Optimising opioids for cancer pain: Investigating the basis of inter-individual analgesic response and side-effect profile

There is significant inter-individual variation in response to morphine in terms of analgesia and side-effects. In recent years there has been growing interest in the possibility that genetic factors may play a role in variability in morphine response. The aims of this thesis were to develop a clinically relevant method of defining response to morphine, to investigate how multiple clinical and genetic factors may interact together to influence response to morphine and to explore constipation as a common side-effect of morphine. Clinical and biological data were collected as part of two clinical trials: 1) A prospective observational study which included patients taking oral morphine for cancer pain (N=298) and 2) A prospective follow-up randomised controlled trial of oral morphine versus oral oxycodone for cancer pain (recruitment ongoing). Symptom complexes were examined using Principal Components Analysis. Genetic association testing was carried out using both the candidate gene approach (sequence-specific primers with polymerase chain reaction) and genome-wide assays. Multivariate regression analyses were used to explore gene-gene and gene-environment interactions. Preliminary testing of a constipation assessment tool was performed. Analgesic response and central side-effects appear to be distinct components of morphine response. The genetic and clinical factors associated with these clinical outcomes and with daily morphine dose requirements are markedly different. There is inter-individual variation in bowel function in cancer patients on oral morphine. Constipation is a common symptom and is generally poorly managed. It is too early to be able to apply the results of genetic association studies of morphine response in cancer pain to clinical practice. Response to morphine is complex, both in terms of clinical confounders and pharmacogenetics. Challenges for future research include carrying out carefully designed studies of adequate power, standardising outcome measures of response to morphine and expansion of the genetic association testing

Recent advances in the use of opioids for cancer pain

Opioids are the mainstay of treatment for moderate to severe cancer pain. In recent years there have been many advances in the use of opioids for cancer pain. Availability and consumption of opioids have increased and opioids other than morphine (including methadone, fentanyl, oxycodone) have become more widely used. Inter-individual variation in response to opioids has been identified as a significant challenge in the management of cancer pain. Many studies have been published demonstrating the benefits of opioid switching as a clinical maneuver to improve tolerability. Constipation has been recognized as a significant burden in cancer patients on opioids. Peripherally restricted opioid antagonists have been developed for the prevention and management of opioid induced constipation. The phenomenon of breakthrough pain has been characterized and novel modes of opioid administration (transmucosal, intranasal, sublingual) have been explored to facilitate improved management of breakthrough cancer pain. Advances have also been made in the realm of molecular biology. Pharmacogenetic studies have explored associations between clinical response to opioids and genetic variation at a DNA level. To date these studies have been small but future research may facilitate prospective prediction of response to individual drugs

Intensity of care in cancer patients in the last year of life: a retrospective data linkage study

BACKGROUND: Delivering high-quality palliative and end-of-life care for cancer patients poses major challenges for health services. We examine the intensity of cancer care in England in the last year of life. METHODS: We included cancer decedents aged 65+ who died between January 1, 2010 and December 31, 2017. We analysed healthcare utilisation and costs in the last 12 months of life including hospital-based activities and primary care. RESULTS: Healthcare utilisation and costs increased sharply in the last month of life. Hospital costs were the largest cost elements and decreased with age (0.78, 95% CI: 0.73–0.72, p < 0.005 for age group 90+ compared to age 65–69 and increased substantially with comorbidity burden (2.2, 95% CI: 2.09–2.26, p < 0.005 for those with 7+ comorbidities compared to those with 1–3 comorbidities). The costs were highest for haematological cancers (1.45, 95% CI: 1.38–1.52, p < 0.005) and those living in the London region (1.10, 95% CI: 1.02–1.19, p < 0.005). CONCLUSIONS: Healthcare in the last year of life for advanced cancer patients is costly and offers unclear value to patients and the healthcare system. Further research is needed to understand distinct cancer populations’ pathways and experiences before recommendations can be made about the most appropriate models of care

Implementation of a complex intervention to improve care for patients whose situations are clinically uncertain in hospital settings: A multi-method study using normalisation process theory

Purpose: To examine the use of Normalisation Process Theory (NPT) to establish if, and in what ways, the AMBER care bundle can be successfully normalised into acute hospital practice, and to identify necessary modifications to optimise its implementation. Method: Multi-method process evaluation embedded within a mixed-method feasibility cluster randomised controlled trial in two district general hospitals in England. Data were collected using (i) focus groups with health professionals (HPs), (ii) semi-structured interviews with patients and/or carers, (iii) non-participant observations of multi-disciplinary team meetings and (iv) patient clinical note review. Thematic analysis and descriptive statistics, with interpretation guided by NPT components (coherence; cognitive participation; collective action; reflexive monitoring). Data triangulated across sources. Results: Two focus groups (26 HPs), nine non-participant observations, 12 interviews (two patients, 10 relatives), 29 clinical note reviews were conducted. While coherence was evident, with HPs recognising the value of the AMBER care bundle, cognitive participation and collective action presented challenges. Specifically: (1) HPs were unable and unwilling to operationalise the concept of ‘risk of dying’ intervention eligibility criteria (2) integration relied on a ‘champion’ to drive participation and ensure sustainability; and (3) differing skills and confidence led to variable engagement with difficult conversations with patients and families about, for example, nearness to end of life. Opportunities for reflexive monitoring were not routinely embedded within the intervention. Reflections on the use of the AMBER care bundle from HPs and patients and families, including recommended modifications became evident through this NPT-driven analysis. Conclusion: To be successfully normalised, new clinical practices, such as the AMBER care bundle, must be studied within the wider context in which they operate. NPT can be used to the aid identification of practical strategies to assist in normalisation of complex interventions where the focus of care is on clinical uncertainty in acute hospital settings

Cancer centre supportive oncology service: health economic evaluation

Objectives: There have been many models of providing oncology and palliative care to hospitals. Many patients will use the hospital non-electively or semielectively, and a large proportion are likely to be in the last years of life. We describe our multidisciplinary service to treatable but not curable cancer patients at University Hospitals Sussex. The team was a mixture of clinical nurse specialists and a clinical fellow supported by dedicated palliative medicine consultant time and oncology expertise. / Methods: We identified patients with cancer who had identifiable supportive care needs and record activity with clinical coding. We used a baseline 2019/2020 dataset of national (secondary uses service) data with discharge code 79 (patients who died during that year) to compare a dataset of patients seen by the service between September 2020 and September 2021 in order to compare outcomes. While this was during COVID-19 this was when the funding was available. / Results: We demonstrated a reduction in length of stay by an average of 1.43 days per admission and a reduction of 0.95 episodes of readmission rates. However, the costs of those admissions were found to be marginally higher. Even with the costs of the service, there is a clear return on investment with a benefit cost ratio of 1.4. / Conclusions: A supportive oncology service alongside or allied to acute oncology but in conjunction with palliative care is feasible and cost-effective. This would support investment in such a service and should be nationally commissioned in conjunction with palliative care services seeing all conditions

Variation in hospital cost trajectories at the end of life by age, multimorbidity and cancer type

Background Approximately thirty thousand people in Scotland are diagnosed with cancer annually, of whom a third live less than one year. The timing, nature and value of hospital-based healthcare for patients with advanced cancer are not well understood. The study's aim was to describe the timing and nature of hospital-based healthcare use and associated costs in the last year of life for patients with a cancer diagnosis. Methods We undertook a Scottish population-wide administrative data linkage study of hospital-based healthcare use for individuals with a cancer diagnosis, who died aged 60 and over between 2012 and 2017. Hospital admissions and length of stay (LOS), as well as the number and nature of outpatient and day case appointments were analysed. Generalised linear models were used to adjust costs for age, gender, socioeconomic deprivation status, rural-urban (RU) status and comorbidity. Results The study included 85,732 decedents with a cancer diagnosis. For 64,553 (75.3%) of them, cancer was the primary cause of death. Mean age at death was 80.01 (SD 8.15) years. The mean number of inpatient stays in the last year of life was 5.88 (SD 5.68), with a mean LOS of 7 days. Admission rates rose sharply in the last month of life. One year adjusted and unadjusted costs decreased with increasing age. A higher comorbidity burden was associated with higher costs. Major cost differences were present between cancer types. Conclusions People in Scotland in their last year of life with cancer are high users of secondary care. Hospitalisation accounts for a high proportion of costs, particularly in the last month of life. Further research is needed to examine triggers for hospitalisations and to identify influenceable reasons for unwarranted variation in hospital use among different cancer cohorts

Functional antibody and T-cell immunity following SARS-CoV-2 infection, including by variants of concern, in patients with cancer: the CAPTURE study

Patients with cancer have higher COVID-19 morbidity and mortality. Here we present the prospective CAPTURE study (NCT03226886) integrating longitudinal immune profiling with clinical annotation. Of 357 patients with cancer, 118 were SARS-CoV-2-positive, 94 were symptomatic and 2 patients died of COVID-19. In this cohort, 83% patients had S1-reactive antibodies, 82% had neutralizing antibodies against WT, whereas neutralizing antibody titers (NAbT) against the Alpha, Beta, and Delta variants were substantially reduced. Whereas S1-reactive antibody levels decreased in 13% of patients, NAbT remained stable up to 329 days. Patients also had detectable SARS-CoV-2-specific T cells and CD4+ responses correlating with S1-reactive antibody levels, although patients with hematological malignancies had impaired immune responses that were disease and treatment-specific, but presented compensatory cellular responses, further supported by clinical. Overall, these findings advance the understanding of the nature and duration of immune response to SARS-CoV-2 in patients with cancer