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Cachexia is common in patients with incurable cancer, particularly of the lung and upper-gastrointestinal tract, and impacts adversely on treatment options, morbidity, quality of life and survival. Current management of cancer cachexia is inadequate and progress is required. This thesis explores the use of exercise as a proactive supportive therapy with a focus on maintaining physical function. The first piece of work was a systematic review of the use of therapeutic exercise in patients with or cured of cancer. Across 65 exercise studies, the median [IQR] rates of uptake, adherence and completion were 63 [33–80]%, 84 [72–93]% and 87 [80–96]% respectively, with no characteristic influencing the proportion of patients taking up or completing a programme. The main reasons reported for refusal were lack of interest or the impracticality of the programme and for withdrawal were medical complication or deterioration. Overall, only about half of patients offered an exercise programme completed one. This review highlighted a need to modify existing programmes or explore novel alternatives if exercise is to be acceptable to the majority of patients. The second study explored exercise preferences in patients with incurable cancer. A questionnaire was used to determine patients’ perceived capability and preparedness to undertake six different exercise programmes, each illustrated by video clips and accompanying text, and preferences for the delivery of the most preferred programme. All 200 patients considered themselves physically capable of undertaking an exercise programme and two-thirds were prepared to undertake one at that moment in time. The most preferred type of exercise was neuromuscular electrical stimulation (NMES) 36 [35−44]%, followed by walking 22 [16−30]% and resistance training 19 [13−26]% and the majority preferred to undertake exercise at home, alone and unsupervised. This survey suggested that it is realistic to offer therapeutic exercise programmes to patients with incurable cancer and provided rationale to explore NMES in this group. The third study was a randomised controlled pilot study of NMES in patients with non-small cell lung cancer. Sixteen patients were randomised to a control group, which received usual care, or NMES group, which received daily stimulation to the quadriceps for up to 30min (frequency 50Hz, on phase 11−25%) for four weeks. All patients found the NMES device acceptable and median (range) adherence to the recommended programme was 80% (69-100). In the NMES group, quadriceps muscle strength and free-living physical activity improved by a mean of 7.4 Newton metres (22%) and 136 steps (11%) respectively, whilst exercise endurance deteriorated by a mean of 20 metres (4%). This compared favourably with the control group however none of the differences were statistically significant. These findings suggested NMES was an acceptable type of exercise and that further study is warranted in patients with lung cancer. The final piece of work was a feasibility study into the use of a lightweight ActivPAL™ monitor to measure physical activity level. The aims were to determine if this form of assessment is acceptable to patients, the optimal period of monitoring and to explore the added value of the monitor's energy expenditure (EE) estimate over a simple step count. Sixty patients with lung or upper-gastrointestinal cancer wore a monitor for one week. All but one found the monitor acceptable and mean [95% CI] adherence was 98 [94−100] %. Mean daily step count and EE values measured over 2 and 4 days were significantly higher than those from 6 days (p<0.01). Step count was strongly related to stepping EE and non-stepping EE. The ActivPAL™ monitor was shown to be an acceptable method of assessing physical activity level. A mean daily step count obtained over 6 days was recommended for use in future cachexia studies. Collectively, this work supports the use of therapeutic exercise and highlights a particular role for novel approaches, e.g. NMES, which may be more acceptable to patients. Findings can be used to guide future research which ultimately will determine if therapeutic exercise can help patients with cancer to maintain their level of physical activity and independence for as long as possible.

'Background: There is growing evidence of socioeconomic inequality in palliative and end-of-life care, yet our understanding of the causes of this inequality and how to address it is lacking. In the context of an ageing and increasingly unequal society, understanding the patterns and determinants of socioeconomic inequality in palliative and end-of-life care is essential for informing ways to deliver care more equitably. Aim: To investigate patterns and determinants of socioeconomic inequality in palliative and end-of-life care for older adults, and to explore potential mediating factors of the relationship between socioeconomic position and patterns of care towards the end of life. Methods: This thesis investigates socioeconomic inequality in palliative and end-of-life care using three secondary analysis studies: i) Systematic review and meta-analysis of existing evidence on the association between socioeconomic position and service use and outcomes in the last year of life, including place of death, hospital admissions in the last three months of life, and access to specialist palliative care. ii) Secondary analysis of data from the English Longitudinal Study of Ageing (ELSA) using mediation analysis to estimate the direct effect of wealth and education (exposures) on place of death and frequent hospital admissions in the last two years of life (outcomes), and the indirect effects via health and function, access to services and social support (mediators). iii) Secondary analysis of routinely collected clinical data to analyse the relationship between area-based deprivation and the symptoms and concerns of hospital inpatients referred to specialist palliative care, using data from a validated patient centred outcome measure, the Integrated Palliative Care Outcome Scale (IPOS). Results: Based on 112 high-to-medium quality studies, the systematic review and meta-analysis found consistent evidence that in high income countries, people with low socioeconomic position were more likely to die in hospital versus home/hospice (OR 1.30, 95% CI 1.23-1.38, p < 0.001), to receive acute hospital-based care in the last 3 months of life (OR 1.16, 95% CI 1.08-1.25, p < 0.001), and to not receive specialist palliative care (OR 1.13, 95% CI 1.07-1.19, p < 0.001). The dose-response analysis found that for a 1 quintile increase in area-based deprivation the log-odds of dying in hospital versus home increased by 1.07 (95% CI 1.05-1.08, p < 0.001), and the log-odds of not receiving specialist palliative care increased by 1.03 (95% CI 1.02-1.05, p < 0.001). The review also found no studies investigating the causes of socioeconomic inequality in palliative and end-of-life care, and no high or medium quality studies using validated patient centred outcome measures to investigate inequality. The secondary analysis of ELSA and of the routinely collected clinical data address these gaps. The mediation analysis using ELSA included 737 participants (median age 78 years (IQR 71-85). For death in hospital, higher wealth had a direct negative effect (probit coefficient -0·16, 95% CI -0·25 to -0·06), which was not mediated by any of the pathways tested. For frequent hospital admissions, health and function mediated the effect of wealth (-0·04, -0·08 to -0·01), accounting for 34·6% of the total negative effect of higher wealth (-0·13, -0·23 to -0·02). The analysis of clinical data on the symptoms and concerns of palliative patients included data on 7,860 patients (median age 82 years (IQR 74-89) found that patients living in more deprived areas had a higher burden from practical and communication concerns. The predicted mean score for practical and communication concerns for the most deprived group was 5.38 (95% CI 5.10, 5.65) compared to 4.82 (95% CI 4.62, 5.02) for the least deprived (higher scores are worse). Area deprivation was not associated with physical or emotional symptoms. Conclusions: The systematic review and meta-analysis provide consistent evidence that low socioeconomic position is a risk factor for death in hospital as well as other service-level indicators of potentially poor-quality end-of-life care and demonstrates consistent evidence of a socioeconomic gradient for death in hospital and access to specialist palliative care. The mediation analysis identifies for the first time, that worse health and function may cause people with lower wealth to have more hospital admissions. This challenges behavioural explanations and highlights the importance of socioeconomically driven health differences in explaining different patterns of hospital use towards the end of life. For hospital inpatients seen by palliative care, the findings suggest that one way to reduce inequalities could be to target resources at addressing the practical and communication concerns of patients who live in more deprived areas. The findings identify several implications for policy, practice and research including, the need to: monitor inequalities and to use this data to inform service delivery; evaluate interventions for unequal effects across social groups; and raise awareness among the public and health care professionals about socioeconomic inequality in palliative and end-of-life care. Methodologically, the thesis provides the first example of a mediation analysis used to study causes of inequality in palliative and end-of-life care and demonstrates novel use of existing longitudinal cohort study data and routinely collected patient centred outcomes data.

Background: By 2060, the highest increase in mortality associated with serious health-related suffering will occur in low- and middle-income countries. Palliative care can relieve serious health-related suffering, lower costs for the health system and families, and is an essential health service within universal health coverage. Nevertheless, in Nigeria and many other low and middle-income countries, palliative care provision has remained at the tertiary level, and lack of integration into primary care denies access to those who are most in need. Aim: To develop an integrated primary palliative care intervention for patients with serious illnesses and their families within primary healthcare in Nigeria, and to test the feasibility of the intervention training among primary healthcare providers. Methods: A sequential mixed methods design was employed, underpinned by the pragmatist approach and the Medical Research Council framework for developing complex interventions. First, a mixed-methods systematic review used a sequential synthesis design to clarify the problem theory i.e., the concept of palliative needs among patients with serious illnesses and their families in Africa. A descriptive qualitative interview study was conducted with 48 participants; people living with selected serious illnesses i.e., cancer, heart failure, tuberculosis and stroke (n=21); their families (n=15); and primary healthcare providers (n=12) from three primary healthcare facilities in Nigeria. Two online theory of change workshops were then conducted to design an integrated primary palliative care intervention, with primary healthcare providers (n=19) and specialist palliative care providers (n=9). Finally, a mixed-method study with a pre-test-post-test design and an embedded focus group discussion was used to evaluate the feasibility of the 3-day intervention training, with primary healthcare providers (n=13) from three primary healthcare centres in Nigeria. Recruitment and retention were evaluated as well as participants knowledge, attitudes, confidence and reaction to the intervention training (satisfaction, engagement, perception of intervention appropriateness, acceptability and feasibility). Results: The systematic review included 159 studies and found context-specific palliative care needs such as managing pregnancy and breastfeeding, preventing infection transmission (physical); health literacy needs, worry about medical bills (psychological); isolation and stigma, overwhelmed families needing a break, struggling to pay children's school fees and selling assets (social and practical needs); and rites associated with cultural and religious beliefs (spiritual). Findings from the qualitative study suggested that integrated primary palliative care must consider three major themes: 1) Engaging patients and families, who have existing trust and bonds from using primary healthcare but lack the individual agency necessary for person-centred care decisions; 2) Managing patients' and families' expectations and preferences, for an easily accessible service that prioritises opportunities for social interaction and adequate communication; 3) Addressing staffing-related issues, including development of healthcare providers to ensure an appropriate clinical response, manage interprofessional trust and ensure clear role delineation. The intervention theory of change highlighted: 1) the prerequisites for integration i.e. availability of specialist palliative care team and willing non-governmental organisations for referrals of complex needs, medicines access and social support needs; 2) the implementation considerations i.e. engaging patients, families and communities through street-to-street awareness and ward health committee meetings, provision of Information, education and communication materials about serious illnesses, and interprofessional palliative care training and supervision for primary healthcare providers; 3) Outcomes i.e. improved knowledge of serious illnesses, feeling heard and valued, physical and psychological symptom relief, reduced financial and caring burden. This model is based on assumptions that patients and family members understand the usefulness and relevance of the intervention and that primary healthcare providers adopt the intervention into their ways of working. Findings from the intervention training feasibility study showed 87% participants' recruitment and 92% of retention targets were met at the end of the training. All who were retained (n=12) agreed or strongly agreed that the intervention is appropriate, acceptable and feasible within primary healthcare, and were very satisfied with the training. Participants' knowledge and confidence scores increased. However, attitude scores increased, reduced and remained unchanged in five, six and one participants respectively. Attitudes became more polarised concerning morphine use, providing spiritual care, caring for the dying within primary healthcare and the ethical obligation of palliative care. Conclusion: Prior evidence on palliative care needs in Africa is more focused on physical and psychological domains. The novel African-specific framework of palliative care needs will be useful for comprehensively assessing the multidimensional palliative care needs of patients with serious illness and their families within primary healthcare. Wide-scale engagement is needed in Nigeria to reinforce the role of primary healthcare in the ongoing management including palliative care of patients with serious illnesses and their families to ensure an appropriate response at the primary healthcare level. The integrated primary palliative care intervention training is perceived as feasible, acceptable and appropriate. The training also improved the knowledge and confidence of primary healthcare providers to deliver the integrated primary palliative care intervention. However, there is a need to further refine the intervention training around attitudes to diverse expressions of spirituality by patients and families, managing dying patients, and safe opioid prescription within primary healthcare.

Background: The population living with advanced cancer or respiratory disease is aging, resulting in changing care needs. Difficulty or inability to perform daily activities, known as disability in activities of daily living (ADLs) is one of the most common unmet needs in these populations. The prevalence of disability in ADLs is set to rise, resulting in a greater demand for care and rehabilitation. Rehabilitation interventions targeting disability in ADLs could help people maintain independence and delay or reduce need for care, but rehabilitation provision is currently inadequate across cancer and respiratory services. A better understanding of disability in ADLs and factors influencing change over time would help improve timing and delivery of rehabilitation interventions and equity in service provision. To understand and compare disability in activities of daily living (ADLs) among adults with advanced cancer or respiratory disease, thereby informing future rehabilitation intervention(s). Method: An observational study was conducted consisting of two components with convergent design. Component 1: Secondary analysis of data from the International Access Rights and Empowerment programme (IARE), pooled from two studies relating to older people receiving palliative care (IARE I) or frail elderly (IARE II). The selected sample consisted of people with advanced solid cancer or Chronic Obstructive Pulmonary Disease (COPD). Measures assessed disability in basic ADLs (Barthel Index), symptom severity (Palliative care Outcome Scale), and assistive device use (self-reported). Component 2: A multi-site prospective cohort study in people with advanced non-small cell lung cancer (NSCLC), COPD or Interstitial Lung Disease (ILD). Self-reported questionnaires were completed at baseline and then monthly over 6-months. Primary measures for basic and instrumental ADLs were assessed using the Barthel Index and the Lawton-Brody IADL Scale respectively. Explanatory variables included difficulty in daily activities (World Health Organization Disability Assessment Schedule-2.0), symptom severity (Palliative care Outcomes Scale - Symptoms), and physical and social isolation (self-reported). The latter measure was introduced in response to the Covid-19 pandemic. Analysis: Univariable and multiple variable logistic regression analysis was used to examine factors associated with disability in ADLs cross-sectionally at baseline, in components 1 and 2. Visual graphical analysis explored individual disability trajectories. Longitudinal data from the cohort study were analysed prospectively over six months and summary statistics were used to determine trajectories of ADL disability at group level. Univariable associations for variables recorded at baseline, between each basic ADL and instrumental ADL disability trajectory (increasing, decreasing, fluctuating) compared to the stable trajectory were explored using the Mann-Whitney-u test and chi-square test of independence. Multiple variable logistic regression analysis was used to examine factors associated with increasing disability in basic and instrumental ADLs over 6-months. Significance levels were set at 0.01 to account for multiple testing. Results: Component 1: The pooled sample consisted of 159 participants (140 (94%) cancer, 19 (6%) COPD). 79% had disability in basic ADLs, which was most prevalent in stair climbing (65%), bathing (48%), dressing (39%), and mobilising (36%). Greater disability was independently associated with increased symptom burden (odds ratio, 1.08 [95% CI:1.02-1.15], P=0.01) and walking unaided (z=2.35, P=0.02), but not with primary diagnosis (z=0.47, P=0.64). There was wide inter-individual variation for change in disability in basic ADLs over time. Component 2: Between March 2020 and January 2021, 110 NSCLC, 72 COPD, 19 ILD (121 (60%) had stage IV disease) participants were recruited, during the first year of the UK Covid-19 pandemic. At baseline, 104 (52%) and 142 (71%) were not fully independent in basic and instrumental ADLs, respectively. One-hundred-and-ninety-seven (96%) had difficulty in undertaking daily activities. In the cross-sectional analysis, disability in basic ADLs was independently related to prolonged physical and social isolation (odds ratio [OR], 1.17 [95% CI: 1.03- 1.33], p=0.01), COPD or ILD (OR, 4.00 [95% CI: 1.20-8.14], p<0.001), and increased symptom severity (OR, 1.12 [95% CI: 1.06-1.19], p<0.001). Disability in instrumental ADLs was independently related to COPD or ILD (OR, 3.6 [95% CI: 1.41-7.10], p=0.005) and increased symptom severity (OR, 1.14 [95% CI: 1.07-1.22], p<0.001). In the longitudinal sample (n=151), individual trajectories of ADL disability revealed wide variation in individual change, which were masked at group-level. Four different patterns emerged: increasing, decreasing, fluctuating, or stable. No independent predictors of basic ADL disability were identified. The only independent predictor of increasing disability in instrumental ADLs was difficulty mobilising (controlling for baseline diagnosis, symptom severity, disability in ADLs, age, sex, living status, assistive device use, and physical activity). Every increase of 1 point on the WHODAS-2.0. mobility domain, increases the odds of a person following a trajectory of increasing disability in instrumental ADLs compared to a stable trajectory (odds ratio, 1.41 [CI: 1.14-1.74], p=0.002). Conclusion: Disability in ADLs affects over half of people with advanced cancer or respiratory disease. Instrumental ADLs are more commonly affected than basic ADLs. Greater symptom severity and Covid-19-related physical and social isolation are associated with increased ADL disability at baseline. There is wide individual variability in disability over time, however, an increasing disability trajectory can be predicted by mobility limitation, which could be used to prompt referral to rehabilitation services. In clinical care, screening for mobility limitation is indicated among people with increased symptom severity, and people who have been physically or socially isolated. When assessing ADL disability, the measurement of difficulty and dependency is recommended, and disability management should be aligned with good symptom control. Further investment into rehabilitation is required to implement these recommendations and improve services for these groups.

Background: Worldwide, more people are diagnosed with and die from thoracic cancer (cancers of the respiratory tract, lung and pleura) than any other cancer. Most present with incurable disease and despite new advances in treatment, will be living with the consequences of advanced disease. Patients experience an array of symptoms, which impact on function and daily life. Rehabilitation aims to ameliorate the functional impairment and improve participation in daily life. Although guidelines recommend that patients should have access to rehabilitation, few cancer services integrate rehabilitation within the core treatment pathway. Aim: This study aims to develop and assess the feasibility of testing a brief integrated rehabilitation intervention for people newly diagnosed with thoracic cancer. Method: A sequential exploratory mixed methods approach, following Medical Council Guidance for the development and evaluation of complex interventions, was used to develop and test the new rehabilitation interventions. During the development phase, a systematic review explored the application of behaviour change theory and techniques in empirical rehabilitation studies in this population. Concurrently, focus groups, held with patients, family members and clinicians, elicited views on the aims, content and delivery of the proposed rehabilitation intervention. These data were integrated with reflection on theory to inform a conceptual model of brief integrated rehabilitation and set out key components, processes and outcomes of the new rehabilitation intervention. Guidelines were followed to produce an Intervention Manual to support fidelity during delivery and evaluation of the intervention in a randomised controlled feasibility trial. During the feasibility phase, participants with a recent diagnosis of lung cancer or pleural mesothelioma on any treatment pathway were recruited to a parallel group 1:1 randomised controlled multicentre feasibility trial of short-term integrated rehabilitation plus standard care versus standard care. Primary outcomes included recruitment and retention. Target recruitment was 30% of eligible participants and for more than 50% to be retained on study at 30 days. Secondary outcomes included intervention fidelity and performance of clinical outcome measuring symptoms, physical activity, self-confidence to manage disease, quality of life and health service use. A post-trial questionnaire elicited experiences of participation in the trial. A final analysis of data integrated from each phase of the study explores how the thesis aims and objectives were met. Results: Twenty-seven studies of exercise (n=15) and symptom self-management (n=12) interventions were identified in the systematic review. Application of behavioural change tools was found to be sub-optimal. Theories were used infrequently; four studies reported use of behavioural change theory and one used a symptom theory. Across studies, a mean (range) of 7 (1-18) behaviour change techniques (BCTs) were identified from intervention reports, representing 26 of 93 possible BCTs from the behaviour change techniques taxonomy vs. The most frequently identified BCTs to enable behaviour change were ‘instructions on how to perform behaviours’ (74%), ‘behavioural practice’ (74%) and ‘action planning’ (70%). BCTs to address barriers were identified less frequently and included ‘information about health consequences’ (22%), and ‘verbal persuasion about capability’ (7%) to change perceptions about benefits and harms. Fifteen clinicians (oncologists, nurse specialists, physiotherapists and occupational therapists), nine patients and five carers participated in the focus group study. A proposed outline rehabilitation model was perceived as highly relevant for this population. Participants recommendations refined the model. Prompt, brief, rehabilitation input, delivered whilst people attend for hospital appointments or at home should maximise accessibility and acceptability. Participants recognized variation in need and all prioritised tailored support for symptom self-management, daily activities and the involvement of carers. Clinicians also prioritised achieving fitness for oncology treatment. Patients and carers prioritised a sensitive manner of approach, positivity and giving hope for the future. Participant’s recommendations for outcome measurement related to confidence in usual daily activities, symptom control, and oncology treatment completion rates over objective measures of cardiorespiratory fitness. Subsequent integration of the systematic review and focus group findings with reflection on theory informed the development of a conceptual model, an intervention manual detailing rehabilitation processes and components, and a trial protocol for testing brief integrated rehabilitation in a multi-centre randomised controlled feasibility trial. The feasibility trial recruited 54 of 159 (34%) eligible patients and 44/54 (82%) and 39/54 (72%) participants provided data at 30 days and 60 days respectively. Intervention fidelity was high: 25/26 participants allocated to integrated rehabilitation received a median 3 (range 1-3) sessions of rehabilitation over 32 (22-45) days. Trial and intervention satisfaction were high. Five participants reported that the questionnaires were difficult or long to complete and two were unhappy with group allocation. Participants who received rehabilitation valued practical advice and face to face contact. Feasibility challenges included integration with oncology services, for example accessing clinic space. Changes in clinical outcomes were modest but most apparent for physical activity levels and health-related quality of life as measured by FACT-L. An estimated sample size for a future trial was calculated based on the observed changes in the FACT-L measure. Assuming a difference of 6 points, which is similar to the point estimate of effect observed, and allowing for 25% attrition, 336 participants would be required to reliably detect this difference (80% power, p=0.05) in a future efficacy trial. Conclusion: This thesis followed Medical Research Council Guidelines to develop and test a theoretically informed intervention. It found that it is feasible to recruit and retain people with thoracic cancer to a trial of brief integrated rehabilitation in the period following diagnosis. A larger trial to examine the efficacy of integrated rehabilitation in this population is feasible, with health-related quality of life as a candidate primary outcome. The conceptual model and intervention manual will be further refined during dissemination of thesis findings. Implications for clinical practice and future research are discussed and recommendations made.