Ollie Minton

A Systematic Review and Meta-Analysis of the Pharmacological Treatment of Cancer-Related Fatigue

BACKGROUND Cancer-related fatigue is an important clinical problem. It is common, distressing, and often difficult to treat. There is a role for drug treatment of cancer-related fatigue, but no consensus has been reached on which drugs are useful. This systematic review and meta-analysis aims to review the available evidence and make recommendations for practice and research. METHODS We searched the Cochrane register of controlled trials (through the second quarter 2007), Medline (January 1, 1966, through August 1, 2007), and EMBASE (January 1, 1980, through August 1, 2007) by use of a predetermined list of search terms. Cochrane Collaboration meta-analysis review methodology was used for this study. The change in fatigue score on the instrument used in each study and other outcomes of interest (adverse events and withdrawal rates) were compared between treatment and control arms by use of the standardized mean difference (SMD) with 95% confidence intervals (CIs). All statistical tests were two-sided. RESULTS We identified 27 eligible trials of drug treatments for cancer-related fatigue (with a total of 6746 participants). The overall effect size for all drug classes was small. A meta-analysis of two studies (n = 264 patients) indicated that methylphenidate (a psychostimulant) was superior to placebo (standardized mean difference [SMD] in change in fatigue score = -0.30, 95% confidence interval [CI] = -0.54 to -0.05; P = .02) for treating cancer-related fatigue. A meta-analysis of 10 studies (n = 2226 patients) evaluating erythropoietin in anemic cancer patients who were undergoing chemotherapy indicated that erythropoietin was superior to placebo (SMD = -0.30, 95% CI = -0.46 to -0.29; P = .008). Among anemic patients (four studies with n = 964 patients), improvement in fatigue was associated with darbepoetin treatment compared with placebo treatment (SMD = -0.13, 95% CI = -0.27 to 0.00; P = .05). Progestational steroids and paroxetine were no better than placebo in the treatment of cancer-related fatigue. CONCLUSIONS There is some evidence that treatment of cancer-related fatigue with methylphenidate appears to be effective. More robust evidence indicates that treatment with hematopoietic agents appears to relieve cancer-related fatigue caused by chemotherapy-induced anemia. Further confirmatory trials are required for both observations.

A systematic review of the scales used for the measurement of cancer-related fatigue (CRF)

BACKGROUND Fatigue in cancer is very common and can be experienced at all stages of disease and in survivors. There is no accepted definition of cancer-related fatigue (CRF) and no agreement on how it should be measured. A number of scales have been developed to quantify the phenomenon of CRF. These vary in the quality of psychometric properties, ease of administration, dimensions of CRF covered and extent of use in studies of cancer patients. This review seeks to identify the available tools for measuring CRF and to make recommendations for ongoing research into CRF. METHODS A systematic review methodology was used to identify scales that have been validated to measure CRF. The inclusion criteria required the scale to have been validated for use in cancer patients and/or widely used in this population. Scales also had to meet a minimum quality score for inclusion. RESULTS The reviewers identified 14 scales that met the inclusion criteria. The most commonly used scales and best validated were the Functional Assessment of Cancer Therapy Fatigue (FACT F), the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ C30) (fatigue subscale) and the Fatigue Questionnaire (FQ). CONCLUSIONS Unidimensional scales are the easiest to administer and have been most widely used. The authors recommend the use of the EORTC QLQ C30 fatigue subscale or the FACT F. The FQ gives a multidimensional assessment and has also been widely used. A substantial minority of the scales identified have not been used extensively or sufficiently validated in cancer patients and cannot be recommended for routine use without further validation.

Cancer-related fatigue

Fatigue is a common symptom in patients with cancer and in disease-free survivors. It has a significant impact on the quality of life. Although subjective fatigue is often related to objective changes in physical functioning or impaired performance status, the two phenomena are not synonymous and need to be distinguished. A number of robust and reliable assessment instruments to measure fatigue severity are now available and criteria for cancer-related fatigue syndrome have been proposed. The underlying mechanisms and pathophysiology of cancer-related fatigue are unclear. Management strategies include the use of psycho-educational interventions, exercise programmes and pharmacological treatments. The best evidence for the effectiveness of drug treatments is for the haematopoietic agents in anaemic patients undergoing chemotherapy and for methylphenidate in an on-treatment population.

A comparison of the characteristics of disease-free breast cancer survivors with or without cancer-related fatigue syndrome.

Purpose To determine the prevalence of cancer-related fatigue syndrome (CRFS) in a population of disease-free breast cancer survivors and to investigate the relationship between CRFS and clinical variables. Patients and methods Women (200) were recruited. All participants were between 3 months and 2 years after completion of primary therapy for breast cancer and were disease free. Subjects completed a diagnostic interview for CRFS and structured psychiatric interview. Participants also completed quality of life, mood and fatigue questionnaires, and provided a blood sample for haematological and biochemical analysis and a 24-h urine specimen for cortisol estimation. Subjects wore a wrist actigraph for 7 days to measure activity and sleep. Results Sixty women (30% of participants) were found to fulfil the criteria for CRFS. There were statistically significant differences between fatigued and non-fatigued women with respect to fatigue severity (p < 0.01), mood (p < 0.01) and quality of life scores (p < 0.05). There were significant differences in blood variables including raised total white cell count and lower sodium (all p < 0.02). There was no difference in the 24 h urinary free cortisol levels. Actigraphic data demonstrated significant differences in sleep quality and disturbance, but not in overall levels of daytime activity or circadian rhythm. Conclusion CRFS affects 30% of women after breast cancer treatment and has significant effects on quality of life and mood. There is some evidence that CRFS is related to sleep disturbance or to a persistent inflammatory or immune response.

Psychostimulants for the management of cancer-related fatigue: a systematic review and meta-analysis.

CONTEXT Cancer-related fatigue (CRF) is a common and distressing symptom affecting patients with cancer. There is an increasing number of drug trials examining potential treatments for CRF. Methylphenidate represents one of the most researched drugs in this area, and an up-to-date assessment of the evidence for its use is needed. OBJECTIVES To assess and summarize the increasing evidence for the use of psychostimulants, particularly methylphenidate, in the treatment of CRF. METHODS A systematic review of electronic databases was conducted from inception to the start of October 2009, together with cross-referencing of cited abstracts and hand searching of relevant cancer journals. RESULTS A meta-analysis was conducted on five psychostimulant trials (n=426 participants). The overall standardized mean difference was -0.28 (95% confidence interval [CI] -0.48, -0.09; P=0.005), although several trials failed to find any benefit over placebo. There were no differences in the frequency of adverse events between methylphenidate and placebo: combined odds ratio 1.24 (95% CI 0.42, 3.62). CONCLUSION There is preliminary evidence for the use of psychostimulants to treat CRF. The absolute numbers still remain small, and further confirmation is needed before firm recommendations on their usage and safety can be made in the treatment of CRF.

Cancer‐related fatigue and its impact on functioning

This article presents the contrasting European and American perspectives on cancer‐related fatigue (CRF) and its impact on functioning in cancer survivors. The content is presented in 3 sections: state of the art, intervention studies, and future areas of research, followed by a discussion. Gaps identified include a lack of understanding of the etiology, definition, and measurement of CRF. Models to guide the study of CRF, selection of biomarkers, and design of interventions are needed. There is overlap between Europe and the United States concerning the future directions for research and collaboration related to CRF. The authors suggest the need for international consensus regarding the defining features of CRF in cancer survivors to identify phenotypes, a harmonized measurement of CRF outcomes using instruments that have demonstrated measurement equivalence across languages and cultures, and interventions (including exercise, rehabilitation, and psychoeducational) that have been manualized to permit intervention fidelity across diverse contexts. Coordinated intercontinental efforts would increase understanding of the biological, psychological, and social mechanisms underlying CRF and assist in the design of future intervention studies as well as revisions to clinical guidelines. Cancer 2013;119(11 suppl):2124‐30.

Beyond treatment - Psychosocial and behavioural issues in cancer survivorship research and practice.

The population of cancer survivors has grown steadily over the past several decades. Surviving cancer, however, is not synonymous with a life free of problems related to the disease and its treatment. In this paper we provide a brief overview of selected physical and psychosocial health problems prevalent among cancer survivors, namely pain, fatigue, psychological distress and work participation. We also address issues surrounding self-management and e-Health interventions for cancer survivors, and programmes to encourage survivors to adopt healthier lifestyles. Finally, we discuss approaches to assessing health-related quality of life in cancer survivors, and the use of cancer registries in conducting psychosocial survivorship research. We highlight research and practice priorities in each of these areas. While the priorities vary per topic, common themes that emerged included: (1) Symptoms should not be viewed in isolation, but rather as part of a cluster of interrelated symptoms. This has implications for both understanding the aetiology of symptoms and for their treatment; (2) Psychosocial interventions need to be evidence-based, and where possible should be tailored to the needs of the individual cancer survivor. Relatively low cost interventions with self-management and e-Health elements may be appropriate for the majority of survivors, with resource intensive interventions being reserved for those most in need; (3) More effort should be devoted to disseminating and implementing interventions in practice, and to evaluating their cost-effectiveness; and (4) Greater attention should be paid to the needs of vulnerable and high-risk populations of survivors, including the socioeconomically disadvantaged and the elderly.

Evaluation of Screening Instruments for Cancer-Related Fatigue Syndrome in Breast Cancer Survivors

PURPOSE Cases of cancer-related fatigue syndrome (CRFS) can be reliably indentified using a diagnostic interview combined with a structured psychiatric interview. However, these interviews are time consuming to conduct, require specialist training, and are not suitable for routine clinical use. The purpose of this study was to identify whether a screening questionnaire could identify patients at high risk of clinically significant fatigue who should be considered for a suitable intervention. PATIENTS AND METHODS The diagnostic interview for CRFS and the structured clinical interview for the diagnostic and statistical manual of mental disorders were used in order to identify breast cancer survivors who fulfilled the criteria for CRFS. Two fatigue questionnaires (the Bidimensional Fatigue Scale [BFS] and the Functional Assessment of Cancer Therapy-Fatigue subscale [FACT-F]) were administered in order to determine their screening properties. RESULTS Two hundred women were interviewed and 60 women fulfilled the criteria for CRFS. The BFS cutoff score of 11 had a sensitivity of 92%, a specificity of 53%, a positive predictive value (PPV) of 46%, and a negative predictive value (NPV) of 94%. The FACT-F cutoff score of 36 had a sensitivity of 80%, a specificity of 71%, a PPV of 55%, and a NPV of 89%. CONCLUSION The BFS and FACT-F cutoff scores can be used to identify breast cancer survivors at higher risk of clinically significant ongoing post treatment fatigue. Neither scale can be used as a diagnostic instrument for CRFS.

Achieving the preferred place of care for hospitalized patients at the end of life

Background: The Department of Health end-of-life strategy contains a number of quality markers which include taking into account patients’ wishes for their final place of care. There is a wide variation in how this information is recorded. Methods: An audit was conducted on discussion of preferred place of care (PPC) for all patients referred to the hospital palliative care team who died during the audit period. Barriers to achieving PPC and the efficacy of a fast track discharge service were also monitored. The audit was first done in 2007 and was repeated in 2009. Results: There was an increase in recording PPC. Overall PPC wishes were ascertained for 87% of the patients seen by the team. The PPC was achieved in 76% of cases. The number of patients wishing to die in hospital significantly increased over the audit cycle (from 10% to 30%). Approximately one-third of patients changed their minds regarding PPC. Conclusions: The data highlights the need to distinguish between preferred place of care and preferred place of death. Patients’ wishes regarding PPC change as death approaches. A greater number of patients wished to die in hospital than was expected.

Identification of Factors Associated With Fatigue in Advanced Cancer: A Subset Analysis of the European Palliative Care Research Collaborative Computerized Symptom Assessment Data Set

CONTEXT This is a subset analysis of fatigue data and associated clinical variables collected as part of the European Palliative Care Research Collaborative Computerized Symptom Assessment (CSA) study. The overall aim of CSA was to determine the prevalence of common symptoms in a mixed advanced cancer group using an electronic data collection system. OBJECTIVES This analysis was conducted to identify factors independently associated with fatigue. METHODS Only patient records containing complete data for all three measured blood parameters in the CSA study (C-reactive protein [CRP], hemoglobin, and albumin) were included in our subset analysis (n=720). Participants with locoregional or metastatic disease of all tumor types were included (with or without concurrent palliative anticancer treatment). A large number of symptoms were recorded using a predesigned computer program and widely used symptom measurement scales. Fatigue was measured using a well-validated three-item fatigue scale taken from the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire. A logistic regression model was developed using a cutoff score based on the available normative data to define the presence or the absence of severe fatigue. RESULTS Cases of fatigue were independently associated with chemotherapy treatment and experiencing other symptoms such as pain and depression. There was a moderate association with hemoglobin level. However, there was no link to cachexia, albumin, or CRP. CONCLUSION Severe fatigue is linked with treatment history and hemoglobin levels rather than CRP, mood, and other common symptoms in a mixed advanced cancer group.