Biomarker endpoints in cancer cachexia clinical trials: Systematic Review 5 of the cachexia endpoint series.

Regulatory agencies require evidence that endpoints correlate with clinical benefit before they can be used to approve drugs. Biomarkers are often considered surrogate endpoints. In cancer cachexia trials, the measurement of biomarkers features frequently. The aim of this systematic review was to assess the frequency and diversity of biomarker endpoints in cancer cachexia trials. A comprehensive electronic literature search of MEDLINE, Embase and Cochrane (1990-2023) was completed. Eligible trials met the following criteria: adults (≥18 years), prospective design, more than 40 participants, use of a cachexia intervention for more than 14 days and use of a biomarker(s) as an endpoint. Biomarkers were defined as any objective measure that was assayed from a body fluid, including scoring systems based on these assays. Routine haematology and biochemistry to monitor intervention toxicity were not considered. Data extraction was performed using Covidence, and reporting followed PRISMA guidance (PROSPERO: CRD42022276710). A total of 5975 studies were assessed, of which 52 trials (total participants = 6522) included biomarkers as endpoints. Most studies (n = 29, 55.7%) included a variety of cancer types. Pharmacological interventions (n = 27, 51.9%) were most evaluated, followed by nutritional interventions (n = 20, 38.4%). Ninety-nine different biomarkers were used across the trials, and of these, 96 were assayed from blood. Albumin (n = 29, 55.8%) was assessed most often, followed by C-reactive protein (n = 22, 42.3%), interleukin-6 (n = 16, 30.8%) and tumour necrosis factor-α (n = 14, 26.9%), the latter being the only biomarker that was used to guide sample size calculations. Biomarkers were explicitly listed as a primary outcome in six trials. In total, 12 biomarkers (12.1% of 99) were used in six trials or more. Insulin-like growth factor binding protein 3 (IGFBP-3) and insulin-like growth factor 1 (IGF-1) levels both increased significantly in all three trials in which they were both used. This corresponded with a primary outcome, lean body mass, and was related to the pharmacological mechanism. Biomarkers were predominately used as exploratory rather than primary endpoints. The most commonly used biomarker, albumin, was limited by its lack of responsiveness to nutritional intervention. For a biomarker to be responsive to change, it must be related to the mechanism of action of the intervention and/or the underlying cachexia process that is modified by the intervention, as seen with IGFBP-3, IGF-1 and anamorelin. To reach regulatory approval as an endpoint, the relationship between the biomarker and clinical benefit must be clarified.

Body weight and composition endpoints in cancer cachexia clinical trials: Systematic Review 4 of the cachexia endpoints series.

Significant variation exists in the outcomes used in cancer cachexia trials, including measures of body composition, which are often selected as primary or secondary endpoints. To date, there has been no review of the most commonly selected measures or their potential sensitivity to detect changes resulting from the interventions being examined. The aim of this systematic review is to assess the frequency and diversity of body composition measures that have been used in cancer cachexia trials. MEDLINE, Embase and Cochrane Library databases were systematically searched between January 1990 and June 2021. Eligible trials examined adults (≥18 years) who had received an intervention aiming to treat or attenuate the effects of cancer cachexia for >14 days. Trials were also of a prospective controlled design and included body weight or at least one anthropometric, bioelectrical or radiological endpoint pertaining to body composition, irrespective of the modality of intervention (e.g., pharmacological, nutritional, physical exercise and behavioural) or comparator. Trials with a sample size of <40 patients were excluded. Data extraction used Covidence software, and reporting followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidance. This review was prospectively registered (PROSPERO: CRD42022276710). A total of 84 clinical trials, comprising 13 016 patients, were eligible for inclusion. Non-small-cell lung cancer and pancreatic cancer were studied most frequently. The majority of trial interventions were pharmacological (52%) or nutritional (34%) in nature. The most frequently reported endpoints were assessments of body weight (68 trials, n = 11 561) followed by bioimpedance analysis (BIA)-based estimates (23 trials, n = 3140). Sixteen trials (n = 3052) included dual-energy X-ray absorptiometry (DEXA)-based endpoints, and computed tomography (CT) body composition was included in eight trials (n = 841). Discrepancies were evident when comparing the efficacy of interventions using BIA-based estimates of lean tissue mass against radiological assessment modalities. Body weight, BIA and DEXA-based endpoints have been most frequently used in cancer cachexia trials. Although the optimal endpoints cannot be determined from this review, body weight, alongside measurements from radiological body composition analysis, would seem appropriate. The choice of radiological modality is likely to be dependent on the trial setting, population and intervention in question. CT and magnetic resonance imaging, which have the ability to accurately discriminate tissue types, are likely to be more sensitive and provide greater detail. Endpoints are of particular importance when aligned with the intervention's mechanism of action and/or intended patient benefit.

Quality of life endpoints in cancer cachexia clinical trials: Systematic review 3 of the cachexia endpoints series.

The use of patient-reported outcomes (PROMs) of quality of life (QOL) is common in cachexia trials. Patients' self-report on health, functioning, wellbeing, and perceptions of care, represent important measures of efficacy. This review describes the frequency, variety, and reporting of QOL endpoints used in cancer cachexia clinical trials. Electronic literature searches were performed in Medline, Embase, and Cochrane (1990-2023). Seven thousand four hundred thirty-five papers were retained for evaluation. Eligibility criteria included QOL as a study endpoint using validated measures, controlled design, adults (>18 years), ≥40 participants randomized, and intervention exceeding 2 weeks. The Covidence software was used for review procedures and data extractions. Four independent authors screened all records for consensus. Papers were screened by titles and abstracts, prior to full-text reading. PRISMA guidance for systematic reviews was followed. The protocol was prospectively registered via PROSPERO (CRD42022276710). Fifty papers focused on QOL. Twenty-four (48%) were double-blind randomized controlled trials. Sample sizes varied considerably (n = 42 to 469). Thirty-nine trials (78%) included multiple cancer types. Twenty-seven trials (54%) featured multimodal interventions with various drugs and dietary supplements, 11 (22%) used nutritional interventions alone and 12 (24%) used a single pharmacological intervention only. The median duration of the interventions was 12 weeks (4-96). The most frequent QOL measure was the EORTC QLQ-C30 (60%), followed by different FACIT questionnaires (34%). QOL was a primary, secondary, or exploratory endpoint in 15, 31 and 4 trials respectively, being the single primary in six. Statistically significant results on one or more QOL items favouring the intervention group were found in 18 trials. Eleven of these used a complete multidimensional measure. Adjustments for multiple testing when using multicomponent QOL measures were not reported. Nine trials (18%) defined a statistically or clinically significant difference for QOL, five with QOL as a primary outcome, and four with QOL as a secondary outcome. Correlation statistics with other study outcomes were rarely performed. PROMs including QOL are important endpoints in cachexia trials. We recommend using well-validated QOL measures, including cachexia-specific items such as weight history, appetite loss, and nutritional intake. Appropriate statistical methods with definitions of clinical significance, adjustment for multiple testing and few co-primary endpoints are encouraged, as is an understanding of how interventions may relate to changes in QOL endpoints. A strategic and scientific-based approach to PROM research in cachexia trials is warranted, to improve the research base in this field and avoid the use of QOL as supplementary measures.

Appetite and dietary intake endpoints in cancer cachexia clinical trials: Systematic Review 2 of the cachexia endpoints series.

There is no consensus on the optimal endpoint(s) in cancer cachexia trials. Endpoint variation is an obstacle when comparing interventions and their clinical value. The aim of this systematic review was to summarize and evaluate endpoints used to assess appetite and dietary intake in cancer cachexia clinical trials. A search for studies published from 1 January 1990 until 2 June 2021 was conducted using MEDLINE, Embase and Cochrane Central Register of Controlled Trials. Eligible studies examined cancer cachexia treatment versus a comparator in adults with assessments of appetite and/or dietary intake as study endpoints, a sample size ≥40 and an intervention lasting ≥14 days. Reporting was in line with PRISMA guidance, and a protocol was published in PROSPERO (2022 CRD42022276710). This review is part of a series of systematic reviews examining cachexia endpoints. Of the 5975 articles identified, 116 were eligible for the wider review series and 80 specifically examined endpoints of appetite (65 studies) and/or dietary intake (21 studies). Six trials assessed both appetite and dietary intake. Appetite was the primary outcome in 15 trials and dietary intake in 7 trials. Median sample size was 101 patients (range 40-628). Forty-nine studies included multiple primary tumour sites, while 31 studies involved single primary tumour sites (15 gastrointestinal, 7 lung, 7 head and neck and 2 female reproductive organs). The most frequently reported appetite endpoints were visual analogue scale (VAS) and numerical rating scale (NRS) (40%). The appetite item from the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) C30/C15 PAL (38%) and the appetite question from North Central Cancer Treatment Group anorexia questionnaire (17%) were also frequently applied. Of the studies that assessed dietary intake, 13 (62%) used food records (prospective registrations) and 10 (48%) used retrospective methods (24-h recall or dietary history). For VAS/NRS, a mean change of 1.3 corresponded to Hedge's g of 0.5 and can be considered a moderate change. For food records, a mean change of 231 kcal/day or 11 g of protein/day corresponded to a moderate change. Choice of endpoint in cachexia trials will depend on factors pertinent to the trial to be conducted. Nevertheless, from trials assessed and available literature, NRS or EORTC QLQ C30/C15 PAL seems suitable for appetite assessments. Appetite and dietary intake endpoints are rarely used as primary outcomes in cancer cachexia. Dietary intake assessments were used mainly to monitor compliance and are not validated in cachexia populations. Given the importance to cachexia studies, dietary intake endpoints must be validated before they are used as endpoints in clinical trials.

Health-related quality of life, depressive symptoms, and chronic fatigue in long-term survivors of Hodgkin lymphoma.

High-dose chemotherapy with autologous stem cell transplantation (HDT-ASCT) is the preferred treatment option in relapsed or refractory Hodgkin lymphoma (HL). We analyzed the association between treatment intensity and health-related quality of life (HRQoL), depressive symptoms, and chronic fatigue (CF) in long-term survivors of HL (HLS), identified in two population-based national cross-sectional studies on late adverse effects. We included 375 HLS treated between 1987 and 2006, 264 with conventional therapy only, and 111 with HDT-ASCT. Despite similar differences to the matched general population, when controlling for other imbalances between the groups, use of HDT-ASCT was not associated with poorer outcome in multivariable analysis. However, work participation, family income, comorbidities, and lifestyle factors had stronger associations with aspects of HRQoL, depressive symptoms, and CF. Our data suggest that better rehabilitation to work participation and adequate income as well as follow-up for comorbidities may reduce differences in long-term outcome after treatment for HL.

Total late effect burden in long-term lymphoma survivors after high-dose therapy with autologous stem-cell transplant and its effect on health-related quality of life.

Lymphoma survivors after high-dose therapy with autologous stem-cell transplant (HDT-ASCT) are at risk of several late effects, which might impair their health-related quality of life (HRQoL). We assessed the total late effect burden in this population, and how it affects HRQoL. All lymphoma survivors treated with HDT-ASCT as adults in Norway between 1987 and 2008 were identified, and 271 (68%) attended both a comprehensive clinical assessment and completed a questionnaire. Severity of 45 conditions in 12 organ-system categories were graded as mild, moderate, severe or life-threatening, according to a modified version of CTCAEv4.03. At a median of 8 years after HDT-ASCT, 98% of survivors had at least one moderate or more severe late effect and 56% had severe or life-threatening late effects. Fourteen percent had low, 39% medium and 47% high late effect burden, defined as having moderate or more severe late effects in 0-1, 2-3 and >3 organsystems, respectively. Female sex, increasing age, B-symptoms at diagnosis and >1 treatment line prior to HDT-ASCT were independently associated with having high late effect burden. The survivors had significantly poorer physical and mental HRQoL assessed by the Short Form-36 compared to age- and sex-matched controls. The prevalence of poor physical and mental HRQoL increased with higher late effect burden (both P<0.001), and the low burden group had better physical HRQoL than controls (P<0.001). In conclusion, lymphoma survivors after HDT-ASCT have impaired HRQoL, seemingly driven by a high late effect burden. This highlights the importance of prevention, regular assessments for early detection and treatment of late effects and modifiable risk factors.

Benefits of Study Participation for Patients with Advanced Cancer Receiving Radiotherapy: A Prospective Observational Study.

Background: Patients with advanced cancer and bone metastases may have unmet palliative care (PC) needs that go unnoticed during clinical oncological practice. This observational study describes interventions that were initiated as the patients participated in the Palliative Radiotherapy and Inflammation Study (PRAIS). It was hypothesized that the patients would benefit from study participation due to PC interventions initiated by the study team. Methods: A retrospective review of patients' electronic records. Patients with advanced cancer and painful bone metastases included in PRAIS were eligible. All patients met with the study team before start of radiotherapy, after completion of Patient Reported Outcome Measures. Interventions initiated by the study team were documented in the patients' electronic records. Results: A total of 133 patients were reviewed: 63% males, mean (standard deviation [SD]) age 65 (9.6) and mean (SD) Karnofsky performance status (KPS) score 73.2 (9.1). Interventions were initiated in 50% (n = 67) of the patients. Changes in opioid management (69%), treatment of constipation (43%), and nausea (24%) and nutritional advice were most frequent (21%). Patients receiving interventions had lower mean KPS (70 vs. 77 p < 0.001), shorter survival time after study inclusion (median 28 vs. 57.5 weeks p = 0.005) and were more often opioid naïve (12% vs. 39% p < 0.001) than those not receiving interventions by the study team. Conclusions: Patients with advanced cancer and painful bone metastasis benefited from study participation due to multiple PC interventions initiated by the study team. The findings call for a systematic integration of PC in patients with advanced cancer. Trial Registration: ClinicalTrials.gov NCT02107664.

Personality and educational level determine self-reported health-related quality-of-life and distress in patients with renal tumors awaiting radical surgery.

Objective: Data on preoperative distress and health-related quality-of-life (HRQoL) is lacking for patients with newly diagnosed renal tumors. This study aims to compare HRQoL within this group with the general population and to study the relationship between distress, HRQoL, personality, coping, and patient/tumor-related factors.Materials and methods: Between January 2011 and June 2014, 153 patients (100 males/53 females), scheduled for surgery were prospectively included. Distress was determined by the General Health Questionnaire (GHQ), HRQoL by EORTC-QLQ-C30 questionnaire, personality by Eysenck Personality Inventory and coping by COPE questionnaire. HRQoL-data from an age and gender matched Norwegian reference population was used for comparison.Results: The study patients had significantly poorer HRQoL than the reference population. GHQ and HRQoL sum scores had a common variance (CV = r2) of 29-35%. In regression models, the measured variables accounted for 33% of the variance for the GHQ score. Significant predictors of the measured variance were neuroticism (18%), education level (3%) and avoidant coping (2%). Similarly, the measured variables accounted for 33-44% of the variance for the HRQoL sum scores. For all HRQoL sum scores, neuroticism predicted 17-28%, while education predicted 4-11% of the measured variance. Large tumor size, comorbidity, performance status and CRP predicted 2-7% of individual sum scores.Conclusions: For both preoperative distress and HRQoL, personality traits such as neuroticism and education level were the most important predictors. Tumor-related factors and other preexisting conditions seemed to be of lesser importance. Thus, preoperatively screening of psychological factors could be helpful to identify those at risk of poor outcomes.

Psychometric properties of the updated EORTC module for assessing quality of life in patients with lung cancer (QLQ-LC29): an international, observational field study.

BACKGROUND: The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Lung Cancer 13 (QLQ-LC13) assesses quality of life (QOL) in patients with lung cancer and was the first EORTC module developed for use in international clinical trials. Since its publication in 1994, major treatment advances with possible effects on QOL have occurred. These changes called for an update of the module and its international psychometric validation. We aimed to investigate the scale structure and psychometric properties of the updated lung cancer module, QLQ-LC29, in patients with lung cancer. METHODS: This international, observational field study was done in 19 hospitals across 12 countries. Patients aged older than 18 years with a confirmed diagnosis of lung cancer and no other previous primary tumour, and who were mentally fit with sufficient language skills to understand and complete the questionnaire were included. Patients were asked during a hospital visit to fill in the paper versions of the core questionnaire EORTC QLQ-C30 plus QLQ-LC29, and investigators selected half of these patients to complete the questionnaire again 2-4 weeks later. Our primary aim was to assess the scale structure and psychometric properties of EORTC QLQ-LC29. We analysed scale structure using confirmatory factor analysis; reliability using Cronbach's α value (internal consistency) and intra-class coefficient (test-retest reliability); sensitivity using independent t tests stratified by Karnofsky performance status; and responsiveness to change over time by ANOVA. This study is registered with ClinicalTrials.gov, NCT02745691. FINDINGS: Between April 12, 2016, and Sept 26, 2018, 523 patients with a confirmed diagnosis of either non-small-cell lung cancer (n=442) or small-cell lung cancer (n=81) were recruited. Confirmatory factor analysis provided a solution composed of five multi-item scales (coughing, shortness of breath, fear of progression, hair problems, and surgery-related symptoms) plus 15 single symptom or side-effect items: χ2=370·233, root mean square error of approximation=0·075, and comparative-fit index=0·901. Cronbach's α for internal consistencies of all multi-item scales were above the threshold of 0·70. Intra-class coefficients for test-retest reliabilities ranged between 0·82 and 0·97. Three (shortness of breath, fear of progression, and hair problems) of the five multi-item scales showed responsiveness to change over time (p values <0·05), as did nine of 15 single symptom items. Four (coughing, shortness of breath, fear of progression, and surgery-related symptoms) of the five multi-item scales and ten of the 15 single symptom items were sensitive to known group differences (ie, lower vs higher Karnofsky performance status). INTERPRETATION: Results determined the psychometric properties of the updated lung cancer module, which is ready for use in international clinical studies. FUNDING: EORTC Quality of Life Group.

Quality of life and symptom intensity over time in people with cancer receiving palliative care: Results from the international European Palliative Care Cancer Symptom study.

BACKGROUND: People with advanced cancer experience multiple symptoms during their illness trajectory, which can fluctuate in intensity. AIM: To describe the course of self-reported quality of life, emotional functioning, physical functioning and symptom intensity over time in cancer patients receiving palliative care. DESIGN: Longitudinal study with monthly assessments, using the EORTC QLQ-C15-PAL. Data were analysed (1) prospectively, from baseline to ≥8-month follow-up; and (2) retrospectively, by taking death as index date and comparing results from three cross-sectional subsamples at different stages of illness (time to death ≥6, 5-3 and 2-0 months). Linear mixed models were calculated. SETTING/PARTICIPANTS: A total of 1739 patients (mean age 66, 50% male) from 30 palliative care centers in 12 countries were included. RESULTS: In prospective analyses, quality of life, functioning and symptoms-except nausea/vomiting-remained generally stable over time. In retrospective analyses, patients 2-0 months before death reported significantly lower quality of life and physical functioning scores than those 5-3 months before death, who in turn scored lower than those ≥6 months before death, suggesting progressive decline. Emotional functioning remained initially unchanged, but decreased in the last months. Pain, fatigue and appetite loss showed a stable increase in intensity towards death. Dyspnea, insomnia and constipation increased from 5-3 to 2-0 months before death. Nausea/vomiting only increased when comparing those ≥6 months before death with those 2-0 months before death. CONCLUSION: While the prospective approach showed predominantly stable patterns for quality of life, functioning and symptom severity throughout study duration, retrospective analyses indicated that deterioration was already apparent before the terminal phase and accelerated close to death. Our findings support the importance of early symptom identification and treatment in this population, and highlight the need for further studies to explore what characterizes those with either lower or higher symptom burden at different time points towards death.

Modifiable factors affecting older patients' quality of life and physical function during cancer treatment.

BACKGROUND: Maintaining physical function and quality of life (QoL) are prioritized outcomes among older adults. We aimed to identify potentially modifiable factors affecting older patients' physical function and QoL during cancer treatment. METHODS: Prospective, multicenter study of 307 patients with cancer ≥70 years, referred for systemic treatment. Pre-treatment, a modified geriatric assessment (mGA) was performed, including registration of comorbidities, medications, nutritional status, cognitive function, depressive symptoms (Geriatric Depression Scale-15 [GDS]), and mobility (Timed Up and Go [TUG]). Patient-reported physical function (PF)-, global QoL-, and symptom scores were assessed at baseline, two, four, and six months by the EORTC Quality of Life Core Questionnaire-C30. The impact of mGA components and symptoms on patients' PF and global QoL scores during six months was investigated by linear mixed models. To identify groups following distinct PF trajectories, a growth mixture model was estimated. RESULTS: 288 patients were eligible, mean age was 76.9 years, 68% received palliative treatment. Higher GDS-scores and poorer TUG were independently associated with an overall level of poorer PF and global QoL throughout follow-up, as were more pain, dyspnea, and appetite loss, and sleep disturbance. Three groups with distinct PF trajectories were identified: a poor group exhibiting a non-linear statistically (p < .001) and clinically significant decline (≥10 points), an intermediate group with a statistically (p = .003), but not clinically significant linear decline, and a good group with a stable trajectory. Higher GDS-scores and poorer TUG, more pre-treatment pain and dyspnea were associated with higher odds of belonging to the poor compared to the good PF group. CONCLUSION: Depressive symptoms, reduced mobility, and more physical symptoms increased the risk of decrements in older patients' PF and global QoL scores during cancer treatment, and represent potential targets for interventions aiming at improving these outcomes.

A prospective study examining cachexia predictors in patients with incurable cancer.

BACKGROUND: Early intervention against cachexia necessitates a predictive model. The aims of this study were to identify predictors of cachexia development and to create and evaluate accuracy of a predictive model based on these predictors. METHODS: A secondary analysis of a prospective, observational, multicentre study was conducted. Patients, who attended a palliative care programme, had incurable cancer and did not have cachexia at baseline, were amenable to the analysis. Cachexia was defined as weight loss (WL) > 5% (6 months) or WL > 2% and body mass index< 20 kg/m2. Clinical and demographic markers were evaluated as possible predictors with Cox analysis. A classification and regression tree analysis was used to create a model based on optimal combinations and cut-offs of significant predictors for cachexia development, and accuracy was evaluated with a calibration plot, Harrell's c-statistic and receiver operating characteristic curve analysis. RESULTS: Six-hundred-twenty-eight patients were included in the analysis. Median age was 65 years (IQR 17), 359(57%) were female and median Karnofsky performance status was 70(IQR 10). Median follow-up was 109 days (IQR 108), and 159 (25%) patients developed cachexia. Initial WL, cancer type, appetite and chronic obstructive pulmonary disease were significant predictors (p ≤ 0.04). A five-level model was created with each level carrying an increasing risk of cachexia development. For Risk-level 1-patients (WL < 3%, breast or hematologic cancer and no or little appetite loss), median time to cachexia development was not reached, while Risk-level 5-patients (WL 3-5%) had a median time to cachexia development of 51 days. Accuracy of cachexia predictions at 3 months was 76%. CONCLUSION: Important predictors of cachexia have been identified and used to construct a predictive model of cancer cachexia. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01362816 .

Pilot testing of the first version of the European Association for Palliative Care basic dataset: A mixed methods study.

BACKGROUND: Inadequate description of palliative care cancer patients in research studies often leads to results having limited generalizability. To standardize the description of the sample, the European Association for Palliative Care basic data set was developed, with 31 core demographic and disease-related variables. AIM: To pilot test the data set to check acceptability, comprehensibility and feasibility. DESIGN: International, multi-centre pilot study at nine study sites in five European countries, using mixed methods. SETTING/PARTICIPANTS: Adult cancer patients and staff in palliative care units, hospices and home care. RESULTS: In all, 191 patients (544 screened) and 190 health care personnel were included. Median time to fill in the patient form was 5 min and the health care personnel form was 7 min. Ethnicity was the most challenging item for patients and requires decisions at a national level about whether or how to include. Health care personnel found weight loss, principal diagnosis, additional diagnoses and stage of non-cancer diseases most difficult to respond to. Registration of diagnoses will be changed from International Statistical Classification of Diseases and Related Health Problems, 10th version code to a predefined list, while weight loss and stage of non-cancer diseases will be removed. The pilot study has led to rewording of items, improvement in response options and shortening of the data set to 29 items. CONCLUSION: Pilot testing of the first version of the European Association for Palliative Care basic data set confirmed that patients and health care personnel understand the questions in a consistent manner and can answer within an acceptable timeframe. The pilot testing has led to improvement, and the new version is now subject to further testing.

Sleep quality with WHO Step III opioid use for cancer pain.

OBJECTIVE: Sleep is often disturbed in patients with advanced cancer. There is limited knowledge about sleep in patients with cancer treated with strong opioids. This study examines sleep quality in patients with advanced cancer who are treated with a WHO Step III opioid for pain. METHODS: An international, multicentre, cross-sectional study with 604 adult patients with cancer pain using WHO Step III opioids. Sleep quality was assessed by the Pittsburgh Sleep Quality Index (PSQI) global score (range; 0-21; score >5 indicates poor sleep). PSQI includes sleep quality, sleep latency, sleep duration, sleep efficiency, sleep disturbances, use of sleep medications and daytime dysfunction. Pain and quality of life were assessed by Brief Pain Inventory and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core30. RESULTS: The median age was 62 years, 42% were female, mean Karnofsky performance score (KPS) was 62.5 (±14.2) and mean oral daily morphine equivalent dose was 303 mg/24 hours (±543.8 mg). The mean PSQI global score was 8.8 (±4.2) (range 0-20). Seventy-eight per cent were poor sleepers. All PSQI components were affected, and 44% reported trouble sleeping caused by pain. In the multiple regression model, predictors of PSQI global scores were pain intensity, emotional function, constipation, financial difficulties and KPS (adjusted R2=0.21). CONCLUSION: The majority (78%) of these patients with cancer treated with Step III opioids experienced poor sleep quality. Pain intensity, emotional function, constipation, financial difficulties and KPS predicted poor PSQI global scores. The clinical implication is that healthcare personnel should routinely assess and treat sleep disturbance in patients with advanced cancer disease.

Survival, Complications and Patient Reported Outcomes after Pancreatic Surgery.

BACKGROUND: Long-term effects of complications in pancreatic surgery have not been systematically evaluated. The objectives were to assess potential effects of complications on survival and patient reported outcomes (PROs) as well as feasibility of PRO questionnaires in patients with periampullary and pancreatic tumors. METHODS: From October 2008 to December 2011, 208 patients undergoing pancreatic surgery were included in a prospective observational study. ESAS, EORTC QLQ-C30 and QLQ-PAN26 questionnaires were completed at inclusion, then every third month. Complications were recorded according to the Clavien-Dindo (CD) classification and Comprehensive Complication Index (CCI). RESULTS: 148 complications were registered in 100 patients (48%), 36 patients (17%) had CD IIIa or above. 125 patients (60%) completed baseline questionnaires, 80 (39%) responded after three and 54 (28%) after six months. Complications were associated with reduced long-term survival in patients with pancreatic ductal adenocarcinoma (PDAC) (p = 0.049) and other malignant diseases. No significant relationship was found between complications and PROs, except for anxiety, which was significantly increased in patients with complications. CONCLUSION: Postoperative complications led to increased anxiety at 3 months after surgery and were associated with reduced long-term survival in patients with malignancy. A short, patient derived, disease specific questionnaire is required in the clinical research context.

A comparison of CT based measures of skeletal muscle mass and density from the Th4 and L3 levels in patients with advanced non-small-cell lung cancer.

BACKGROUND: Muscle mass and density assessed from CT-images at the L3 level are prognostic for survival and predict toxicity in cancer patients. However, L3 is not always included on routine CT-scans. We aimed to investigate whether images at the Th4 level may be used instead. METHODS: Patients from three chemotherapy trials in advanced NSCLC were eligible (n = 1305). Skeletal muscle area (cm2), skeletal muscle index (SMI, cm2/m2) and skeletal muscle density (SMD) at Th4 and L3 levels were assessed from baseline CT-scans. SMI and SMD at the Th4 and L3 level were transformed into z-scores and the agreement between scores was investigated by Bland-Altman plots and estimated by intra-class correlation analyses. Linear regression was used to test if Th4 SMI and SMD z-scores predicted L3 SMI and SMD z-scores. RESULTS: CT-images from 401 patients were analysable at both levels. There was a moderate agreement between Th4 and L3 SMI z-scores with an intra-class correlation of 0.71 (95% CI 0.64-0.77) for men and 0.53 (95% CI 0.41-0.63) for women. Regression models predicting L3 SMI z-scores from Th4 SMI z-scores showed coefficients of 0.71 (95% CI 0.62-0.80) among men and 0.53 (95% CI 0.40-0.66) among women. R-squares were 0.51 and 0.28, respectively, indicating moderate agreement. A similar, moderate agreement between Th4 and L3 SMD z-scores was observed. CONCLUSION: There was only moderate agreement between muscle measures from Th4 and L3 levels, indicating that missing data from the L3 level cannot be replaced by analysing images at the Th4 level.

Effects of individualized nutrition after allogeneic hematopoietic stem cell transplantation following myeloablative conditioning; a randomized controlled trial.

BACKGROUND & AIMS: Reduced quality of life (QoL) is prevalent after allogeneic hematopoietic stem cell transplantation (allo-HSCT). In this randomized trial we examined the effect of individualized nutritional support during hospitalization for allo-HSCT. Primary outcome was change in global QoL three months post-HSCT with oral mucositis (OM) and acute graft-versus-host disease (aGVHD) as main secondary outcomes. METHODS: Whereas the intervention group received recommended minimum daily intakes of 126 kJ/kg and 1.5-2.0 g protein/kg as food, supplements, enteral or parenteral nutrition, the controls received routine feeding. QoL was self-reported using the EORTC QLQ-C30 questionnaire. RESULTS: Between August, 2010 and February, 2016, we randomized 59 and 60 patients to intervention and control, respectively; 40 and 48 being eligible for analysis of QoL. There was no difference between the two groups in mean global QoL after three months (-3.10, 95% CI -11.90-5.69; P = 0.49). Nor were there any differences in OM grades 3 or 4 (RR (vs grades 0-2), 1.11, 95% CI 0.59-2.11 and 0.95, 95% CI 0.72-1.25, respectively; P = 0.78), or aGVHD grades 3 or 4 (RR (vs grades 0-2) 0.44, 95% CI 0.12-1.60; and 0.65, 95% CI 0.20-2.20, respectively; P = 0.37). CONCLUSION: Individualized nutritional support with recommended energy and protein intakes during hospitalization had no effect on QoL, OM or aGVHD three months after allo-HSCT compared to routine nutrition.