REVOLUTION (Routine EValuatiOn of people LivIng with caNcer)-Protocol for a prospective characterisation study of patients with incurable cancer.

INTRODUCTION: There is a pressing need for a holistic characterisation of people with incurable cancer. In this group, where quality of life and improvement of symptoms are therapeutic priorities, the physical and biochemical manifestations of cancer are often studied separately, giving an incomplete picture. In order to improve care, spur therapeutic innovation, provide meaningful endpoints for trials and set priorities for future research, work must be done to explore how the tumour influences the clinical phenotype. Characterisation of the host-tumour interaction may also provide information regarding prognosis, allowing appropriate planning of investigations, treatment and referral to palliative medicine services. METHODS: Routine EValuatiOn of people LivIng with caNcer (REVOLUTION) is a prospective observational study that aims to characterise people with incurable cancer around five key areas, namely body composition, physical activity, systemic inflammatory response, symptoms, and quality of life by developing a bio-repository. Participants will initially be recruited from a single centre in the UK and will have assessments of body composition (bio-impedance analysis [BIA] and computed tomography [CT]), assessment of physical activity using a physical activity monitor, measurement of simple markers of inflammation and plasma cytokine proteins and three symptom and quality of life questionnaires. DISCUSSION: This study aims to create a comprehensive biochemical and clinical characterisation of people with incurable cancer. Data in this study can be used to give a better understanding of the 'symptom phenotype' and quality of life determinants, development of a profile of the systemic inflammatory response and a detailed characterisation of body composition.

Power Comparisons and Clinical Meaning of Outcome Measures in Assessing Treatment Effect in Cancer Cachexia: Secondary Analysis From a Randomized Pilot Multimodal Intervention Trial.

Background: New clinical trials in cancer cachexia are essential, and outcome measures with high responsiveness to detect meaningful changes are crucial. This secondary analysis from a multimodal intervention trial estimates sensitivity to change and between treatment effect sizes (ESs) of outcome measures associated with body composition, physical function, metabolism, and trial intervention. Methods: The study was a multicenter, open-label, randomized pilot study investigating the feasibility of a 6-week multimodal intervention [exercise, non-steroidal anti-inflammatory drugs, and oral nutritional supplements containing polyunsaturated fatty acids (n-3 PUFAs)] vs. standard cancer care in non-operable non-small-cell lung cancer and advanced pancreatic cancer. Body composition measures from computerized tomography scans and circulating biomarkers were analyzed. Results: Forty-six patients were randomized, and the analysis included 22 and 18 patients in the treatment and control groups, respectively. The between-group ESs were high for body weight (ES = 1.2, p < 0.001), small for body composition and physical function [handgrip strength (HGS)] measures (ES < 0.25), moderate to high for n-3 PUFAs and 25-hydroxyvitamin D (25-OH vitamin D) (ES range 0.64-1.37, p < 0.05 for all), and moderate for serum C-reactive protein (ES = 0.53, p = 0.12). Analysis within the multimodal treatment group showed high sensitivity to change for adiponectin (ES = 0.86, p = 0.001) and n-3 PUFAs (ES > 0.8, p < 0.05 for all) and moderate for 25-OH vitamin D (ES = 0.49, p = 0.03). In the control group, a moderate sensitivity to change for body weight (ES = -0.84, p = 0.002) and muscle mass (ES = -0.67, p = 0.016) and a high sensitivity to change for plasma levels of 25-OH vitamin D (ES = -0.88, p = 0.002) were found. Conclusion: Demonstrating high sensitivity to change and between treatment ES and body composition measures, body weight still stands out as a clinical and relevant outcome measure in cancer cachexia. Body composition and physical function measures clearly are important to address but demand large sample sizes to detect treatment group differences. Trial registration: ClinicalTrials.gov identifier: NCT01419145.

A systematic review examining nutrition support interventions in patients with incurable cancer.

PURPOSE: Recent guidelines by the European Society for Clinical Nutrition and Metabolism (ESPEN) have advocated increased attention to nutritional support in all patients with cancer; however, little is known about the optimal type of nutritional intervention. The aim of this review was to assess the current evidence for nutrition support in patients with incurable cancer. METHODS: This review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Embase, MEDLINE and CINAHL were searched from 1990 to 2018. Evidence was appraised using a modified risk of bias table, based on guidance from the Cochrane Handbook for Systematic Reviews of Interventions. RESULTS: Sixty studies were assessed of which twelve met the eligibility criteria. Eleven studies examined body composition, with six studies reporting improvements in weight. Six studies examined nutritional status with three studies reporting an improvement. Nine studies examined nutritional intake with six showing improvements including significant improvements in dietary and protein intake. Ten studies examined quality of life, with six studies reporting improvements following intervention. The most common nutritional interventions examined were nutrition counselling and dietary supplementation. CONCLUSIONS: There is moderate quality evidence to support the need for increased attention to nutrition support in patients with incurable cancer; however, despite some statistically significant results being reported, the clinical effects of them were small. Key questions remain as to the optimal timing for these interventions to be implemented (e.g. cachexia stage, illness stage and timing with anticancer therapy) and the most appropriate endpoint measures.

Chronic pelvic pain in women: an embedded qualitative study to evaluate the perceived benefits of the meridian balance method electro-acupuncture treatment, health consultation and National Health Service standard care.

INTRODUCTION: Chronic pelvic pain (CPP) - defined as intermittent or constant pain in the lower abdomen or pelvis of at least 6 months' duration, not occurring exclusively with menstruation or intercourse and not associated with pregnancy - is estimated to affect 6-27% of women worldwide. In the United Kingdom, over 1 million women suffer from CPP, which has been highlighted as a key area of unmet need. Current medical treatments for CPP are often associated with unacceptable side effects. A specific style of acupuncture, the meridian balance method electro-acupuncture (BMEA) and traditional Chinese medicine health consultation (TCM HC (BMEA + TCM HC = BMEA treatment)), may be effective for CPP in women. AIM: Three focus group discussions and semi-structured telephone interviews were embedded in a randomised controlled feasibility trial to gain in-depth description of the perceived benefits of the participants' respective interventions. METHODS: Women with CPP were randomised into the BMEA treatment, TCM HC or National Health Service standard care (NHS SC). Focus group discussions were recorded, transcribed and analysed thematically. Semi-structured telephone interviews were conducted post focus group discussions. FINDINGS: A total of 30 women were randomised into BMEA treatment, TCM HC or NHS SC. A total of 11 participants attended the three focus group discussions. Thematic analysis of focus group discussions showed: a perceived pain reduction, enhanced sleep, energy level and sense of well-being in the BMEA treatment and TCM HC groups; a dislike for the adverse effects of medications, frustration at the lack of effective treatment, heavy reliance on medications and services that are helpful, in the NHS SC group. Semi-structured telephone interviews showed that the methodology was acceptable to the participants. CONCLUSION: The embedded focus group discussions captured the rich and complex narratives of the participants and provided insights into the perceived benefits of the BMEA treatment, TCM HC and NHS SC interventions.

Combined exercise and nutritional rehabilitation in outpatients with incurable cancer: a systematic review.

PURPOSE: The optimal components for rehabilitation in patients with incurable cancer are unclear. However, principles of exercise and nutrition-based interventions used in cancer cachexia may be applied usefully to this population of cancer patients. This systematic review examines current evidence for rehabilitation combining exercise and nutritional support in patients with incurable cancer. METHODS: MEDLINE, EMBASE and Cochrane databases were searched. Eligible studies included patients with incurable cancer and rehabilitation programmes combining exercise and nutritional interventions. Studies of cancer survivors, curative treatments, reviews, case note reviews, protocols and abstracts were excluded. Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria were applied to patient-important outcomes. RESULTS: Of the 2424 search results, 67 abstracts were reviewed and 24 full texts examined. Eight studies (n = 685) were included comprising two randomised control trials, three prospective, one exploratory and two secondary analyses. All examined multi-modal outpatient programmes. GRADE analysis revealed moderate evidence (B) for improvements in depression and physical endurance, low-quality evidence (C) for quality of life and fatigue and very low-quality evidence (D) for overall function and nutritional status. CONCLUSION: There are limited data for multi-modal rehabilitation programmes combining exercise and nutritional interventions in patients with incurable cancer. However, studies to date report improvements in multiple domains, most notably physical endurance and depression scores. This supports the concept that multi-modal rehabilitation incorporating principles of cachexia management may be appropriate for the wider group of patients with incurable cancer. Further, high-quality studies are needed to define the optimal approach and outcome measures.

Integration of oncology and palliative care: a Lancet Oncology Commission.

Full integration of oncology and palliative care relies on the specific knowledge and skills of two modes of care: the tumour-directed approach, the main focus of which is on treating the disease; and the host-directed approach, which focuses on the patient with the disease. This Commission addresses how to combine these two paradigms to achieve the best outcome of patient care. Randomised clinical trials on integration of oncology and palliative care point to health gains: improved survival and symptom control, less anxiety and depression, reduced use of futile chemotherapy at the end of life, improved family satisfaction and quality of life, and improved use of health-care resources. Early delivery of patient-directed care by specialist palliative care teams alongside tumour-directed treatment promotes patient-centred care. Systematic assessment and use of patient-reported outcomes and active patient involvement in the decisions about cancer care result in better symptom control, improved physical and mental health, and better use of health-care resources. The absence of international agreements on the content and standards of the organisation, education, and research of palliative care in oncology are major barriers to successful integration. Other barriers include the common misconception that palliative care is end-of-life care only, stigmatisation of death and dying, and insufficient infrastructure and funding. The absence of established priorities might also hinder integration more widely. This Commission proposes the use of standardised care pathways and multidisciplinary teams to promote integration of oncology and palliative care, and calls for changes at the system level to coordinate the activities of professionals, and for the development and implementation of new and improved education programmes, with the overall goal of improving patient care. Integration raises new research questions, all of which contribute to improved clinical care. When and how should palliative care be delivered? What is the optimal model for integrated care? What is the biological and clinical effect of living with advanced cancer for years after diagnosis? Successful integration must challenge the dualistic perspective of either the tumour or the host, and instead focus on a merged approach that places the patient's perspective at the centre. To succeed, integration must be anchored by management and policy makers at all levels of health care, followed by adequate resource allocation, a willingness to prioritise goals and needs, and sustained enthusiasm to help generate support for better integration. This integrated model must be reflected in international and national cancer plans, and be followed by developments of new care models, education and research programmes, all of which should be adapted to the specific cultural contexts within which they are situated. Patient-centred care should be an integrated part of oncology care independent of patient prognosis and treatment intention. To achieve this goal it must be based on changes in professional cultures and priorities in health care.

The impact of meridian balance method electro-acupuncture treatment on chronic pelvic pain in women: a three-armed randomised controlled feasibility study using a mixed-methods approach.

INTRODUCTION: Chronic pelvic pain (CPP) is estimated to affect 6%-27% of women worldwide. In the United Kingdom, over 1 million women suffer from CPP and it has been highlighted as a key area of unmet need. Standard treatments are associated with unacceptable side effects. The meridian balance method electro-acupuncture (BMEA), and traditional Chinese medicine health consultation (TCM HC) (BMEA + TCM HC = BMEA treatment) may be an effective adjunct to standard treatment. AIM: The aim of our study was to evaluate the feasibility of a future trial, to determine the effectiveness of the BMEA treatment for CPP in women. The primary objectives were to determine recruitment and retention rates. The secondary objectives were to assess the effectiveness of the BMEA treatment and acceptability of the study's methodology. METHODS: Women with CPP were randomised into BMEA treatment (group 1), TCM HC alone (group 2) (each intervention administered twice weekly for 4 weeks) or National Health Service standard care (NHS SC, group 3). Primary outcomes were assessed by the proportion of eligible participants randomised, and the proportion of randomised participants who returned follow-up questionnaires. Interventions were assessed by validated pain/physical/emotional functioning questionnaires at baseline (0), 4, 8 and 12 weeks. Focus groups and semi-structured telephone interviews were embedded in the study. RESULTS: A total of 30 women (51% of those referred) were randomised over 8 months. Retention rates were 80% (95% confidence interval (CI): 74-96), 53% (95% CI: 36-70) and 87% (95% CI: 63-90), in groups 1, 2, and 3, respectively. Qualitative data suggested a favourable trial experience in groups 1 and 3. DISCUSSION: Group 2 retention rate was problematic and has implications for our next trial. CONCLUSION: Our study suggests that a future trial to determine the effectiveness of BMEA treatment for women with CPP is feasible but with modifications to the study design.

Cancer cachexia: rationale for the MENAC (Multimodal-Exercise, Nutrition and Anti-inflammatory medication for Cachexia) trial.

Cancer cachexia is a multifactorial syndrome characterised by an ongoing loss of skeletal muscle mass that cannot be fully reversed by conventional nutritional support alone. Cachexia has a high prevalence in cancer and a major impact on patient physical function, morbidity and mortality. Despite the consequences of cachexia, there is no licensed treatment for cachexia and no accepted standard of care. It has been argued that the multifactorial genesis of cachexia lends itself to therapeutic targeting through a multimodal treatment. Following a successful phase II trial, a phase III randomised controlled trial of a multimodal cachexia intervention is under way. Termed the MENAC trial (Multimodal-Exercise, Nutrition and Anti-inflammatory medication for Cachexia), this intervention is based on evidence to date and consists of non-steroidal anti-inflammatory drugs and eicosapentaenoic acid to reduce inflammation, a physical exercise programme using resistance and aerobic training to increase anabolism, as well as dietary counselling and oral nutritional supplements to promote energy and protein balance. Herein we describe the development of this trial. TRIAL REGISTRATION NUMBER: NCT02330926.

Results of a Double-Blind, Randomized, Placebo-Controlled Study of Nabiximols Oromucosal Spray as an Adjunctive Therapy in Advanced Cancer Patients with Chronic Uncontrolled Pain.

CONTEXT: Prior Phase 2/3 studies found that cannabinoids might provide adjunctive analgesia in advanced cancer patients with uncontrolled pain. OBJECTIVES: To assess adjunctive nabiximols (Sativex®), an extract of Cannabis sativa containing two potentially therapeutic cannabinoids (Δ9-tetrahydrocannabinol [27 mg/mL] and cannabidiol [25 mg/mL]), in advanced cancer patients with chronic pain unalleviated by optimized opioid therapy. METHODS: Phase 3, double-blind, randomized, placebo-controlled trial in patients with advanced cancer and average pain Numerical Rating Scale scores ≥4 and ≤8 despite optimized opioid therapy. Patients randomized to nabiximols (n = 199) or placebo (n = 198) self-titrated study medications over a two-week period, followed by a three-week treatment period at the titrated dose. RESULTS: Median percent improvements in average pain Numerical Rating Scale score from baseline to end of treatment in the nabiximols and placebo groups were 10.7% vs. 4.5% (P = 0.0854) in the intention-to-treat population (primary variable) and 15.5% vs. 6.3% (P = 0.0378) in the per-protocol population. Nabiximols was statistically superior to placebo on two of three quality-of-life instruments at Week 3 and on all three at Week 5. In exploratory post hoc analyses, U.S. patients, but not patients from the rest of the world, experienced significant benefits from nabiximols on multiple secondary endpoints. Possible contributing factors to differences in nabiximols efficacy include: 1) the U.S. participants received lower doses of opioids at baseline than the rest of the world and 2) the subgroups had different distribution of cancer pain types, which may have been related to differences in pathophysiology of pain. The safety profile of nabiximols was consistent with earlier studies. CONCLUSIONS: Although not superior to placebo on the primary efficacy endpoint, nabiximols had benefits on multiple secondary endpoints, particularly in the U.S. PATIENTS: Nabiximols might have utility in patients with advanced cancer who receive a lower opioid dose, such as individuals with early intolerance to opioid therapy.

A randomized phase II feasibility trial of a multimodal intervention for the management of cachexia in lung and pancreatic cancer.

BACKGROUND: Cancer cachexia is a syndrome of weight loss (including muscle and fat), anorexia, and decreased physical function. It has been suggested that the optimal treatment for cachexia should be a multimodal intervention. The primary aim of this study was to examine the feasibility and safety of a multimodal intervention (n-3 polyunsaturated fatty acid nutritional supplements, exercise, and anti-inflammatory medication: celecoxib) for cancer cachexia in patients with incurable lung or pancreatic cancer, undergoing chemotherapy. METHODS: Patients receiving two cycles of standard chemotherapy were randomized to either the multimodal cachexia intervention or standard care. Primary outcome measures were feasibility assessed by recruitment, attrition, and compliance with intervention (>50% of components in >50% of patients). Key secondary outcomes were change in weight, muscle mass, physical activity, safety, and survival. RESULTS: Three hundred and ninety-nine were screened resulting in 46 patients recruited (11.5%). Twenty five patients were randomized to the treatment and 21 as controls. Forty-one completed the study (attrition rate 11%). Compliance to the individual components of the intervention was 76% for celecoxib, 60% for exercise, and 48% for nutritional supplements. As expected from the sample size, there was no statistically significant effect on physical activity or muscle mass. There were no intervention-related Serious Adverse Events and survival was similar between the groups. CONCLUSIONS: A multimodal cachexia intervention is feasible and safe in patients with incurable lung or pancreatic cancer; however, compliance to nutritional supplements was suboptimal. A phase III study is now underway to assess fully the effect of the intervention.

The BMEA study: the impact of meridian balanced method electroacupuncture on women with chronic pelvic pain-a three-arm randomised controlled pilot study using a mixed-methods approach.

INTRODUCTION: Chronic pelvic pain (CPP) affects 3-4% of women worldwide. Proven treatments for CPP are limited and unsatisfactory. The meridian balance method (BM) electroacupuncture (EA) treatment (BMEA + Traditional Chinese Medicine Health Consultation (TCM HC) may be effective for CPP. Previous EA studies have demonstrated an analgesic effect. Large-scale studies on acupuncture for other chronic pain conditions suggest that patient-healthcare provider interaction might play a role in pain reduction. We propose a pilot study to explore the effectiveness of the meridian BMEA treatment in managing women with CPP to inform a future large randomised controlled trial. METHODS AND ANALYSIS: A 3-armed randomised controlled pilot study is proposed with an aim to recruit 30 women with CPP in National Health Service (NHS) Lothian. Randomisation will be to BMEA treatment, TCM HC or standard care (SC). Validated pain, physical and emotional functioning questionnaires will be administered to all participants at weeks 0, 4, 8 and 12. Focus group discussions will be conducted when week 12 questionnaires are completed. The primary objective is to determine, recruitment and retention rates. The secondary objectives are to assess the effectiveness and acceptability of the proposed methods of recruitment, randomisation, interventions and assessment tools. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the Scotland Research Ethics Committee (REC 14/SS/1022). Data will be published in peer-reviewed journals and presented at international conferences. TRIAL REGISTRATION NUMBER: NCT02295111.

Cancer pain: part 1: Pathophysiology; oncological, pharmacological, and psychological treatments: a perspective from the British Pain Society endorsed by the UK Association of Palliative Medicine and the Royal College of General Practitioners.

OBJECTIVE: This discussion document about the management of cancer pain is written from the pain specialists' perspective in order to provoke thought and interest in a multimodal approach to the management of cancer pain, not just towards the end of life, but pain at diagnosis, as a consequence of cancer therapies, and in cancer survivors. It relates the science of pain to the clinical setting and explains the role of psychological, physical, interventional and complementary therapies in cancer pain. METHODS: This document has been produced by a consensus group of relevant health care professionals in the United Kingdom and patients' representatives making reference to the current body of evidence relating to cancer pain. In the first of two parts, pathophysiology, oncological, pharmacological, and psychological treatment are considered. CONCLUSIONS: It is recognized that the World Health Organization (WHO) analgesic ladder, while providing relief of cancer pain towards the end of life for many sufferers worldwide, may have limitations in the context of longer survival and increasing disease complexity. To complement this, it is suggested that a more comprehensive model of managing cancer pain is needed that is mechanism-based and multimodal, using combination therapies including interventions where appropriate, tailored to the needs of an individual, with the aim to optimize pain relief with minimization of adverse effects.