Lactate dehydrogenase: relationship with the diagnostic GLIM criterion for cachexia in patients with advanced cancer.

BACKGROUND: Although suggestive of dysregulated metabolism, the relationship between serum LDH level, phenotypic/aetiologic diagnostic Global Leadership Initiative on Malnutrition (GLIM) criteria and survival in patients with advanced cancer has yet to examined. METHODS: Prospectively collected data from patients with advanced cancer, undergoing anti-cancer therapy with palliative intent, across nine sites in the UK and Ireland between 2011-2016, was retrospectively analysed. LDH values were grouped as <250/250-500/>500 Units/L. Relationships were examined using χ2 test for linear-by-linear association and binary logistics regression analysis. RESULTS: A total of 436 patients met the inclusion criteria. 46% (n = 200) were male and 59% (n = 259) were ≥65 years of age. The median serum LDH was 394 Units/L and 33.5% (n = 146) had an LDH > 500 Units/L. LDH was significantly associated with ECOG-PS (p < 0.001), NLR (p < 0.05), mGPS (p < 0.05) and 3-month survival (p < 0.001). LDH was significantly associated with 3-month survival independent of weight loss (p < 0.01), BMI (p < 0.05), skeletal muscle mass (p < 0.01), metastatic disease (p < 0.05), NLR (p < 0.05) and mGPS (p < 0.01). DISCUSSION: LDH was associated with performance status, systemic inflammation and survival in patients with advanced cancer. LDH measurement may be considered as an aetiologic criteria and become a potential therapeutic target in the treatment of cancer cachexia.

The Value of In Vivo Reflectance Confocal Microscopy as an Assessment Tool in Chemotherapy-Induced Peripheral Neuropathy: A Pilot Study.

BACKGROUND: There is a lack of standardized objective and reliable assessment tools for chemotherapy-induced peripheral neuropathy (CIPN). In vivo reflectance confocal microscopy (RCM) imaging offers a non-invasive method to identify peripheral neuropathy markers, namely Meissner's corpuscles (MC). This study investigated the feasibility and value of RCM in CIPN. PATIENTS AND METHODS: Reflectance confocal microscopy was performed on the fingertip to evaluate MC density in 45 healthy controls and 9 patients with cancer (prior, during, and post-chemotherapy). Quantification was completed by 2 reviewers (one blinded), with maximum MC count/3 × 3 mm image reported. Quantitative Sensory Testing (QST; thermal and mechanical detection thresholds), Grooved pegboard test, and patient-reported outcomes measures (PROMS) were conducted for comparison. RESULTS: In controls (25 females, 20 males; 24-81 years), females exhibited greater mean MC density compared with males (49.9 ± 7.1 vs 30.9 ± 4.2 MC/3 × 3 mm; P = .03). Differences existed across age by decade (P < .0001). Meissner's corpuscle density was correlated with mechanical detection (ρ = -0.51), warm detection (ρ = -0.47), cold pain (ρ = 0.49) thresholds (P < .01); and completion time on the Grooved pegboard test in both hands (P ≤ .02). At baseline, patients had reduced MC density vs age and gender-matched controls (P = .03). Longitudinal assessment of MC density revealed significant relationships with QST and PROMS. Inter-rater reliability of MC count showed an intraclass correlation of 0.96 (P < .0001). CONCLUSIONS: The findings support the clinical utility of RCM in CIPN as it provides meaningful markers of sensory nerve dysfunction. Novel, prospective assessment demonstrated the ability to detect subclinical deficits in patients at risk of CIPN and potential to monitor neuropathy progression.

Relief of Neuropathic Pain Through Epidermal Growth Factor Receptor Inhibition: A Randomized Proof-of-Concept Trial.

OBJECTIVE: Case reports and a case series have described relief of neuropathic pain (NP) after treatment with epidermal growth factor receptor inhibitors (EGFR-Is). These observations are supported by preclinical findings. The aim of this trial was to explore a potential clinical signal supporting the therapeutic efficacy of EGFR-Is in NP. METHODS: In a proof-of-concept trial using a randomized, double-blind, placebo-controlled design, 14 patients with severe, chronic, therapy-resistant NP due to compressed peripheral nerves or complex regional pain syndrome were randomized to receive a single infusion of the EGFR-I cetuximab and placebo in crossover design, followed by a single open-label cetuximab infusion. RESULTS: The mean reduction in daily average pain scores three to seven days after single-blinded cetuximab infusion was 1.73 points (90% confidence interval [CI] = 0.80 to 2.66), conferring a 1.22-point greater reduction than placebo (90% CI = -0.10 to 2.54). Exploratory analyses suggested that pain reduction might be greater in the 14 days after treatment with blinded cetuximab than after placebo. The proportion of patients who reported ≥50% reduction in average pain three to seven days after cetuximab was 36% (14% after placebo), and comparison of overall pain reduction suggests a trend in favor of cetuximab. Skin rash (grade 1-2) was the most frequent side effect (12/14, 86%). CONCLUSIONS: This small proof-of-concept evaluation of an EGFR-I against NP did not provide statistical evidence of efficacy. However, substantial reductions in pain were reported, and confidence intervals do not rule out a clinically meaningful treatment effect. Evaluation of EGFR-I against NP therefore warrants further investigation.

The use of opioids in cancer patients with renal impairment-a systematic review.

PURPOSE: Opioids are recommended for moderate to severe cancer pain; however, in patients with cancer, impaired renal function can affect opioid metabolism. The aim of this systematic review was to evaluate the current evidence for the use of opioids in cancer patients with renal impairment. METHODS: A systematic review was conducted and the following databases were searched: MEDLINE (1966 to 2015), EMBASE (1980 2015) and Cochrane Central Register of Controlled Trials (up to 2015). Eligible studies met the following criteria: patients with cancer pain taking an opioid (defined as per the WHO ladder); >18 years; renal impairment (serum creatinine > normal range (study dependent), creatinine clearance (CrCl) or glomerular filtration rate (GFR) measurements <90 ml/min, or as per the study definition); clinical outcome related to renal impairment. All eligible studies were appraised using the Grading of Recommendation Assessment, Development and Evaluations (GRADE) system. RESULTS: Eighteen studies (n = 2422) were eligible but heterogeneity meant meta-analysis was not possible. Morphine was examined in eight studies (n = 1418), oxycodone in two studies (n = 325), and fentanyl, alfentanil or sufentanil were discussed in six studies in total (n = 442). No recommendations could be formulated on the preferred opioid in patients with renal impairment. CONCLUSION: There is lack of consensus within the existing literature on the relationship between morphine, creatinine levels and morphine-related side effects. Based on the current evidence, morphine should be used with caution; however, more evidence is needed. Fentanyl, alfentanil and sufentanil are recommended in patients with renal impairment based on pharmacokinetics and clinical experience. However, the present systematic review found very little clinical evidence for this. Overall, the quality of the existing evidence on opioid treatment in cancer patients with renal impairment is low. There remains a need for high-quality clinical studies examining opioids in patients with renal impairment.

A systematic review of opioid effects on the hypogonadal axis of cancer patients.

PURPOSE: Opioids are the mainstay of analgesic therapy in patients with cancer-related pain. While many of the side effects of opioids are well documented, the effect on the hypogonadal axis is less well understood. The aim of this systematic review is to examine the relationship between opioid therapy and hypogonadism in patients with cancer. METHODS: An electronic search of the following databases was undertaken: MEDLINE, Embase and CINAHL from 1974 to August 2013. To be eligible for inclusion, studies had to meet the following criteria: adult patients (>18 years) with cancer taking any opioid by any route for any duration, gonadal function measured and the relationship between opioid use and gonadal function examined. All potentially eligible papers were reviewed independently and data extracted using a pro forma. RESULTS: Four studies met the inclusion criteria. Due to the heterogeneous nature of the studies, it was not possible to amalgamate the results. Three studies suggested a relationship between opioid use and hypogonadism in patients with cancer. These studies also suggested this relationship to be dose dependent. There was evidence to suggest that hypogonadism was symptomatic and associated with reduced survival. One study showed no link between opioids and hypogonadism. CONCLUSIONS: Studies conducted have suggested an association between opioids and hypogonadism in patients with cancer. This warrants further investigation. A longitudinal study examining the impact of opioids on the hypogonadal axis would be of interest.

Using animal models to understand cancer pain in humans.

Cancer pain is not a single entity but a complex pain state involving different pain syndromes, with inflammatory, neuropathic, compressive, and ischaemic mechanisms. Current therapeutic regimens are based largely on opioids, although opioid treatment can lead to many side effects. Studies using animal models of cancer pain are aimed at understanding cancer pain and developing novel therapies. The most frequently reported models are of bone cancer pain, predominantly modelling pain associated with tumour growth within bone marrow. Here we summarise recent findings from studies using animal models of cancer pain and discuss the methodological quality of these studies.

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.

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.

Are CT-Derived Muscle Measurements Prognostic, Independent of Systemic Inflammation, in Good Performance Status Patients with Advanced Cancer?

The present study examined the relationships between CT-derived muscle measurements, systemic inflammation, and survival in advanced cancer patients with good performance status (ECOG-PS 0/1). Data was collected prospectively from patients with advanced cancer undergoing anti-cancer therapy with palliative intent. The CT Sarcopenia score (CT-SS) was calculated by combining the CT-derived skeletal muscle index (SMI) and density (SMD). The systemic inflammatory status was determined using the modified Glasgow Prognostic Score (mGPS). The primary outcome of interest was overall survival (OS). Univariate and multivariate Cox regressions were used for survival analysis. Three hundred and seven patients met the inclusion criteria, out of which 62% (n = 109) were male and 47% (n = 144) were ≥65 years of age, while 38% (n = 118) were CT-SS ≥ 1 and 47% (n = 112) of patients with pre-study blood were inflamed (mGPS ≥ 1). The median survival from entry to the study was 11.1 months (1-68.1). On univariate analysis, cancer type (p < 0.05) and mGPS (p < 0.001) were significantly associated with OS. On multivariate analysis, only mGPS (p < 0.001) remained significantly associated with OS. In patients who were ECOG-PS 0, mGPS was significantly associated with CT-SS (p < 0.05). mGPS may dominate the prognostic value of CT-derived sarcopenia in good-performance-status patients with advanced cancer.

Physical function endpoints in cancer cachexia clinical trials: Systematic Review 1 of the cachexia endpoints series.

In cancer cachexia trials, measures of physical function are commonly used as endpoints. For drug trials to obtain regulatory approval, efficacy in physical function endpoints may be needed alongside other measures. However, it is not clear which physical function endpoints should be used. The aim of this systematic review was to assess the frequency and diversity of physical function endpoints in cancer cachexia trials. Following a comprehensive electronic literature search of MEDLINE, Embase and Cochrane (1990-2021), records were retrieved. Eligible trials met the following criteria: adults (≥18 years), controlled design, more than 40 participants, use of a cachexia intervention for more than 14 days and use of a physical function endpoint. Physical function measures were classified as an objective measure (hand grip strength [HGS], stair climb power [SCP], timed up and go [TUG] test, 6-min walking test [6MWT] and short physical performance battery [SPPB]), clinician assessment of function (Karnofsky Performance Status [KPS] or Eastern Cooperative Oncology Group-Performance Status [ECOG-PS]) or patient-reported outcomes (physical function subscale of the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaires [EORTC QLQ-C30 or C15]). Data extraction was performed using Covidence and followed PRISMA guidance (PROSPERO registration: CRD42022276710). A total of 5975 potential studies were examined and 71 were eligible. Pharmacological interventions were assessed in 38 trials (54%). Of these, 11 (29%, n = 1184) examined megestrol and 5 (13%, n = 1928) examined anamorelin; nutritional interventions were assessed in 21 trials (30%); and exercise-based interventions were assessed in 6 trials (8%). The remaining six trials (8%) assessed multimodal interventions. Among the objective measures of physical function (assessed as primary or secondary endpoints), HGS was most commonly examined (33 trials, n = 5081) and demonstrated a statistically significant finding in 12 (36%) trials (n = 2091). The 6MWT was assessed in 12 trials (n = 1074) and was statistically significant in 4 (33%) trials (n = 403), whereas SCP, TUG and SPPB were each assessed in 3 trials. KPS was more commonly assessed than the newer ECOG-PS (16 vs. 9 trials), and patient-reported EORTC QLQ-C30 physical function was reported in 25 trials. HGS is the most commonly used physical function endpoint in cancer cachexia clinical trials. However, heterogeneity in study design, populations, intervention and endpoint selection make it difficult to comment on the optimal endpoint and how to measure this. We offer several recommendations/considerations to improve the design of future clinical trials in cancer cachexia.

Characterization of cancer-induced bone pain: an exploratory study.

PURPOSE: Cancer-induced bone pain (CIBP) is the commonest cause of pain in patients with cancer. Its association with increased morbidity combined with limitations of currently available therapies makes it a clinical challenge. Clinical characterization of this complex pain syndrome is essential in underpinning clinical management and informing future research. The aim of this exploratory study was to characterise CIBP using self-rating scales. PATIENTS AND METHODS: A cross-sectional survey of patients with CIBP was carried out in a regional oncology centre. Patients described their pain over the preceding 24 h using the McGill Pain Questionnaire, Brief Pain Inventory (BPI), and a breakthrough pain questionnaire. Multiple linear regression analyses were conducted. RESULTS: Fifty-five patients were recruited. Annoying, gnawing, aching, and nagging were the most commonly used words to describe CIBP. From the BPI, median average pain was 4/10 and worst pain was 7/10 on a 0-10 Numerical Rating Scale. The worst pain score correlated more strongly with BPI interference score (p=0.001). Forty-one patients had breakthrough pain. Patients with breakthrough pain had higher total BPI interference scores than those with no breakthrough pain; median (IQR); 35.0 (2.5-44.7) vs. 18.5 (5.5-26.7), p<0.01. Of the patients, 20/41 (48%) had breakthrough pain of rapid onset (less than 5 min) and short duration (less than 15 min). CONCLUSION: In CIBP, worst pain most accurately reflects the characteristics of pain flares and functional impairment. Breakthrough pain is often unpredictable, sudden onset and short duration. Further characterization studies of CIBP in the broader cancer population are needed.

Interaction of gonadal status with systemic inflammation and opioid use in determining nutritional status and prognosis in advanced pancreatic cancer.

PURPOSE: Hypogonadism has been linked with systemic inflammation and opioid use in males with advanced cancer. We aimed to investigate the interaction of gonadal status with systemic inflammation and opioids in determining nutritional status and prognosis in advanced pancreatic cancer. METHODS: One hundred and seventy-five patients (92 males, 83 postmenopausal females) with unresectable pancreatic cancer were studied. Serum sex steroids (total testosterone [TT], calculated free testosterone [cFT], oestradiol, sex hormone binding globulin), gonadotropins (follicle-stimulating hormone and luteinising hormone) and pro-inflammatory mediators (C-reactive protein [CRP], interleukin-6 [IL-6], soluble tumour necrosis factor receptor 75 [sTNFR75]) were measured, and nutritional assessment and opioid use recorded. RESULTS: Seventy-three percent of males were hypogonadal (by cFT definition). cFT correlated positively with BMI (r (2) =0.349; p< 0.001) and grip strength (r (2) = 0.229; p = 0.034) and inversely with weight loss (r (2) = -0.287; p = 0.007), CRP (r (2) = -0.426; p < 0.001) and IL-6 (r (2) = -0.303; p = 0.004). CRP (p= 0.007), opioid dosage (p = 0.009) and BMI (p = 0.005) were independent determinants of cFT on ANOVA. Hypogonadal males demonstrated worsened survival compared with eugonadal patients (TT: OR of death = 2.87; p < 0.001; cFT: OR = 2.26; p = 0.011). Furthermore, male opioid use was associated with decreased TT (p < 0.001) and cFT (p < 0.001) and worsened survival (OR = 1.96; p = 0.012). In contrast, 18% of postmenopausal females exhibited premenopausal ("hyperoestrogenic") oestradiol levels. Oestradiol correlated positively with sTNFR75 (r (2) = 0.299; p = 0.008). CRP (p < 0.001) was an independent determinant of oestradiol. Hyperoestrogenic females demonstrated worsened survival compared with eugonadal patients (OR = 2.43; p = 0.013). CONCLUSIONS: In males with pancreatic cancer, systemic inflammation and opioid use are associated with hypogonadism. Male hypogonadism and female hyperoestrogenism are associated with shortened survival in advanced pancreatic cancer.

A systematic review of combination step III opioid therapy in cancer pain: an EPCRC opioid guideline project.

BACKGROUND: The use of combinations of opioids is a common clinical practice; however, this is not advocated by the World Health Organization (WHO) analgesic ladder. As opioid combination therapy becomes used increasingly, a review of the evidence on this practice was conducted. AIMS: To carry out a systematic review of the use of strong opioids in combination in cancer pain. METHODS: The following databases were searched electronically: Embase (1980-2010 week 2), Medline (1950-2010 week 1) and the Cochrane Database of Systematic Reviews (fourth quarter 2009). Only strong opioids as defined by the WHO ladder and full opioid agonists were examined. Only studies conducted in human, adult patients with chronic cancer pain were eligible. Studies must have contained data on efficacy and/or side effects in the key point. Appraisal was conducted using predetermined criteria set by the EAPC guideline development group. All potential papers were reviewed independently by both authors. RESULTS: In total 596 articles were retrieved resulting in only two eligible studies, which were rated as grade C and grade D evidence. These examined morphine in combination with oxycodone or fentanyl/methadone. CONCLUSION: Only a weak recommendation can be used to support combination opioid therapy. This recommendation is also based on the caveat that the desirable effects of combination opioid therapy is outweighed by any disadvantages that this would confer. Prospective randomized trials are needed to clarify the benefits and safety of combination opioid therapy.

The Emerging Role of Interleukin 1ß (IL-1ß) in Cancer Cachexia.

Treatment of cancer cachexia remains an unmet need. The host-tumour interface and the resulting sequestration of the pro-inflammatory cytokine Il-1ß is critical in cachexia development. Neuroinflammation mediated via IL-1ß through the hypothalamic pituitary axis results in increased muscle proteolysis and adipose lipolysis, thus creating a prolonged stress-like environment with loss of appetite and increased resting energy expenditure. Recent trials using a monoclonal antibody targeting IL-1ß, canakinumab, have shown a potential role in lung cancer; however, a potential role of targeting IL-1ß to treat cachexia in patients with lung cancer is unclear, yet the underlying pathophysiology provides a sound rationale that this may be a viable therapeutic approach.

A randomized, feasibility trial of an exercise and nutrition-based rehabilitation programme (ENeRgy) in people with cancer.

BACKGROUND: Despite rehabilitation being increasingly advocated for people living with incurable cancer, there is limited evidence supporting efficacy or component parts. The progressive decline in function and nutritional in this population would support an approach that targets these factors. This trial aimed to assess the feasibility of an exercise and nutrition based rehabilitation programme in people with incurable cancer. METHODS: We randomized community dwelling adults with incurable cancer to either a personalized exercise and nutrition based programme (experimental arm) or standard care (control arm) for 8 weeks. Endpoints included feasibility, quality of life, physical activity (step count), and body weight. Qualitative and health economic analyses were also included. RESULTS: Forty-five patients were recruited (23 experimental arm, 22 control arm). There were 26 men (58%), and the median age was 78 years (IQR 69-84). At baseline, the median BMI was 26 kg/m2 (IQR: 22-29), and median weight loss in the previous 6 months was 5% (IQR: -12% to 0%). Adherence to the experimental arm was >80% in 16/21 (76%) patients. There was no statistically significant difference in the following between trial arms: step count - median % change from baseline to endpoint, per trial arm (experimental -18.5% [IQR: -61 to 65], control 5% [IQR: -32 to 50], P = 0.548); weight - median % change from baseline to endpoint, per trial arm (experimental 1%[IQR: -3 to 3], control -0.5% [IQR: -3 to 1], P = 0.184); overall quality of life - median % change from baseline to endpoint, per trial arm (experimental 0% [IQR: -20 to 19], control 0% [IQR: -23 to 33], P = 0.846). Qualitative findings observed themes of capability, opportunity, and motivation amongst patients in the experimental arm. The mean incremental cost of the experimental arm versus control was £-319.51 [CI -7593.53 to 6581.91], suggesting the experimental arm was less costly. CONCLUSIONS: An exercise and nutritional rehabilitation intervention is feasible and has potential benefits for people with incurable cancer. A larger trial is now warranted to test the efficacy of this approach.

Intention-to-Treat Analyses for Randomized Controlled Trials in Hospice/Palliative Care: The Case for Analyses to be of People Exposed to the Intervention.

CONTEXT: Minimizing bias in randomized controlled trials (RCTs) includes intention-to-treat analyses. Hospice/palliative care RCTs are constrained by high attrition unpredictable when consenting, including withdrawals between randomization and first exposure to the intervention. Such withdrawals may systematically bias findings away from the new intervention being evaluated if they are considered nonresponders. OBJECTIVES: This study aimed to quantify the impact within intention-to-treat principles. METHODS: A theoretical model was developed to assess the impact of withdrawals between randomization and first exposure on study power and effect sizes. Ten reported hospice/palliative care studies had power recalculated accounting for such withdrawal. RESULTS: In the theoretical model, when 5% of withdrawals occurred between randomization and first exposure to the intervention, change in power was demonstrated in binary outcomes (2.0%-2.2%), continuous outcomes (0.8%-2.0%), and time-to-event outcomes (1.6%-2.0%), and odds ratios were changed by 0.06-0.17. Greater power loss was observed with larger effect sizes. Withdrawal rates were 0.9%-10% in the 10 reported RCTs, corresponding to power losses of 0.1%-2.2%. For studies with binary outcomes, withdrawal rates were 0.3%-1.2% changing odds ratios by 0.01-0.22. CONCLUSION: If blinding is maintained and all interventions are available simultaneously, our model suggests that excluding data from withdrawals between randomization and first exposure to the intervention minimizes one bias. This is the safety population as defined by the International Committee on Harmonization. When planning for future trials, minimizing the time between randomization and first exposure to the intervention will minimize the problem. Power should be calculated on people who receive the intervention.

Are cancer pain and depression interdependent? A systematic review.

OBJECTIVE: Pain and depression are common in cancer patients. As these are both highly prevalent, the issue of a possible interdependent association has been raised. The aim of this systematic review was to examine the available literature and explore whether there is any evidence to support a causal relationship between cancer pain and depression. METHODS: An extensive literature search was undertaken. The following databases were searched electronically: Medline (1950-2007), Embase (1988-2007), CINAHL (1982-2007) and the Cochrane Database of Systematic Reviews (Issue 2 2007). The initial literature search revealed 892 articles. Following initial screening 41 articles were independently reviewed in detail. Fourteen articles were eligible for inclusion. RESULTS: The mean prevalence of both depression and pain was 36.5% (range 22.1-49.0). In 9 out of 14 studies a statistically significant association was demonstrated between pain and depression. Pain intensity positively correlated with depression (P<0.05). Items such as 'worst pain' and 'enjoyment of life' (on the Brief Pain Inventory) correlated significantly with depression. When using the McGill Pain Questionnaire, depressed patients used more affective pain descriptors. It was also shown that the longer the duration of pain, the higher the risk of depression. CONCLUSIONS: Pain and depression are highly prevalent in cancer patients; however, there have been no appropriately designed studies to examine a causal relationship. Although associations exist, the evidence available is not sufficient to support an interdependent relationship between pain and depression. A suitably designed longitudinal study to examine causality would be a relevant step in the research agenda.

Meaningful measures in cancer cachexia: implications for practice and research.

PURPOSE OF REVIEW: Cancer cachexia is a complex inflammatory syndrome, which presents with a variety of discrete symptoms and signs. This creates a challenge for both clinicians and researchers in recognizing and assessing the syndrome. This review explores the evidence for various measures used in the assessment of cachexia. RECENT FINDINGS: Objectively, cachexia may be assessed using CT-derived measures of skeletal muscle [skeletal muscle index (SMI) and skeletal muscle density (SMD)]. Evidence suggests that SMD may be of equal or greater value than SMI in assessing cachexia. Inflammatory markers are also used, and include interleukin(IL)-1α; IL-1ß; IL-6 and Interferon Gamma (IFNγ). Other robust measures include performance status and the modified Glasgow prognostic score (mGPS). These measures, however, are more commonly used in academia. By comparison, clinical assessment is limited to individual measures of patient function, such as hand grip strength (HGS), calf circumference, gait speed, and the 'timed up and go test' (TUG). These have each been linked with components of cachexia but are less well evidenced. Evidence also exists for patient-reported quality-of-life measures, based upon the EORTC- QLQ-C30 questionnaire, in assessing cachexia. SUMMARY: Further assessment is required to compare clinical measures of cachexia and determine their utility.

The Management of Opioid-Induced Nausea and Vomiting in Patients with Cancer: A Systematic Review.

BACKGROUND: Opioids are the foundation of treatment for cancer pain but can cause side-effects, one of the most common being nausea and vomiting, which can impair quality of life. OBJECTIVE: To evaluate the evidence for the management of opioid-induced nausea and vomiting. This systematic review was undertaken as part of an update of the European Association for Palliative Care's opioid guidelines. DESIGN: Searches of MEDLINE (1966-2017) and EMBASE (1980-2017) were done. Key eligibility criteria were: randomized controlled trials conducted in patients with cancer. The Grading of Recommendations Assessment Development and Evaluations system was applied to formulate recommendations. RESULTS: Fifteen studies were eligible (1524 patients). The studies were grouped as follows: opioid switching (n = 8); the use of antiemetics to treat opioid-induced nausea and vomiting (n = 4); and change of route of administration of the opioid (n = 3). Three recommendations were formulated: A weak recommendation for switching from morphine to oxycodone in cancer patients with nausea (quality D); a weak recommendation for switching from tramadol to either codeine or hydrocodone for pain in cancer patients with nausea (quality D); and a weak recommendation for switching from morphine/oxycodone to methadone using the three-day switch method in patients with increasing pain considered untreatable with further opioid titration and/or with opioid-related side effects (quality C). CONCLUSIONS: This systematic review can make only weak recommendations for the management of opioid-induced nausea and vomiting. There remains a need for high-quality studies before strong recommendations on the management of opioid-induced nausea and vomiting can be made.