The short-term impact of methylprednisolone on patient-reported sleep in patients with advanced cancer in a randomized, placebo-controlled, double-blind trial.

PURPOSE: Although corticosteroids are frequently used in patients with advanced cancer, few studies have examined the impact of these drugs on patient-reported sleep. We aimed to examine the short-term impact of methylprednisolone on patient-reported sleep in patients with advanced cancer. METHODS: Patient-reported sleep was a predefined secondary outcome in a prospective, randomized, placebo-controlled, double-blind trial that evaluated the analgesic efficacy of corticosteroids in advanced cancer patients (18+), using opioids, and having pain ≥ 4 past 24 h (NRS 0-10). Patients were randomized to the methylprednisolone group with methylprednisolone 16 mg × 2/day or placebo for 7 days. The EORTC QLQ-C30 (0-100) and the Pittsburgh Sleep Quality Index questionnaire (PSQI) (0-21) were used to assess the impact of corticosteroids on sleep at baseline and at day 7. RESULTS: Fifty patients were randomized of which 25 were analyzed in the intervention group and 22 in the control group. Mean age was 64 years, mean Karnofsky performance status was 67 (SD 13.3), 51% were female, and the mean oral daily morphine equivalent dose was 223 mg (SD 222.77). Mean QLQ-C30 sleep score at baseline was 29.0 (SD 36.7) in the methylprednisolone group and 24.2 (SD 27.6) in the placebo group. At day 7, there was no difference between the groups on QLQ-C30 sleep score (methylprednisolone 20.3 (SD 32.9); placebo 28.8 (SD 33.0), p = 0.173). PSQI showed similar results. CONCLUSIONS: Methylprednisolone 16 mg twice daily for 7 days had no impact on patient-reported sleep in this cohort of patients with advanced cancer. TRIAL REGISTRATION: Clinical trial information NCT00676936 (13.05.2008).

Differences in Patient-Reported Outcomes That Are Most Frequently Detected in Randomized Controlled Trials in Patients With Solid Tumors: A Pooled Analysis of 229 Trials.

OBJECTIVES: Patient-reported outcome (PRO) measurements used in cancer research can assess a number of health domains. Our primary objective was to investigate which broad types of PRO domains (namely, functional health, symptoms, and global quality of life [QoL]) most frequently yielded significant differences between treatments in randomized controlled trials (RCTs). METHODS: A total of 229 RCTs published between January 2004 and February 2019, conducted on patients diagnosed with the most common solid malignancies and assessed using the European Organization for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30, were considered. Studies were identified systematically using literature searches in key electronic databases. Unlike other PRO measurements typically used in RCTs, the scoring algorithm of the multidimensional EORTC QLQ-C30 allowed us to clearly distinguish the 3 broad types of PRO domains. RESULTS: In total, 134 RCTs (58.5%) reported statistically significant differences between treatment arms for at least 1 of the QLQ-C30 domains. Most frequently, differences were reported for 2 or all 3 broad types of PRO domains (78 of 134 trials; 58.2%). In particular, 35 trials (26.1%) found significant differences for symptoms, functional health, and global QoL, 24 trials (17.9%) for symptoms and functional health, 11 trials (8.2%) for functional health and global QoL, and 8 trials (6.0%) for symptoms and global QoL. The likelihood of finding a statistically significant difference between treatment arms was not associated with key study characteristics, such as study design (ie, open-label vs blinded trials) and industry support. CONCLUSIONS: Our findings emphasize the importance of a multidimensional PRO assessment to most comprehensively capture the overall burden of therapy from the patients' standpoint.

Sleep quality in hospitalized patients with advanced cancer: an observational study using self-reports of sleep and actigraphy.

PURPOSE: Although patients with advanced cancer report poor sleep quality, few studies have assessed sleep quality with a combination of subjective and objective measures. We aimed to examine sleep quality in hospitalized patients with advanced cancer by combining patient-reported outcome-measures (PROMs) and polysomnography (PSG) or actigraphy. METHODS: A one-night prospective observational study of sleep in hospitalized patients with metastatic cancer using WHO step III opioids was conducted. Total sleep time, sleep onset latency, number of awakenings, and wake after sleep onset were assessed by PROMs and actigraphy. Sleep quality was assessed by the Pittsburgh Sleep Quality Index (PSQI) (range; 0-21), where higher scores indicate worse sleep quality. RESULTS: Forty patients were monitored. Median age was 70, median oral morphine equivalent dose was 80 mg/24 h (10-1725), median Karnofsky Performance Score was 50 (20-90), and median time to death from inclusion was 38 days (4-319). Mean PSQI score was 6.5 (SD ± 3.4). PROMs and actigraphy of mean (SD) sleep onset latency were 46 (± 64) and 35 min (± 61), respectively, while mean time awake at night was 37 (± 35) and 40 min (± 21). PROMs and actigraphy differed on number of awakenings (mean 2 (± 1) vs. 24 (± 15), p Ë‚ 0.001). Bland-Altman plots showed large individual differences between PROMs and actigraphy. PSG was not feasible. CONCLUSIONS: PROMs and actigraphy documented poor sleep quality, but a lack of agreement across methods. The study demonstrates a need to improve assessment of sleep quality and treatment of sleep disturbance in hospitalized patients with advanced cancer near end of life.

Exploratory analyses of the Danish Palliative Care Trial (DanPaCT): a randomized trial of early specialized palliative care plus standard care versus standard care in advanced cancer patients.

BACKGROUND: Early and integrated specialized palliative care is often recommended but has still only been investigated in relatively few randomized clinical trials. OBJECTIVE: To investigate the effect of early specialized palliative care plus standard care versus standard care on the explorative outcomes in the Danish Palliative Care Trial (DanPaCT). METHODS: We conducted a randomized multicentre, parallel-group clinical trial. Consecutive patients with metastatic cancer were included if they had symptoms or problems that exceeded a predefined threshold according to the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30). Outcomes were estimated as the differences between the intervention and the control groups in the change from baseline to the weighted mean of the 3- and 8-week follow-ups measured as areas under the curve. RESULTS: In total, 145 patients were randomized to early specialized palliative care plus standard care versus 152 to standard care only. Early specialized palliative care had no significant effect on any of the symptoms or problems. Of the 21 items addressing satisfaction, specialized palliative care improved the item 'overall satisfaction with the help received from the health care system' with 9 points (95% confidence interval 3.8 to 14.2, p = 0.0006) and three other items (all p < 0.05). CONCLUSION: In line with the analyses of the primary and secondary outcomes in DanPaCT, we did not find that specialized palliative care, as provided in DanPaCT, affected symptoms and problems. However, patients in the intervention group seemed more satisfied with the health care received than those in the standard care group. TRIAL REGISTRATION: NCT01348048.

Do the unlabeled response categories of the Minnesota Living with Heart Failure Questionnaire satisfy the monotonicity assumption of simple-summated scoring?

PURPOSE: Half of the 21-item Minnesota Living with Heart Failure Questionnaire (MLHFQ) response categories are labeled (0 = No, 1 = Very little, 5 = Very much) and half are not (2, 3, and 4). We hypothesized that the unlabeled response options would not be more likely to be chosen at some place along the scale continuum than other response options and, therefore, not satisfy the monotonicity assumption of simple-summated scoring. METHODS: We performed exploratory and confirmatory factor analyses of the MLHFQ items in a sample of 1437 adults in the Better Effectiveness After Transition-Heart Failure study. We evaluated the unlabeled response options using item characteristic curves from item response theory-graded response models for MLHFQ physical and emotional health scales. Then, we examined the impact of collapsing response options on correlations of scale scores with other variables. RESULTS: The sample was 46% female; 71% aged 65 or older; 11% Hispanic, 22% Black, 54% White, and 12% other. The unlabeled response options were rarely chosen. The standard approach to scoring and scores obtained by collapsing adjacent response categories yielded similar associations with other variables, indicating that the existing response options are problematic. CONCLUSIONS: The unlabeled MLHFQ response options do not meet the assumptions of simple-summated scoring. Further assessment of the performance of the unlabeled response options and evaluation of alternative scoring approaches is recommended. Adding labels for response options in future administrations of the MLHFQ should be considered.

Consistency matters: measurement invariance of the EORTC QLQ-C30 questionnaire in patients with hematologic malignancies.

PURPOSE: To ensure that observed differences in the scores of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) reflect actual differences in health-related quality of life (HRQoL) rather than measurement bias, measurement invariance needs to be established. We investigated the assumption of measurement invariance of the EORTC QLQ-C30 in patients with hematological malignancies across age, sex, comorbidity, disease type, and time. METHODS: We used a large database of patients with hematological malignancies, which included HRQoL data collected with the EORTC QLQ-C30. We used the structural equation modeling approach to test for measurement (metric and scalar) invariance across groups (age, sex, comorbidity, disease) and time (baseline, 1 month and 2 month follow-up). Longitudinal invariance was examined in a subgroup of patients diagnosed with myelodysplastic syndromes. RESULTS: Confirmatory factor analyses demonstrated full measurement invariance for age and comorbidity and over time, while support for partial scalar invariance was obtained for sex and disease. Violations of invariance for sex were observed for items of the physical functioning scale and the emotional functioning scale, while for disease type, violations of invariance were observed for items of the physical functioning scale, emotional functioning scale, and the cognitive functioning scale. CONCLUSIONS: Our findings support measurement invariance of the EORTC QLQ-C30 in a large sample of patients with hematological malignancies. The results showed that the number of non-invariant items was negligible, suggesting that this questionnaire is a valid and robust measurement tool in patients with hematological malignancies, also for comparisons across groups and time.

Validation of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 Summary Score in Patients With Hematologic Malignancies.

OBJECTIVES: We investigated the validity of the recently developed European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) summary score in patients with hematologic malignancies. Specifically, we evaluated the adequacy of a single-factor measurement model for the QLQ-C30, and its known-groups validity and responsiveness to change over time. METHODS: We used confirmatory factor analysis to test the single-factor model of the QLQ-C30, using baseline QLQ-C30 data (N = 2134). The QLQ-C30 summary score was compared to the original QLQ-C30 scales using general (age, sex, Eastern Cooperative Oncology Group performance status, comorbidity) and disease-specific (red blood cell transfusion dependency) groups. Repeated measurements allowed us to investigate responsiveness to change in a subgroup of patients with acute myeloid leukemia. RESULTS: The single-factor model of the QLQ-C30 exhibited adequate fit in patients with hematologic malignancies. Known-group comparisons generally supported the construct validity of the summary score when using more general grouping variables (sociodemographics, broad clinical parameters). Nevertheless, when groups were formed on the basis of disease-specific variables (eg, transfusion dependency), the summary score performed less well the some of the original, separate scales of the QLQ-C30. CONCLUSION: Our findings provide support for the validity of the single-factor model of the EORTC QLQ-C30 in patients with hematologic malignancies. Specifically, the results suggest that the summary score can be used as an endpoint in this population when symptom- or other health domain-specific hypotheses are not available.

Randomised clinical trial of early specialist palliative care plus standard care versus standard care alone in patients with advanced cancer: The Danish Palliative Care Trial.

BACKGROUND: Beneficial effects of early palliative care have been found in advanced cancer, but the evidence is not unequivocal. AIM: To investigate the effect of early specialist palliative care among advanced cancer patients identified in oncology departments. SETTING/PARTICIPANTS: The Danish Palliative Care Trial (DanPaCT) (ClinicalTrials.gov NCT01348048) is a multicentre randomised clinical trial comparing early referral to a specialist palliative care team plus standard care versus standard care alone. The planned sample size was 300. At five oncology departments, consecutive patients with advanced cancer were screened for palliative needs. Patients with scores exceeding a predefined threshold for problems with physical, emotional or role function, or nausea/vomiting, pain, dyspnoea or lack of appetite according to the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) were eligible. The primary outcome was the change in each patient's primary need (the most severe of the seven QLQ-C30 scales) at 3- and 8-week follow-up (0-100 scale). Five sensitivity analyses were conducted. Secondary outcomes were change in the seven QLQ-C30 scales and survival. RESULTS: Totally 145 patients were randomised to early specialist palliative care versus 152 to standard care. Early specialist palliative care showed no effect on the primary outcome of change in primary need (-4.9 points (95% confidence interval -11.3 to +1.5 points); p = 0.14). The sensitivity analyses showed similar results. Analyses of the secondary outcomes, including survival, also showed no differences, maybe with the exception of nausea/vomiting where early specialist palliative care might have had a beneficial effect. CONCLUSION: We did not observe beneficial or harmful effects of early specialist palliative care, but important beneficial effects cannot be excluded.

The Edmonton Symptom Assessment System: Poor performance as screener for major depression in patients with incurable cancer.

BACKGROUND: Depressive symptoms are prevalent in patients with advanced cancer, sometimes of a severity that fulfil the criteria for a major depressive episode. AIM: The aim of this study was to investigate how the item on depression in the Edmonton Symptom Assessment System with a 0-10 Numerical Rating Scale performed as a screener for major depressive episode. A possible improved performance by adding the Edmonton Symptom Assessment System-Anxiety item was also examined. DESIGN: An international cross-sectional study including patients with incurable cancer was conducted. The Edmonton Symptom Assessment System score was compared against major depressive episode as assessed by the Patient Health Questionnaire-9. Screening performance was examined by sensitivity, specificity and the kappa coefficient. SETTING: Patients with incurable cancer (n = 969), median age 63 years and from eight nationalities provided report. Median Karnofsky Performance Status was 70. Median survival was 229 days (205-255 days). RESULTS: Patient Health Questionnaire-9 major depressive episode was present in 133 of 969 patients (13.7%). Edmonton Symptom Assessment System-Depression screening ability for Patient Health Questionnaire-9 major depressive episode was limited. Area under the receiver operating characteristic curve was 0.71 (0.66-0.76). Valid detection or exclusion of Patient Health Questionnaire-9 major depressive episode could not be concluded at any Edmonton Symptom Assessment System-Depression cut-off; by the cut-off Numerical Rating Scale ⩾ 2, sensitivity was 0.69 and specificity was 0.60. By the cut-off Numerical Rating Scale ⩾ 4, sensitivity was 0.51 and specificity was 0.82. Combined mean ratings by Edmonton Symptom Assessment System-Depression and Edmonton Symptom Assessment System-Anxiety revealed similar limited screening ability. CONCLUSION: The depression and anxiety items of the Edmonton Symptom Assessment System, a frequently used assessment tool in palliative care settings, seem to measure a construct other than major depressive episode as assessed by the Patient Health Questionnaire-9 instrument.

Sensitivity and responsiveness of the patient-reported TED-QOL to rehabilitative surgery in thyroid eye disease.

We tested the sensitivity and responsiveness of the TED-QOL to rehabilitative surgery in thyroid eye disease (TED). The 3-item TED-QOL and 16-item GO-QOL, which assess quality of life (QoL) in TED, were administered to consecutive patients undergoing rehabilitative surgery. The questionnaires were completed pre-and post-operatively to assess sensitivity (ability to discriminate between different surgical groups) and responsiveness (ability to detect within patient changes over time).56 patients underwent 69 procedures for TED (29 orbital decompressions, 15 strabismus operations, 25 eyelid procedures). The differences in scores between the three types of surgery (a measure of sensitivity) were statistically significant at the 5% level pre-operatively and post-operatively for all 3 TED-QOL scales and for both GO-QOL scales, but much more so for the TED-QOL scales in each case. The within-patient changes between the pre- and post-operative scores for the same subjects (a measure of responsiveness) were statistically very highly significant for the TED-QOL overall and appearance scales for each of the surgeries. The pre- and post-operative difference for the TED-QOL functioning scale was highly statistically significant for strabismus surgery but not for decompression or lid surgery. The change between the pre- and post-operative scores for the GO-QOL was significant for the functioning scale with strabismus and lid surgery, and was highly significant for the appearance scale with lid surgery but not for strabismus surgery or decompression. The 3-item TED-QOL is sensitive and responsive to rehabilitative surgery in TED and compares favorably with the lengthier GO-QOL for these parameters.

Quality of patient-reported outcome reporting across cancer randomized controlled trials according to the CONSORT patient-reported outcome extension: A pooled analysis of 557 trials.

BACKGROUND: The main objectives of this study were to identify the number of randomized controlled trials (RCTs) including a patient-reported outcome (PRO) endpoint across a wide range of cancer specialties and to evaluate the completeness of PRO reporting according to the Consolidated Standards of Reporting Trials (CONSORT) PRO extension. METHODS: RCTs with a PRO endpoint that had been performed across several cancer specialties and published between 2004 and 2013 were considered. Studies were evaluated on the basis of previously defined criteria, including the CONSORT PRO extension and the Cochrane Collaboration's tool for assessing the risk of bias of RCTs. Analyses were also conducted by the type of PRO endpoint (primary vs secondary) and by the cancer disease site. RESULTS: A total of 56,696 potentially eligible records were scrutinized, and 557 RCTs with a PRO evaluation, enrolling 254,677 patients overall, were identified. PROs were most frequently used in RCTs of breast (n = 123), lung (n = 85), and colorectal cancer (n = 66). Overall, PROs were secondary endpoints in 421 RCTs (76%). Four of 6 evaluated CONSORT PRO items were documented in less than 50% of the RCTs. The level of reporting was higher in RCTs with a PRO as a primary endpoint. The presence of a supplementary report was the only statistically significant factor associated with greater completeness of reporting for both RCTs with PROs as primary endpoints (ß = .19, P = .001) and RCTs with PROs as secondary endpoints (ß = .30, P < .001). CONCLUSIONS: Implementation of the CONSORT PRO extension is equally important across all cancer specialties. Its use can also contribute to revealing the robust PRO design of some studies, which might be obscured by poor outcome reporting.

Methods for specifying the target difference in a randomised controlled trial: the Difference ELicitation in TriAls (DELTA) systematic review.

BACKGROUND: Randomised controlled trials (RCTs) are widely accepted as the preferred study design for evaluating healthcare interventions. When the sample size is determined, a (target) difference is typically specified that the RCT is designed to detect. This provides reassurance that the study will be informative, i.e., should such a difference exist, it is likely to be detected with the required statistical precision. The aim of this review was to identify potential methods for specifying the target difference in an RCT sample size calculation. METHODS AND FINDINGS: A comprehensive systematic review of medical and non-medical literature was carried out for methods that could be used to specify the target difference for an RCT sample size calculation. The databases searched were MEDLINE, MEDLINE In-Process, EMBASE, the Cochrane Central Register of Controlled Trials, the Cochrane Methodology Register, PsycINFO, Science Citation Index, EconLit, the Education Resources Information Center (ERIC), and Scopus (for in-press publications); the search period was from 1966 or the earliest date covered, to between November 2010 and January 2011. Additionally, textbooks addressing the methodology of clinical trials and International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) tripartite guidelines for clinical trials were also consulted. A narrative synthesis of methods was produced. Studies that described a method that could be used for specifying an important and/or realistic difference were included. The search identified 11,485 potentially relevant articles from the databases searched. Of these, 1,434 were selected for full-text assessment, and a further nine were identified from other sources. Fifteen clinical trial textbooks and the ICH tripartite guidelines were also reviewed. In total, 777 studies were included, and within them, seven methods were identified-anchor, distribution, health economic, opinion-seeking, pilot study, review of the evidence base, and standardised effect size. CONCLUSIONS: A variety of methods are available that researchers can use for specifying the target difference in an RCT sample size calculation. Appropriate methods may vary depending on the aim (e.g., specifying an important difference versus a realistic difference), context (e.g., research question and availability of data), and underlying framework adopted (e.g., Bayesian versus conventional statistical approach). Guidance on the use of each method is given. No single method provides a perfect solution for all contexts.

Should linking replace regression when mapping from profile-based measures to preference-based measures?

BACKGROUND: Profile instruments are frequently used to assess health-related quality of life and other patient-reported outcomes. However, preference-based measures are required for health-economic cost-utility evaluations. RESULTS: Although regression-based approaches are commonly used to map from profile measures to preference measures, we show that this results in biased estimates because of regression to the mean. CONCLUSIONS: Linking (scale-aligning) is proposed as an alternative.

Weight loss, appetite loss and food intake in cancer patients with cancer cachexia: three peas in a pod? - analysis from a multicenter cross sectional study.

BACKGROUND: How to assess cachexia is a barrier both in research and in clinical practice. This study examines the need for assessing both reduced food intake and loss of appetite, to see if these variables can be used interchangeably. A secondary aim is to assess the variance explained by food intake, appetite and weight loss by using tumor-related factors, symptoms and biological markers as explanatory variables. MATERIAL AND METHODS: One thousand and seventy patients with incurable cancer were registered in an observational, cross sectional multicenter study. A total of 885 patients that had complete data on food intake (PG-SGA), appetite (EORTC QLQ-C30) and weight loss were included in the present analysis. The association between reduced food intake and appetite loss was assessed using Spearman's correlation. To find the explained variance of the three symptoms a multivariate analysis was performed. RESULTS: The mean age was 62 years with a mean survival of 247 days and a mean Karnofsky performance status of 72. Thirteen percent of the patients who reported eating less than normal had good appetite and 25% who had unchanged or increased food intake had reduced appetite. Correlation between appetite loss and food intake was 0.50. Explained variance for the regression models was 44% for appetite loss, 27% for food intake and only 13% for weight loss. CONCLUSION: Both appetite loss and food intake should be assessed in cachectic patients since conscious control of eating may sometimes overcome appetite loss. The low explained variance for weight loss is probably caused by the need for more knowledge about metabolism and inflammation, and is consistent with the cancer cachexia definition that claims that in cachexia weight loss is not caused by reduced food intake alone. The questions concerning appetite loss from EORTC-QLQ C30 and food intake from PG-SGA seem practical and informative when dealing with advanced cancer patients.

Overcoming barriers to the implementation of patient-reported outcomes in cancer clinical trials: the PROMOTION Registry.

Every cancer treatment, irrespective of its clinical effectiveness, has an impact on patients' quality of life (QoL). Even recently developed targeted therapies might have side effects and significantly impact patients' QoL. Thus, understanding the advantages and disadvantages of different treatments from the patient's standpoint has become a must in clinical research and is highly valued by major stakeholders. Thousands of cancer patients are enrolled into randomized controlled trials (RCTs) each year and many complete patient-reported outcome (PRO) instruments to obtain patient-centered information as part of the assessment of the overall effectiveness of the new therapy. Some of these RCTs have generated high quality PRO evidence forming the basis for approval (or support to approval) of drugs by the US Food and Drug Administration. However, a consistent strategy to determine the quality of patient centered evidence presented in RCTs has until recently been lacking. One of the fundamental questions when including PROs in clinical research revolves around methodological robustness and consistency of outcome reporting. Cancer patients, physicians and healthcare system stakeholders need to rely on solid information to make the best possible choice regarding treatment. Therefore generating high-quality findings from PRO assessment in cancer trials is of paramount importance. In an effort to improve quality of PRO assessment and reporting in the near future, the Patient-Reported Outcome Measurements Over Time In ONcology (PROMOTION) Registry was developed. The scope of this Registry is to identify, track, analyse, and store information on all cancer RCTs that have included PROs, and assess the quality of their PRO assessments.

Don't middle your MIDs: regression to the mean shrinks estimates of minimally important differences.

Minimal important differences (MIDs) for patient-reported outcomes (PROs) are often estimated by selecting a clinical variable to serve as an anchor. Then, differences in the clinical anchor regarded as clinically meaningful or important can be used to estimate the corresponding value of the PRO. Although these MID values are sometimes estimated by regression techniques, we show that this is a biased procedure and should not be used; alternative methods are proposed.

Use of methods for specifying the target difference in randomised controlled trial sample size calculations: Two surveys of trialists' practice.

BACKGROUND: Central to the design of a randomised controlled trial (RCT) is a calculation of the number of participants needed. This is typically achieved by specifying a target difference, which enables the trial to identify a difference of a particular magnitude should one exist. Seven methods have been proposed for formally determining what the target difference should be. However, in practice, it may be driven by convenience or some other informal basis. It is unclear how aware the trialist community is of these formal methods or whether they are used. PURPOSE: To determine current practice regarding the specification of the target difference by surveying trialists. METHODS: Two surveys were conducted: (1) Members of the Society for Clinical Trials (SCT): participants were invited to complete an online survey through the society's email distribution list. Respondents were asked about their awareness, use of, and willingness to recommend methods; (2) Leading UK- and Ireland-based trialists: the survey was sent to UK Clinical Research Collaboration registered Clinical Trials Units, Medical Research Council UK Hubs for Trial Methodology Research, and the Research Design Services of the National Institute for Health Research. This survey also included questions about the most recent trial developed by the respondent's group. RESULTS: Survey 1: Of the 1182 members on the SCT membership email distribution list, 180 responses were received (15%). Awareness of methods ranged from 69 (38%) for health economic methods to 162 (90%) for pilot study. Willingness to recommend among those who had used a particular method ranged from 56% for the opinion-seeking method to 89% for the review of evidence-base method. Survey 2: Of the 61 surveys sent out, 34 (56%) responses were received. Awareness of methods ranged from 33 (97%) for the review of evidence-base and pilot methods to 14 (41%) for the distribution method. The highest level of willingness to recommend among users was for the anchor method (87%). Based upon the most recent trial, the target difference was usually one viewed as important by a stakeholder group, mostly also viewed as a realistic difference given the interventions under evaluation, and sometimes one that led to an achievable sample size. LIMITATIONS: The response rates achieved were relatively low despite the surveys being short, well presented, and having utilised reminders. CONCLUSION: Substantial variations in practice exist with awareness, use, and willingness to recommend methods varying substantially. The findings support the view that sample size calculation is a more complex process than would appear to be the case from trial reports and protocols. Guidance on approaches for sample size estimation may increase both awareness and use of appropriate formal methods.

The systemic inflammatory response and its relationship to pain and other symptoms in advanced cancer.

INTRODUCTION: Inflammation has been identified as a hallmark of cancer and may be necessary for tumorgenesis and maintenance of the cancer state. Inflammation-related symptoms are common in those with cancer; however, little is known about the relationship between symptoms and systemic inflammation in cancer. The aim of the present study was to examine the relationship between symptoms and systemic inflammation in a large cohort of patients with advanced cancer. METHODS: Data from an international cohort of patients with advanced cancer were analyzed. Symptoms and patient-related outcomes were recorded using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire--Core Questionnaire. Systemic inflammation was assessed using C-reactive protein levels. The relationship between these symptoms and systemic inflammation was examined using Spearman rank correlation (ρ) and the Mann-Whitney U test. RESULTS: Data were available for 1,466 patients across eight European countries; 1,215 patients (83%) had metastatic disease at study entry. The median survival was 3.8 months (interquartile range [IQR] 1.3-12.2 months). The following were associated with increased levels of inflammation: performance status (ρ = .179), survival (ρ = .347), pain (ρ = .154), anorexia (ρ = .206), cognitive dysfunction (ρ = .137), dyspnea (p= .150), fatigue (ρ = .197), physical dysfunction (ρ = .207), role dysfunction (ρ = .176), social dysfunction (ρ = .132), and poor quality of life (ρ = .178). All were statistically significant at p < .001. CONCLUSION: The results show that the majority of cancer symptoms are associated with inflammation. The strength of the potential relationship between systemic inflammation and common cancer symptoms should be examined further within the context of an anti-inflammatory intervention trial.

Evaluating complex interventions in end of life care: the MORECare statement on good practice generated by a synthesis of transparent expert consultations and systematic reviews.

BACKGROUND: Despite being a core business of medicine, end of life care (EoLC) is neglected. It is hampered by research that is difficult to conduct with no common standards. We aimed to develop evidence-based guidance on the best methods for the design and conduct of research on EoLC to further knowledge in the field. METHODS: The Methods Of Researching End of life Care (MORECare) project built on the Medical Research Council guidance on the development and evaluation of complex circumstances. We conducted systematic literature reviews, transparent expert consultations (TEC) involving consensus methods of nominal group and online voting, and stakeholder workshops to identify challenges and best practice in EoLC research, including: participation recruitment, ethics, attrition, integration of mixed methods, complex outcomes and economic evaluation. We synthesised all findings to develop a guidance statement on the best methods to research EoLC. RESULTS: We integrated data from three systematic reviews and five TECs with 133 online responses. We recommend research designs extending beyond randomised trials and encompassing mixed methods. Patients and families value participation in research, and consumer or patient collaboration in developing studies can resolve some ethical concerns. It is ethically desirable to offer patients and families the opportunity to participate in research. Outcome measures should be short, responsive to change and ideally used for both clinical practice and research. Attrition should be anticipated in studies and may affirm inclusion of the relevant population, but careful reporting is necessitated using a new classification. Eventual implementation requires consideration at all stages of the project. CONCLUSIONS: The MORECare statement provides 36 best practice solutions for research evaluating services and treatments in EoLC to improve study quality and set the standard for future research. The statement may be used alongside existing statements and provides a first step in setting common, much needed standards for evaluative research in EoLC. These are relevant to those undertaking research, trainee researchers, research funders, ethical committees and editors.

Thalidomide for previously untreated elderly patients with multiple myeloma: meta-analysis of 1685 individual patient data from 6 randomized clinical trials.

The role of thalidomide for previously untreated elderly patients with multiple myeloma remains unclear. Six randomized controlled trials, launched in or after 2000, compared melphalan and prednisone alone (MP) and with thalidomide (MPT). The effect on overall survival (OS) varied across trials. We carried out a meta-analysis of the 1685 individual patients in these trials. The primary endpoint was OS, and progression-free survival (PFS) and 1-year response rates were secondary endpoints. There was a highly significant benefit to OS from adding thalidomide to MP (hazard ratio = 0.83; 95% confidence interval 0.73-0.94, P = .004), representing increased median OS time of 6.6 months, from 32.7 months (MP) to 39.3 months (MPT). The thalidomide regimen was also associated with superior PFS (hazard ratio = 0.68, 95% confidence interval 0.61-0.76, P < .0001) and better 1-year response rates (partial response or better was 59% on MPT and 37% on MP). Although the trials differed in terms of patient baseline characteristics and thalidomide regimens, there was no evidence that treatment affected OS differently according to levels of the prognostic factors. We conclude that thalidomide added to MP improves OS and PFS in previously untreated elderly patients with multiple myeloma, extending the median survival time by on average 20%.