investigation, therefore contributing to delayed diagnosis (Ellis and Vandermeer 2011). Ellis and Vandermeer (2011) carried out a survey in a cohort of patients in Canada newly diagnosed with lung cancer and found that when patients first presented to a doctor they often received treatments such as antibiotics, inhalers or cough syrup to treat a possible infection. Furthermore, a retrospective audit of cancer cases in general practices in Scotland demonstrated that patients with lung cancer waited longer for specialist referral than patients with most other cancers (Baughan et al. 2009). Missed opportunities to establish a lung cancer diagnosis might be a contributing factor to late stage presentation at diagnosis and for these reasons it is necessary to increase lung cancer awareness and improve methods of early detection. The next section discusses the issues around screening and early detection initiatives to demonstrate the current drive towards an early diagnosis.

2.3 Screening and initiatives 2.3.1 Screening

Due to late diagnosis and high mortality rates in lung cancer, screening seems a practical modality to detect lung cancer early and possibly reduce mortality (Pastorino 2010). The aim of lung cancer screening is to detect the disease at an early stage where it is not causing symptoms, when treatment is most successful (Wood et al. 2012). The amount of false-positive results should be low to prevent unnecessary additional testing and the large percent of the population without the disease should not be harmed (those at low risk) (Wood et al. 2012). Debates throughout the last four decades on whether lung cancer screening is viable and cost-effective have emerged and still today it is unclear as to the best possible clinical management of early detection in lung cancer. There have been various screening methods suggested and trialled and results are currently inconclusive to advise the best possible way forward for practice (Pastorino 2010, Bach et al. 2012, Wood et al. 2012).

Early lung cancer screening trials (Melamed et al. 1984, Tockman 1986, Mao et al. 1994) involving Chest X-Rays (CXR) and/or sputum cytology found that these strategies detected slightly more lung cancers at an earlier stage. However, this was not accompanied by a reduction in lung cancer deaths. Results from a 25 year follow up study (Marcus et al. 2006) showed that overall mortality was higher in the CXR arm (non-significant, p=0.09) even though more people were diagnosed with earlier stage disease. These results alongside occurrence of overdiagnosis confirmed the inefficiency of CXR screening. Pastorino (2010) suggests that overdiagnosis (the detection and treatment of slow-growing disease) may be one explanation for the lack of mortality reduction seen in screening studies. Overdiagnosis bias refers to the screening related detection of cancers that otherwise would not have contributed to the death of a patient due to other competing causes of death or because the lesion was indolent (Pastorino 2010).

A further drive for lung cancer screening was introduced when low dose Computed Tomography (CT) was considered, as it is able to detect smaller nodules than CXR. Since the 1990s RCTs comparing CT with CXR or no screening measure have been underway worldwide. Two of the largest studies in the literature examining CT screening are the National Lung Screening Trial (NLST) (Clark et al. 2009) conducted in America with over 53, 000 participants, and the Dutch Belgian randomised study (NELSON) (van den Bergh et al. 2008) with over 15,000 participants. To date, the NLST is the only RCT in which a significant lung cancer mortality reduction has been found. The NLST study demonstrated a 20% lower mortality risk in the CT arm. However, reports of smaller studies have not found the same risk reduction, many smaller studies have lacked justification of or sufficient sample size (Welch et al. 2007, Infante et al. 2009, Bach et al. 2012). Importantly, the underlying risk for lung cancer varied between studies (some studies included participants that were at low (e.g. never smokers) or moderate risk of lung cancer). The NLST study recruited only high risk participants whereas the NELSON study and others (Blanchon et al. 2007, Infante et al. 2009) included patients with a broad range of risk (giving a heterogeneous overall sample between studies). The results concerning mortality in the NELSON study are still pending.

The results from the NLST study indicate that screening may be most beneficial for those at high risk (for example, known risk factors include: smoking, exposure to second hand smoke, residential radon exposure, occupational exposure to known human carcinogens, history of lung disease, family history of lung cancer and cancer history) (Wood et al. 2012). If screening is not effective, then patients may be harmed from overdiagnosis, increased invasive testing, and the anxiety of a potential cancer diagnosis (Bach et al. 2012, Wood et al. 2012). Thus, as evidence is inconclusive, current recommendations from the National Comprehensive Cancer Network (NCCN) lung cancer screening panel (Wood et al. 2012) suggest that moderate and low risk individuals should not be screened.

In the UK, a large scale RCT termed the UK Lung Screen (UKLS) (Baldwin et al. 2011) is currently in its pilot phase. It aims to recruit 4,000 participants, with an aim of undertaking a large study involving 32,000 high risk individuals in an RCT to either receive CT screening or usual care (no CT or CXR). Furthermore, in Scotland a large RCT termed EarlyCDT Lung Cancer Scotland (ECLS) (ECLS 2013) is underway. ECLS aims to recruit 10,000 high risk individuals, half to receive a blood test (to detect autoantibodies of tumour antigens) and half to receive usual care (no screening) to validate potential blood biomarkers and determine if it is possible to efficiently detect lung cancer before presentation from blood antibodies.

The issue of early detection biomarkers in lung cancer has recently been reviewed (Hassanein et al. 2012). Hassanein et al. (2012) explain that discovering these biomarkers has the potential to improve early detection beyond the use of CT scans. They suggest that a biofluids-based molecular test may improve the selection of high-risk individuals for CT screening, distinguish those with malignant nodules from benign lesions, and identify patients with particularly aggressive cancer. However, research in this area is in its infancy and currently none of the published candidate biomarkers of risk of lung cancer diagnosis are ready for clinical use, although a few have moved to phase III of biomarker development (Hassanein et al. 2012).

Other methods of early detection have taken the form of awareness campaigns to detect lung cancer early. The following section discusses some of the UK initiatives trialled in recent years.

2.3.2 Initiatives to detect lung cancer early

Knowing a symptom is associated with cancer has been linked with seeking medical attention promptly (Robb et al. 2009) and thus the UK government has become more active in lung cancer awareness in recent years (Simon et al. 2012). There is now some evidence to show that initiatives to detect lung cancer early, like the Be clear on Cancer Campaign trialled in England, have increased awareness of symptoms amongst the general public and increased the percentage of lung cancer being detected earlier (Calvert and Chatterji 2013). Some recent studies carried out in England have shown reduced emergency diagnosis (Cheyne et al. 2012) and increases in surgical resection rates (Hobbins and Woolhouse 2012) after implementation of early awareness campaigns. Other initiatives are underway (many supported by the Roy Castle Lung Cancer Foundation) to encourage awareness of lung cancer in the UK with the hope that individuals will be more aware of symptoms and risks and therefore present with earlier stage disease, thus reducing lung cancer mortality. The following section discusses the current management and treatment of lung cancer.

2.4 Management and Treatment2.4.1 Diagnosis and prognosis

Lung cancer is histologically defined into two groups, Non-Small Cell Lung Cancer (NSCLC) and Small Cell Lung Cancer (SCLC). Each has significantly different outcomes and management and will be discussed separately over the following sections.

Non-small cell lung cancer arises from the epithelial cells of the lung of the central bronchi to terminal alveoli (Goldstraw et al. 2011). The histological type of NSCLC correlates with its site of origin. NSCLC compromises of three main types; adenocarcinoma, squamous cell carcinoma and large cell carcinoma (Moore 2009). These different subtypes are classified together under NSCLC because the approach to diagnosis, staging, prognosis and treatment are similar (Moore 2009).

For patients diagnosed with NSCLC (approximately 85% of those diagnosed with lung cancer) survival rates remain much higher than for those diagnosed with SCLC (Sher et al. 2008), in particular for those deemed eligible for tumour resection (Molina et al. 2008) where five year survival has been reported to be between 25% and 75% depending on the stage of disease at diagnosis (Lang-Lazdunski 2013). However, more than 65% of people diagnosed with NSCLC present with locally advanced or metastatic disease, limiting the possibility of surgical treatment (Morgensztern et al. 2010).

Small-cell lung cancer arises from neuroendocrine cells of the bronchial tree and consists of small cells with scant cytoplasm (van Meerbeeck et al. 2011, NCI 2014a). Most (90%) cases involve only small cells and the remaining cases are classified as combined disease in which the tumour contains large cell components (Franklin 2010). It is a highly malignant cancer which grows rapidly and metastasises early (Inoue et al. 2012, NCI 2014a) (common sites include: bone, liver, lymph node, central nervous system, adrenal glands, subcutaneous tissue and pleura) (Sher et al. 2008). For these reasons the majority of people diagnosed with SCLC will receive palliative care, usually compromising of chemotherapy and/or radiotherapy. Patients are typically men, older than 70 years, who are heavy current or ex-smokers and who have various other comorbidities (pulmonary, cardiovascular, and metabolic) (van Meerbeeck et al. 2011).

Median survival for patients with limited-stage (staging is explained in section 2.4.2) SCLC is approximately 1520 months, and for those with extensive-stage disease 813 months (Lally et al. 2007). The median survival from diagnosis without treatment has been estimated between two to four months (NCI 2014a). Overall five year survival rates range between 5% (extensive stage disease) up to 25% (limited stage disease) (NCI 2014a).

SCLC and squamous cell carcinoma are the types most closely linked with smoking (Youlden et al. 2008). However, statistics are now showing a rise in adenocarcinomas from smoking (Youlden et al. 2008). The reason for this is unclear, however, there is a debate as to whether this is related to filtered cigarettes which lead to deeper inhalation, in turn possibly affecting more peripheral tissue (Devesa et al. 2005).

2.4.2 Staging

To ensure patients receive appropriate treatment it is important to establish the type and stage of the disease by identifying the size of the tumor and any metastatic spread. NSCLC and SCLC are staged differently. NSCLC is staged using the pathological Tumor-Node-Metastasis (TNM) system (Mirsadraee et al. 2012). There are four main stages (1-4), stage 1 being the least invasive with no spread, to stage 4 being the most advanced with spread to lymph nodes and other parts of the body (CRUK 2012b). The main metastatic areas of spread in NSCLC are the stomach, liver, lung and abdominal cavity (van Meerbeeck et al. 2011).

Due to the quick progression of SCLC, staging is split into two stages, limited and extensive stage disease (CRUK 2012b). Limited stage is when the cancer is only in one side of the chest and can be treated within a single radiation field. Extensive stage (diagnosed in approximately 70% of people with SCLC) (Sher et al. 2008)) is used to describe cancers that have spread widely throughout the lung, to the other lung, to lymph nodes on the other side of the chest, or to other organs (NCI 2014a).

2.4.3 Treatment

Treatment options for lung cancer are dependent on the type and stage of disease and can include systemic therapy (chemotherapy and/or targeted therapy), radiotherapy, surgery or a combination of these (Evans 2013). As the management of NSCLC and SCLC differs, each will be presented separately with a focus and discussion on radical treatment, this being the area related to this PhD.

2.4.3.1 NCSLC

Surgical removal remains the best curative option for patients with early stage (stages I and II) NSCLC and for appropriately selected patients with locally advanced disease (stage IIIA) (Evans 2013). Those deemed ineligible for tumour resection - either because the tumour is not resectable or the patient is not suitable for surgery due to other factors (cardiopulmonary insufficiency, which determines the functional limit of resection, is the main cause of inoperability) (Divisi et al. 2012) - can either be prescribed radical radiotherapy or combination therapy (chemo-radiotherapy). The following paragraphs discuss in more detail the issues surrounding radical treatment including the impact of treatment, outcomes, and recurrence, with a focus on surgical treatment, management and treatment related burden. Patients who are not eligible for radical treatment will receive palliative treatment. However, this goes beyond the scope of this PhD and will therefore not be discussed in the following sections.

2.4.3.1.1 Radical treatment

The term radical treatment can be referred to as treatment with intent to improve survival substantially which may amount to cure (Lim et al. 2010). In 2010 the British Thoracic Society (BTS) produced guidelines (Lim et al. 2010) for the radical management of patients with lung cancer. These recommendations explained how various tests such as pulmonary function and cardiopulmonary exercise testing can help identify the most suitable treatment option for people with lung cancer. Based on survival outcome, surgery alone is recommended as the best treatment option for Stage I lung cancers (Lee 2010). However, as the stage increases, multimodality therapies such as chemo-radiotherapy are available and advised (Lim et al. 2010). The guidelines state that radical radiotherapy or radical chemo-radiotherapy should be offered to patients who have early stage or locally advanced NCSLC and selected patients with limited stage SCLC who have unacceptable risk of surgical complications (Lim et al. 2010).

2.4.3.1.1.1 Radiotherapy

In patients with stages I and II disease, where the tumour is localised and potentially resectable but where an operation is not feasible, radical radiotherapy may provide a curative option (Lim et al. 2010). For some stage III NSCLC tumours, if the disease (primary tumour and any nodal spread) is contained in a radical radiotherapy field, radiotherapy combined with chemotherapy is the optimum treatment advised (Lim et al. 2010).

The side effects experienced by patients receiving radiotherapy can include general side effects (experienced by the majority of patients receiving radiotherapy) such as fatigue, hair loss at the targeted area and a skin reaction similar to sunburn (Macmillan 2012). Fatigue is possibly the most common and debilitating side effect of cancer treatment and high levels of fatigue have been reported both during and after radiotherapy treatment (Hofman et al. 2007) the burden of fatigue is discussed further in section 2.5.2 (treatment related burden).

Specific disease/site related side effects from radiotherapy can include chest pain and difficulty swallowing (the oesophagus can be affected and become narrower, making swallowing difficult) (Macmillan 2012). Radiotherapy for lung cancer can sometimes cause long-term side effects such as inflammation or fibrosis of the lungs, in turn causing symptoms such as shortness of breath and a prolonged cough (Macmillan 2012). Furthermore, the bones in the chest may become thinner and more brittle (Macmillan 2012). These symptoms are much rarer than the short term side effects but can take months, or even years, to develop (Macmillan 2012).

Mortality rates after radiotherapy for early stage inoperable lung cancer vary depending on the stage at diagnosis and the radiotherapy technique used (Timmerman et al. 2010). Conventional radiotherapy often fails to control the primary lung tumor (Dosoretz et al. 1996). Two year survival has been reported to be less than 40% (Timmerman et al. 2010). Newer radiotherapy delivery techniques to control for movement of breathing may improve survival and symptom burden but are not currently standard practice throughout the UK (Panakis et al. 2008). For example, Stereotactic Radiation Therapy (SRT) has shown to have higher rates of local tumor control in medically inoperable patients with Stage I NSCLC (McGarry et al. 2005, Timmerman et al. 2006, Fakiris et al. 2009, Timmerman et al. 2010). Mortality rates have been reported to be up to 55.8% at three years (Timmerman et al. 2010). However, these studies are few and are limited by small sample sizes. Research into this area is ongoing and developments are beginning to emerge in clinical practice (details of newer radiotherapy techniques are discussed in section 2.4.3.3).

Furthermore, radiotherapy can also be used as a preventative treatment. For example, Prophylactic Cranial Irradiation (PCI) is sometimes used during the treatment of lung cancer (both NSCLC and SCLC) as there is a risk that the cancer will spread to the brain. PCI involves treating the whole brain with a low dose of radiation. Studies have shown reduced brain metastasis in patients receiving PCI compared with patients who were observed (Russell et al. 1991, Arriagada et al. 1995, Pttgen et al. 2007). However, a large RCT study by Gore et al. (2011) found (although brain metastasis were 2.25 times more likely to develop in the observation arm) no significant effect on overall survival. The authors suggest that the selection process in this study may have unintentionally selected patients with favorable prognostic factors (e.g. some patients may not have been eligible because of disease failures occurring after treatment but before consideration of enrolment in the study) that may predict for lower rates of bone metastasis in the patient sample and result in longer overall survival than seen in previous studies (Gore et al. 2011).

2.4.3.1.1.2 Chemotherapy

In the treatment of NSCLC, chemotherapy is sometimes given prior to surgery to decrease the tumour size, after surgery to reduce the risk of cancer recurrence, to relieve symptoms if surgery isn't possible, and as treatment for recurrent disease (Davies and Reid 2012). Data confirming the benefits of chemotherapy for NSCLC has increased over the last ten years (Crin et al. 2010, Goldstraw et al. 2011).

In the neoadjuvant setting it is unclear as to the optimal role of chemotherapy. Some authors suggest chemotherapy may be beneficial in terms of survival (Burdett et al. 2007), but others advise that patients should not routinely be offered preoperative chemotherapy (Lim et al. 2010). Adjuvant chemotherapy following surgery has been shown to result in a small (approximately 5%) survival benefit for some patients, in particular for patients with stage II or IIIa disease (Pignon et al. 2008, Crin et al. 2010, Califano et al. 2012). However, research in this area is emerging and further research into genomic markers will likely predict which subsets of patients may benefit or be harmed from adjuvant chemotherapy (Moore 2009).

The combination of chemotherapy with radiotherapy compared with radiotherapy alone has been shown to confer a survival advantage (median survival advantage of 7-14%) in patients with stage III NSCLC (Le Chevalier et al. 1991, Jeremic et al. 1996, Curran et al. 2011). In this instance, radiotherapy can either be given concurrently with chemotherapy or following chemotherapy (sequential). Further work in the area is needed to determine the optimal regime for particular subsets of NSCLC (Curran et al. 2011).

Chemotherapy for NSCLC can cause many side effects including anaemia, neutropenia, thrombocytopenia, nausea, vomiting, diarrhoea, constipation, peripheral neuropathy, alopecia, infection, pain, and fatigue which can be very distressing for some patients (Davies and Reid 2012). These side effects occur because chemotherapy drugs attack both cancer cells and rapidly dividing normal cells for example, bone marrow, blood, intestinal, oral, and hair cells (CRUK 2014b). Not every side effect of chemotherapy may be experienced. The frequency and severity of side effects may depend on factors such as the dosage, route (intravenous or oral), and frequency of chemotherapy (Davies and Reid 2012). Further discussion about disease and treatment related burden is presented in section 2.5.

2.4.3.1.1.3 Surgery

At present few patients diagnosed with lung cancer are eligible for surgical resection, approximately 10% (NHS 2009), owing to the stage of disease, limited functional capacity and/or associated comorbidities (Little et al. 2005). However, this number rises (approximately 21% in 2012 (HSCIC 2013)) when SCLC is removed from the equation and only histologically confirmed NSCLC is included. Resection rates in the UK are low compared with the rest of Europe 10% versus 15-25% (NHS 2009), however, Riaz et al. (2012) point out that most international reported resection rates are quoted as a proportion of patients with confirmed NSCLC whereas previous UK data has used the total lung cancer population as the denominator. Also, accessibility to thoracic specialists may possibility contribute to this gap (Lau et al. 2013).

Lau et al. (2013) examined resection rates in England and concluded that the large variations found across the country were in part related to the local availability of specialist thoracic surgeons. Data from the National Lung Cancer Audit has shown that the UK has nearly doubled the number of practicing specialist thoracic surgeons from 2005 - 2010 and a small increase in resection rates has followed (Lau et al. 2013). Lim and Popat (2013) reported that in the last five years a slight increase in resection rates in England and Wales (from 10%-14%) may be partly due to updated guidelines on the radical management of lung cancer and an increased national awareness. However, the greatest improvements in resection rates have been found in units with an increase of specialist thoracic surgeons (Lau et al. 2013).

In addition, resection rates across the UK vary from less than 5% to over 25% (NHS 2009). Moore et al. (2009) suggest that this variation is of concern because it may imply patients who could be operable are not being considered as surgical candidates in some areas. Furthermore, the resection rate in NSCLC patients declines above the age of 70 years (Peake et al. 2003) (even though they respond equally well as younger patients (Chambers et al. 2010)), and in those with higher levels of socio-economic deprivation (Riaz et al. 2012).

Surgical treatment is usually lobectomy with systemic nodal dissection or pneumonectomy (CRUK 2014c). Occasionally, patients will have a segmentectomy or wedge resection (where the tumour is wedged out rather than the lobe removed) or a bi-lobectomy if the tumour crosses two lobes (CRUK 2014c). The traditional method is via thoracotomy, but, over the last few years Video Assisted Thorascopic Surgery (VATS) has become increasingly common and has been found to be more acceptable because of reduced level of pain and length of hospital stay (Flores et al. 2009). It has been suggested that VATS may enable patients with marginal performance status who are not candidates for a thoracotomy to undergo surgical treatment (Mckenna 2010).

Five-year survival rates for resected NSCLC range depending on tumour size and nodal status (Strand et al. 2006). The five-year survival for stage I lung cancer after resection is approximately 60%, however, the five-year survival after a VATS lobectomy for stage I lung cancer has been reported to be between 72% and 94%. This may be related to patient selection, rather than any true benefit from the VATS approach (Mckenna 2010). Five year survival for surgically resected stage II is much lower ranging between 30-40% (Steliga 2010).

Due to the relatively high risk of disease recurrence and metastasis after surgery, adjuvant treatments such as radiotherapy and chemotherapy have each been investigated. As mentioned previously in section 2.4.3.1.1.2, trials have demonstrated that postoperative chemotherapy is beneficial for patients diagnosed with stage II or IIIA disease. However, the role of postoperative radiation therapy remains to be defined (Wozniak and Gadgeel 2009). Table 2.1 explains the type of treatment most often prescribed at each stage of the disease.

Table 2.1 Treatment of NSCLC by stage (adapted from (Hunt 2012))

Stage

Treatment

I - Small tumour with no lymph node involvement

Usually surgery, sometimes followed by chemotherapy, sometimes radiation therapy

II - Larger tumour or lymph node involvement, but only nodes within the affected lung

Usually surgery, usually followed by chemotherapy, sometimes radiation

III - Tumour very large or invasive, or lymph node involvement in the central chest (mediastinum)

Usually chemotherapy and radiation, sometimes followed by surgery

IV - Distant spread

Usually chemotherapy, sometimes radiation therapy. Rarely surgery to relieve specific symptoms

Although pulmonary resection is the best curative option for patients with early stage NSCLC, reported risks and side effects must be considered. The risks for pulmonary resection depend primarily on the preoperative status of the patient. For example, factors such as preoperative pulmonary function, comorbidities and overall functional status must be measured (Crabtree 2010). Complications of pulmonary resection include both intraoperative (e.g. massive haemorrhage, cardiac ischemia, arrhythmias, contralateral pneumothorax, nerve injuries and injuries to the oesophagus and thoracic duct) and postoperative difficulties (e.g. pneumonia, respiratory failure, empyema, broncho-pleural fistulae, prolonged air leaks, post-pneumonectomy pulmonary oedema, post-pneumonectomy syndrome, and death (Crabtree 2010)).

Recent studies have demonstrated improved outcomes in patients undergoing pulmonary resection for cancer compared with previously (Allen et al. 2006, Strand et al. 2007). Improvements in patient survival and reduction in complications have been attributed to better patient selection for surgery as well as improved postoperative care (Crabtree 2010). Some studies suggest that mortality rates may depend on the extent of lung resection (Romano and Mark 1992, Wada et al. 1998). For example, Wada et al. (1998) reported on 7099 surgical resections and found mortality rates (death within 30 days post-surgery) to be 3.2% for pneumonectomy, 1.2% for lobectomy, and 0.8% for sublobar resections. They also reported significantly more deaths in patients with increasing age however, the majority of procedures were performed by thoracotomy. In a more recent study (Allen et al. 2006) (including 1,111 participants), there were no trends toward increased mortality or complications with larger pulmonary resections although this study was not designed to examine differences in resection procedure (thoracotomy was performed in the majority of cases).

Apart from the risks associated with pulmonary resection, many studies have demonstrated that patients have also reported reduced Quality Of Life (QOL) and functional limitations post-surgery (Handy et al. 2002, Myrdal et al. 2003, Sarna et al. 2004) - these are discussed in section 2.5.3. Thus, it is timely to investigate possible interventions to improve outcomes as a predicted rise in the numbers of surgical resection (from a rise in early diagnosis from screening) will evoke improved management of this population.

2.4.3.2 SCLC

Treatments for SCLC are usually palliative and typically include chemotherapy and/ or radiotherapy if the patient is able and desires treatment (Sher et al. 2008, Moore 2009, van Meerbeeck et al. 2011). SCLC is highly sensitive to chemotherapy and therefore is an essential treatment for people diagnosed with SCLC (Kalemkerian et al. 2013). For patients with extensive-stage disease, chemotherapy alone is the recommended treatment, although radiotherapy may be used in select patients for palliation of symptoms (Kalemkerian et al. 2013). Adjuvant chemotherapy is recommended for those who have undergone surgical resection. However, surgery is rarely an option for SCLC because the disease is most often advanced and metastasised at diagnosis (Moore 2009, van Meerbeeck et al. 2011).

Approximately 30% of patients with SCLC have limited stage disease (Sher et al. 2008). These patients are most often considered for combined chemo-radiotherapy treatment as the addition of radiation to chemotherapy produces modest but significant improvement in survival in SCLC (estimated at 5% improvement in 3-year survival rates for patients receiving combination therapy compared to chemotherapy alone) (Warde and Payne 1992, Sher et al. 2008).

The use of surgery in limited stage SCLC remains a controversial topic (Inoue et al. 2012). Meerbeeck et al. (2011) suggest that immediate surgery should be considered for individuals with limited stage disease, but only after node negativity has been confirmed. However, the literature is inconclusive and of two RCTs identified both suggested that surgery did not provide survival benefit compared with radiation therapy alone (Fox and Scadding 1973) or compared with no intervention after chemotherapy (Lad et al. 1994). However, these studies may be considered outdated (both pre 2000) and criticisms have been made apparent in the literature (van Meerbeeck et al. 2011, Inoue et al. 2012). Inoue et al. (2012) suggest that the staging in these studies could be considered inaccurate as the diagnostic imaging available at that time was minimal. Furthermore, a review of the data from these studies, suggests that the usefulness of surgery was underestimated because resection was not complete in all patients assigned surgery (van Meerbeeck et al. 2011). Retrospective reports suggest that surgery led to good local control and favorable long-term survival in selected patients with stage IIII SCLC (Lim et al. 2008, Yu et al. 2010).

As the majority of patients with non-metastatic SCLC present with unresectable stage III tumors, the role of surgery has never been significantly explored (van Meerbeeck et al. 2011). This remains a novel field of research presenting its own challenges for example the recruitment of the appropriate number of patients with limited stage disease that could be considered for surgery for a large RCT is extremely difficult at present.

Price and Nichols (2010) present four examples where surgery may be an appropriate method of treatment for SCLC: SCLC presenting as a Solitary Pulmonary Nodule (SPN) and diagnosed at the time of surgery; mixed histology (i.e., SCLC and non-SCLC combined); salvage therapy for local failure of chemo/radiotherapy; and, planned multimodality therapy consisting of induction chemotherapy followed by surgery for limited-stage SCLC. However, the exact role of surgery in treating SCLC remains elusive because of the paucity of up-to-date information.

2.4.3.3 Emerging therapies 2.4.3.3.1 Targeted therapy

Lung cancer is a complex disease to treat and with advances in genotyping and genetic profiling Hensing et al. (2014) suggest that the simple division of lung cancer into two groups (NSCLC and SCLC) is no longer sufficient. Due to advances in the understanding of biological and molecular mechanisms of tumours, lung cancer is no longer seen as a single disease entity but is now being divided into molecular subtypes allowing for particular targeted therapies to be developed and used in a more personalised manner (Li et al. 2013). NCSLC, in particular, has been at the forefront of these advances, in particular with the understanding of activating mutations in Epidermal Growth Factor Receptor (EGRF) (Hensing et al. 2014).

Targeted therapy treatments aim to target specific molecules involved in tumour growth and progression and are currently most often used in combination with traditional chemotherapies in advanced NSCLC (Janku et al. 2010). The development of such drugs may provide advantages over traditional chemotherapy, in particular with regards to side-effects (Moore 2009). Traditional chemotherapy is generally effective in fast dividing cells, such as cancer cells, but also affects other bodily cells, for example, gastrointestinal lining, bone marrow and hair follicles. This explains the common side effects of treatment (nausea and vomiting, immunosuppression and hair loss). Newer biological/targeted therapies however are more targeted towards the tumour and less harmful to normal cells with the benefit of fewer systemic side effects (NCI 2012).

Most targeted therapies focus on proteins involved in cell signalling pathways that govern basic cellular functions, such as cell division, movement, responses to specific external stimuli, and apoptosis (cell death) (NCI 2012). For example, some targeted therapies block the growth and division of cancer cells whilst others cause cancer cell death directly, by specifically inducing apoptosis, or indirectly, by stimulating the immune system to recognise and destroy cancer cells (NCI 2012).

In lung cancer, newer drugs such as Gefitinib, Erlotinib and Bevacizumab have a more targeted approach than chemotherapy and therefore do not have the same side-effect profile, particularly with regard to myelosuppresssion (Moore 2009). In 40% to 80% of patients with NSCLC, EGFR is overexpressed and is associated with a poor prognosis (Chirieac and Dacic 2010). EGRF is thought to play a key role in increasing proliferation, decreasing apoptosis and enhancing cell motility and angiogenesis (formation of the blood supply to the tumour) (Wieduwilt and Moasser 2008). Studies suggest that patients who have a particular EGFR mutation are likely to benefit the most from these drugs (Mok et al. 2009, Rosell et al. 2009); however, response rates can be low if it is given to unselected patients (Shepherd et al. 2005).

2.4.3.3.2 Radio Frequency Ablation (RFA) and Stereotactic Radiation Therapy (SRT)

Newer therapies (not available UK wide) that have been shown to be successful in improving survival of inoperable stage I NSCLC are Radio Frequency Ablation (RFA) and Stereotactic Radiation Therapy (SRT) (Bilal et al. 2012). RFA involves a CT guided needle electrode placed into the tumour. Radiofrequency energy then creates heat within the tumour which causes local coagulation of tissue killing cancer cells (CRUK 2013b). A small rim of normal tissue is also treated to help reduce the risk of recurrence (NICE 2010).

SRT is a non-invasive treatment which involves the use of extremely high doses of radiation usually delivered in three to eight treatment fractions within a 2-week period (Haasbeek et al. 2008). SRT is characterised by; (a) reproducible immobilization to avoid patient movement during treatment sessions; (b) measures to account for tumour motion during imaging, planning, and delivery; and (c) use of dose distributions tightly covering the tumour, with rapid dose falloff in surrounding normal tissues in order to reduce toxicity (Haasbeek et al. 2008).

In early stage lung cancer, studies investigating these newer treatments have suggested increased survival over other conventional methods of treatment (e.g. conventional radiotherapy (Haasbeek et al. 2008, Bilal et al. 2012)) for inoperable patients, however, disease recurrence is common (Beland et al. 2010). Beland et al. (2010) retrospectively examined frequency, location, and time of recurrence in 79 patients who had undergone RFA and reported a recurrence rate of 43% within four years (Beland et al. 2010), while median disease free survival was reported to be 23 months. Increasing tumour size and disease stage at the time of RFA were shown to be significantly associated with likelihood of recurrence. This has been reported elsewhere; a review by Bilal et al. (2012) documented increased recurrence rates with larger tumours and advanced disease stage following RFA. Although tumours five centimetres in size can be effectively treated with RFA, the results from this review demonstrated that outcomes are better for tumours 3 cm (Bilal et al. 2012).

A review by Renaud et al. (2013) addressed the question of which radiotherapy technique is best for treating NSCLC (SRT or RFA) and found that studies reported better local control and survival rates for SRT compared with RFA. However, the role of SRT and RFA is still being established either as stand-alone therapies or in combination with other therapy (Beland et al. 2010). Although they are considered in the treatment of early stage lung cancer they have not been shown to be as successful as surgery in terms of potentially curative treatment (for patients who are operable) (Haasbeek et al. 2008). Due to the infancy of studies in this area, investigation of optimal timing, frequency and intensity remain under investigation. Side effects have been reported as minimal with a risk of pneumothorax in RFA (Bilal et al. 2012). However, as studies investigate components such as the timing, frequency and intensity of treatment this may become more apparent (Haasbeek et al. 2008).

As presented in this section treatment for lung cancer can trigger many negative side effects which add to the burden of the disease. The following section discusses patient experience and addresses the needs that have been expressed in the literature and the limitations of the evidence to date.

2.5 Patient experience of lung cancer and surgical treatment

Studies throughout the literature illustrate the severity of the burden experienced by people diagnosed with lung cancer. Compared with the symptom experiences of patients in a variety of cancer populations, people diagnosed with lung cancer have been shown to experience both the greatest number of symptoms and concerns about health and existential issues (Weisman and Worden 1976, Zabora et al. 2001). Independent of treatment regime, people diagnosed with lung cancer can face many obstacles (physical, social, emotional, psychological) (Molassiotis et al. 2011). Important in the study of all health care research is understanding patient experience of the disease and its treatments and side effects in order to gain insight into patient needs - the Medical Research Council (MRC) framework (Craig et al. 2008) for developing complex interventions advocates that it is important to consult those at whom an intervention is targeted in order to best inform the development of effective interventions to address patient reported needs.

The aim of this section is to present and discuss the disease and treatment related burden of lung cancer (with a focus on surgical treatment) from a patient perspective. A variety of adverse physical, emotional, functional and psychological consequences of lung cancer and its treatment will be discussed. Whilst some of the physical side effects of treatments have been mentioned in previous sections, they will be covered in depth in the following section.

2.5.1 Burden related to lung cancer

A diagnosis of lung cancer can be an emotional and distressing experience which can generate fear and turmoil in the lives of patients and their families (Zabora et al. 2001, Ellis 2012). Studies of patients diagnosed with lung cancer report high rates of clinically significant depressive symptomatology shortly after diagnosis and after treatment completion (Montazeri et al. 1998, Hopwood et al. 2000). These rates exceed those observed for other cancer sites (Gonzalez and Jacobsen 2012). Gonzalez and Jacobsen (2012) suggest that one of the contributing factors that may be related to depressive symptomatology in people with lung cancer opposed to other types of cancer is perceived stigma.

Perceived stigma is the perception that one is subjected to the uniform responses from others expected for an individual with a certain label (Gonzalez and Jacobsen 2012). Stigma and its effects have been examined in people who are HIV-positive where individuals often perceive (accurately or inaccurately) that they are subjected to uniform responses from society as a result of their medical condition due to the fact that this disease is often transmitted via sexual behavior and intravenous drug use (Purcell et al. 2001). Given the strong association between lung cancer and tobacco use, lung cancer is commonly viewed as a preventable disease and thus patients often feel stigmatised for having caused the illness because of their past or current smoking habit (Holland et al. 2010). Consequently, patients may blame themselves and others may blame patients for developing lung cancer (Chapple et al. 2004).

People with lung cancer have reported feeling stigmatised whether they have smoked or not and describe feelings of blame and difficulties accessing support (Chapple et al. 2004, Else-Quest et al. 2009). Stigma can lead to feelings of guilt and shame and may increase distress, possibly contributing to psychological and social morbidity (Chapple et al. 2004). Chapple et al. (2004) explored the perceptions and experience of stigma in 45 participants with lung cancer and reported that participants felt that their cancer was more stigmatised than other cancers due to the strong relationship between smoking and lung cancer.

Apart from the burden patients experience of being diagnosed with lung cancer, each person experiences their own symptom burden with regards to different treatments and their side effects. For the purposes of this PhD project the following section focuses on the burden patients experience related to the surgical pathway.

2.5.2 Burden and needs related to surgical treatment

Despite the possibility of a cure, surgical resection is associated with significant morbidity, functional limitations and decreased QOL post-surgery (Handy et al. 2002, Kenny et al. 2008). Patients radically operated for lung cancer experience impairments in physical functioning (Ostroff et al. 2011) and report persistent respiratory problems, mostly dyspnoea (Larsen et al. 1997, Sarna et al. 2004, Ostroff et al. 2011), resulting in reduced QOL (Sarna et al. 2002). Dyspnoea, fatigue, pain and depression have been reported to be very distressing symptoms after lung cancer surgery often resulting in reduced function and ability to return to normal activities (McManus 2003, Sarna et al. 2008, Sarna et al. 2010).

Studies of post-treatment morbidity in lung cancer have focused mainly on patient outcomes in people treated with chemotherapy and/or radiotherapy (Molassiotis et al. 2011). There is limited research available on the study of patient experience of symptoms after lung cancer surgery (Sarna et al. 2008, Sarna et al. 2010).

Two studies carried out by Sarna et al. (2008, 2010) explored the symptom experience of patients treated surgically for lung cancer. The first study surveyed 94 patients one, two, and four months after lung cancer surgery. This study noted multiple symptoms experienced by patients over the first four months post-surgery including: fatigue (57%), dyspnoea (49%), cough (29%), and pain (20%), and found that these symptoms were amplified in participants with significant mood distress (Sarna et al. 2008).

In this study the frequency of patients with the most severe symptoms decreased significantly over time for all symptoms except cough. The most common symptom at each time point was fatigue followed by shortness of breath. Problems with appetite decreased the most and cough decreased the least. The number of patients with depressed mood decreased by 9% from one month to four months, but 26% of patients presented with depressed mood at four months. Severe pain (according to the categorical definitions for severe pain from the Brief Pain Inventory) was reported by 26% of patients at one month, 17% at two months, and 12% at four months. Although some symptoms reduced over the time period measured, this study demonstrates that symptoms can prevail for many months after surgery.

Their latter study (Sarna et al. 2010) examined QOL in 119 women who were disease free up to six years after lung cancer surgery. Patients were assessed at three time-points; study entry, and three and six months after baseline. Depressive symptoms remained common (29%) and were associated with reduced QOL (Sarna et al. 2010). These two studies however focused on specific scale measurements using a quantitative approach limiting the scope of understanding of patient experience of symptoms.

What is evident in the literature concerning symptoms from cancer treatment is that symptoms rarely present in isolation (Burkett and Cleeland 2007, Shi et al. 2011). Emerging research suggests that multiple symptoms may stem from the same aetiology (e.g., inflammatory cytokines) (Rausch et al. 2010, Wang et al. 2010, Kirkova et al. 2011). More recently there has been a growing awareness that symptoms frequently co-occur in symptom clusters (Dodd et al. 2001) and that understanding these clusters may improve the management of ongoing and unrelieved symptoms in patients (Cheville et al. 2011, Maguire et al. 2014). For example, patients experiencing dyspnoea, a common symptom experienced in patients with lung cancer, can often become anxious, which can then exacerbate the sensation of breathlessness, creating a regenerative feedback loop (Buchanan et al. 2010). However, to date, research examining the effects of multiple symptoms among individuals with lung cancer has primarily focused on the active treatment phase or in those with advanced disease (Burkett and Cleeland 2007, Molassiotis et al. 2011).

Only more recently have the unmet needs of patients surviving surgical resection started to be investigated (Yun et al. 2013). Yun et al. (2013) found there were substantial unmet needs for information regarding psychological support, education for diet and exercise, and financial support. Yun et al. (2013) surveyed 830 people in Korea who had undergone curative lung cancer surgery, the highest level of need was seen in the information domain, in particular in relation to treatment and prognosis. The supportive care domain showed moderate levels of need in relation to side effects for cancer therapy and in particular the management of pain, fatigue and appetite loss.

The needs of people undergoing lung cancer surgery have not been given much attention in the literature to date. However, the burden related to surgical treatment needs to be considered, especially due to the projected increase of surgical candidates. Furthermore, and of importance in the rationale for this PhD, symptoms such as dyspnoea and fatigue are often not adequately relieved by pharmacological interventions which can often cause adverse effects (Bausewein et al. 2008). Non-pharmacological interventions such as education, inspiratory muscle training and physical activity have been shown to be effective in respiratory diseases such as COPD and included as part of pulmonary rehabilitation to address negative symptoms (Wagland et al. 2012). Thus Wagland et al. (2012) have suggested that these may be transferable and effective in lung cancer settings to reduce symptom burden.

Lastly, adverse functional impairments can reduce the patients ability to perform normal daily activities and tolerate physical activity (Jones et al. 2009b). Many patients become less physically active during treatment for cancer and often do not return to pre-diagnosis levels once treatment is over (Blanchard et al. 2003, Pinto and Trunzo 2005), thus reducing their exercise capacity and functional ability [poor exercise capacity can increase a patients susceptibility to other common age-related diseases, poor QOL and premature death (Jones et al. 2009b)]. Therefore, it is not solely the direct treatment side effects that can contribute to co-morbidity and survival but also the indirect effects of entering a cycle of deconditioning. This further demonstrates the complex relationships between symptoms and outcomes that need to be addressed in intervention development.

2.6 Conclusion

It is evident from this chapter that lung cancer, its management, treatment and related burden is complex and each area requires ongoing investigation and development. Although at present the minority of patients diagnosed with lung cancer will undergo surgery, a government focus on the early detection of cancer alongside lung cancer screening programmes being trialled across the country, may result in an increase in the number of patients with early stage disease, thus increasing the number of curative treatments being performed (SG 2011). With the knowledge that surgical resection can increase symptom burden and decrease QOL and functioning, a need for investigation of improvement in surgical management and novel interventions to improve patient outcomes is warranted.

Cancer care is being directed toward developing interventions that improve overall functioning as well as longevity (McNeely et al. 2006). There has been a growing interest in the use of non-pharmacological interventions, such as exercise, both during and after cancer treatment. Exercise intervention for people with cancer will be the focus of the next chapter in order to give insight into the evidence available and provide a base for the work carried out in this PhD project.

Chapter 3: Exercise and cancer3.1 Introduction

In the previous chapter, an overview of lung cancer was provided and the rationale for an intervention to improve outcomes for patients who are surgically treated for lung cancer was presented. This chapter examines the use of exercise as an intervention for people during and beyond a diagnosis of cancer and provides an evidence base for the work carried out in this PhD project.

The chapter will start by providing the context of exercise intervention in relation to health and go on to discuss the literature in the field of exercise and cancer. It will cover the most recent literature regarding exercise during different stages of the patient pathway (during and post-treatment, and pre-treatment) and demonstrate where the evidence is most compelling. It does not cover the areas of primary and secondary prevention and palliative care as it was felt that these lie out with the focus of this PhD. It will further discuss the development of exercise guidelines for people with cancer before specifically covering the evidence in relation to exercise for people diagnosed with lung cancer. Finally, concerning the theoretical underpinning to this study, research into exercise behaviour change theories will be discussed and the underpinning theoretical framework used throughout this thesis will be justified.

3.2 Exercise intervention in the context of health

The World Health Organization (WHO) (2010) reported that physical inactivity is the fourth leading risk factor for global mortality, accounting for 6% of deaths globally. A recent analysis of the worldwide burden of disease estimated that physical inactivity was responsible for 7% of type 2 diabetes, 6% of the incidence of coronary heart disease, 10% of breast cancer, and 10% of colon cancer (Lee et al. 2012).

Despite evidence that physical inactivity is a risk factor for a number of diseases (Wilmot et al. 2012, Henson et al. 2013), only 58% of men and 46% of women are meeting government targets for physical activity in the UK (Townsend 2015). In 2011, the Department Of Health (DOH) published physical activity guidelines (Department Of Health. DOH 2011) for healthy adults in the UK (at least 150 minutes of moderate intensity exercise per week and resistance exercises on at least two non-consecutive days of the week). Although current guidelines are not specific regarding daily sedentary time, the DOH (DOH 2011) recommend reducing total sedentary time and breaking up extended periods of sitting.

Exercise and physical activity have played a role in the prevention and/or management of many chronic conditions, including coronary heart disease (Swift et al. 2013), hypertension (Ash et al. 2013), type II diabetes (Colberg et al. 2010), obesity (Hopps and Caimi 2011), stroke (Pang et al. 2013), COPD (Maltais 2013), and mental health problems (Dunn and Jewell 2010, Carek et al. 2011, Rimer et al. 2012). The health benefits of exercise are widely understood and structured exercise training has been established as the cornerstone of primary and secondary disease prevention in multiple clinical settings. For example, cardiopulmonary rehabilitation (of which exercise is a major component) has been a key health care service in both cardiac and pulmonary diseases such as Cardio Vascular Disease (CVD) and Chronic Obstructiv