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 prognostic impact of pre-treatment cachexia in resectional surgery for oesophagogastric cancer: a meta-analysis and meta-regression.

BACKGROUND: Cancer cachexia is not purely an end-stage phenomenon and can influence the outcomes of patients with potentially curable disease. This review examines the effect of pre-treatment cachexia on overall survival, in patients undergoing surgical resection of oesophagogastric cancer. METHODS: A systematic literature search of MEDLINE, EMBASE and Cochrane Library databases was conducted, from January 2000 to May 2022, to identify studies reporting the influence of cachexia on patients undergoing an oesophagogastric resection for cancer with curative intent. Meta-analyses of the primary (overall survival) and secondary (disease-free survival and postoperative mortality) outcomes were performed using random-effects modelling. Meta-regression was used to examine disease stage as a potential confounder. RESULTS: Ten non-randomized studies, comprising 7186 patients, were eligible for inclusion. The prevalence of pre-treatment cachexia was 35 per cent (95 per cent c.i.: 24-47 per cent). Pooled adjusted hazard ratios showed that cachexia was adversely associated with overall survival (HR 1.46, 95 per cent c.i.: 1.31-1.60, P < 0.001). Meta-analysis of proportions identified decreased overall survival at 1-, 3- and 5-years in cachectic cohorts. Pre-treatment cachexia was not a predictor of disease-free survival and further data are required to establish its influence on postoperative mortality. The proportion of patients with stage III/IV disease was a significant moderator of between-study heterogeneity. Cachexia may have a greater influence on overall survival in studies where more patients have a locally advanced malignancy. CONCLUSION: Pre-treatment cachexia adversely influences overall survival following resection of an oesophagogastric malignancy.

Cancer cachexia - adopting a systems wide approach.

PURPOSE OF REVIEW: Cancer cachexia results in the death of approximately 2 million people worldwide annually. Despite the impact of this devastating condition, there is limited therapy and no standard of care. Although multiple definitions exist, confusion remains as a true understanding of the biology has not yet been achieved and distinct phases of cachexia have not been examined. Research has mainly focused on weight loss and muscle wasting, but cachexia is increasingly recognized as a multiorgan disorder involving adipose tissue, liver, brain, gut and heart, with systemic inflammation a central unifying feature. RECENT FINDINGS: In this review, we will discuss some of the extra-muscular features and multisystem interactions in cachexia, and describe how moving our focus beyond muscle can lead to a greater understanding of the mechanisms and clinical features seen in cachexia. SUMMARY: We describe the need for robust characterization of patients with cachexia, to allow clinical phenotypes and multisystem mechanisms to be untangled, and to enable the implementation of multimodal treatment strategies.

Cancer cachexia: a nutritional or a systemic inflammatory syndrome?

Cancer cachexia has long been perceived as a nutritional syndrome. However, nutritional interventions have continued to be ineffective. With the recent recognition of the importance of systemic inflammation in the definition of this syndrome and treatment, has the time come to consider whether this syndrome is primarily a manifestation of systemic inflammation with the consequent implications for future treatment?

The relationship between frailty, nutritional status, co-morbidity, CT-body composition and systemic inflammation in patients with COVID-19.

BACKGROUND: Frailty, determined by the Canadian Study of Health and Aging-Clinical Frailty Scale (CFS), is strongly associated with clinical outcomes including mortality in patients with COVID-19. However, the relationship between frailty and other recognised prognostic factors including age, nutritional status, obesity, sarcopenia and systemic inflammation is poorly understood. Therefore, the aim of this study was to examine the relationship between frailty and other prognostic domains, in patients admitted with COVID-19. METHODS: Patients who presented to our institutions between 1st April 2020-6th July 2020 with confirmed COVID-19 were assessed for inclusion. Data collected included general demographic details, clinicopathological variables, CFS admission assessment, Malnutrition Universal Screening Tool (MUST), CT-BC measurements and markers of systemic inflammation. RESULTS: 106 patients met the study inclusion criteria. The majority of patients were aged ≥ 70 years (67%), male (53%) and frail (scoring > 3 on the CFS, 72%). The majority of patients were not malnourished (MUST 0, 58%), had ≥ 1 co-morbidity (87%), were sarcopenic (low SMI, 80%) and had systemic inflammation (mGPS ≥ 1, 81%, NLR > 5, 55%). On multivariate binary logistics regression analysis, age (p < 0.01), COPD (p < 0.05) and NLR (p < 0.05) remained independently associated with frailty. On univariate binary logistics regression, NLR (p < 0.05) was significantly associated with 30-day mortality. CONCLUSION: Frailty was independently associated with age, co-morbidity, and systemic inflammation. The basis of the relationship between frailty and clinical outcomes in COVID-19 requires further study. Trial registration Registered with clinicaltrials.gov (NCT04484545).

Understanding Cancer Cachexia and Its Implications in Upper Gastrointestinal Cancers.

OPINION STATEMENT: Considerable advances in the investigation and management of oesophagogastric cancer have occurred over the last few decades. While the historically dismal prognosis associated with these diseases has improved, outcomes remain very poor. Cancer cachexia is an often neglected, yet critical, factor for this patient group. There is a persuasive argument that a lack of assessment and treatment of cachexia has limited progress in oesophagogastric cancer care. In the curative setting, the stage of the host (based on factors such as body composition, function, and inflammatory status), alongside tumour stage, has the potential to influence treatment efficacy. Phenotypical features of cachexia may decrease the survival benefit of (peri-operative) chemoradiotherapy, immunotherapy, or surgical resection in patients with potentially curative malignancy. Most patients with oesophagogastric cancer unfortunately present with disease which is not amenable, or is unlikely to respond, to these treatments. In the palliative setting, host factors can similarly impair results from systemic anti-cancer therapies, cause adverse symptoms, and reduce quality of life. To optimise treatment pathways and enhance patient outcomes, we must utilise this information during clinical decision-making. As our understanding of the genesis of cancer cachexia improves and more therapeutic options, ranging from basic (e.g. exercise and nutrition) to targeted (e.g. anti-IL1 α and anti-GDF-15), become available, there can be grounds for optimism. Cachexia can change from a hitherto neglected condition to an integral part of the oesophagogastric cancer treatment pathway.

Non-steroidal anti-inflammatory drugs (NSAIDs) in cancer pain: A database analysis to determine recruitment feasibility for a clinical trial.

BACKGROUND: Insufficient evidence exists to support or refute use of NSAIDs for managing cancer pain. Palliative physicians support a placebo-controlled trial of NSAIDs as strong opioid adjuncts for cancer-induced bone pain as the most pragmatic design to benefit clinical practice. AIM: We aimed to determine patient numbers receiving palliative radiotherapy for cancer-induced bone pain, estimate the suitability of NSAID prescription and determine survival, guiding future trial feasibility. DESIGN: A retrospective observational database analysis was undertaken using 5 years of routinely collected regional radiotherapy and healthcare data, filtered to achieve a cohort with cancer-induced bone pain. Demographics and survival were linked to available serology and co-morbidity data. SETTING/PARTICIPANTS: Data was sourced from the regional Leeds Cancer Centre, a tertiary care setting. Patients who underwent palliative single fraction 8 gray (Gy) radiotherapy treatment for cancer-induced bone pain were included, totalling 2411 over 5 years. RESULTS: A mean of 478 patients received palliative radiotherapy for cancer-induced bone pain annually. Median age (IQR) was 70 (62-77); negatively skewed (-0.69). 65.3% died within 1 year of radiotherapy; 48.0% within 6 months. Age was not associated with survival on univariable analysis (HR 0.999 (95% CI 0.996-1.003)). Serology from 1063 patients (44.2%) were available; eGFR was ⩾60 mL/min/1.73 m2 in 83.0%. From available data (1352 pts; 51.6% of sample), 20.2% had a coded co-morbidity contra-indicating NSAIDs. Combining serology and co-morbidities, 68.5% could be considered for NSAID prescription. CONCLUSIONS: Patient numbers at a regional radiotherapy centre support the feasibility of trial recruitment. Available serology and co-morbidity data suggest two-thirds may be suitable for NSAID prescription.

The prevalence and prognostic value of frailty screening measures in patients undergoing surgery for colorectal cancer: observations from a systematic review.

INTRODUCTION: Frailty is a complex multifactorial syndrome characterised by a significant increase in vulnerability and worsened health outcomes. Despite a range of proposed frailty screening measures, the prevalence and prognostic value of frailty in patients undergoing surgery for colorectal cancer is not clear. AIM: The aim of this present review was to examine the use of commonly employed frailty screening measures in patients undergoing surgery for colorectal cancer. METHODS: A systematic search of PubMed and Medline was carried out to identify studies reporting the use of frailty screening tools or measures in patients undergoing surgery for colorectal cancer. The screening measure used and prevalence of frailty within the population were recorded. Outcomes of interest were the incidence of post-operative complications, 30-day mortality and overall survival. RESULTS: Of the 15 studies included (n = 97, 898 patients), 9 studies were retrospective and included patients aged 70 years or older (n = 96, 120 patients). 5 of 12 studies reported that frailty was independently associated with the incidence of post-operative complications. There was also evidence that frailty was independently associated with 30-day mortality (1 of 4 studies, n = 9, 252 patients) and long-term survival (2 of 3 studies, n = 1, 420 patients). CONCLUSIONS: Frailty was common in patients with colorectal cancer and the assessment of frailty may have prognostic value in patients undergoing surgery. However, the basis of the relationship between frailty and post-operative outcomes is not clear and merits further study.

Relation Between Body Composition, Systemic Inflammatory Response, and Clinical Outcomes in Patients Admitted to an Urban Teaching Hospital with COVID-19.

BACKGROUND: COVID-19 has been associated with cases of severe respiratory illness, admissions to intensive therapy units (ITUs), and high mortality rates. OBJECTIVES: The aim of the present study was to examine the relation between computed tomography- body composition (CT-BC) measurements, systemic inflammation, and clinical outcomes in those with COVID-19. METHODS: Patients who presented to our institution between March 17 and May 1, 2020, with a positive PCR test for COVID-19 or characteristic radiological changes, were assessed for inclusion. Data collected included general demographic details, clinicopathological variables, poGPS, NLR , CT-BC measurements, and clinical outcomes including ITU admission and 30-d mortality, of those admitted. RESULTS: Sixty-three patients met the study inclusion criteria. Forty-two patients (67%) were aged ≥70 y, 30 (47.6%) were male and 34.9% ( n = 22) had a poGPS ≥1. ITU admission was significantly associated with a high VFA ( P < 0.05). Thirty-day mortality was associated with high VFA (P < 0.05) and low SMI (P < 0.05). CONCLUSIONS: Sarcopenia in the presence of obesity was associated with clinical outcomes including greater 30-d mortality.

Determinants of quality of life in patients with incurable cancer.

BACKGROUND: Optimizing quality of life (QoL) remains the central tenet of care in patients with incurable cancer; however, determinants of QoL are not clear. The objective of the current study was to examine which factors influence QoL in patients with incurable cancer. METHODS: A multicenter study of adult patients with advanced cancer was conducted in Ireland and the United Kingdom between 2011 and 2016. Data were collected from patients at study entry and included patient demographics, Eastern Cooperative Oncology Group performance status (ECOG-PS), nutritional parameters (the percentage weight loss [%WL]), muscle parameters assessed using computed tomography images (skeletal muscle index and skeletal muscle attenuation), inflammatory markers (modified Glasgow Prognostic score [mGPS]), and QoL data (the European Organization for Research and Treatment Quality-of-Life Questionnaire C-30). The relation between clinical, nutritional, and inflammatory parameters with QoL was assessed using the Spearman rank correlation coefficient and multivariate binary logistic regression. Components of the European Organization for Research and Treatment Quality-of-Life Questionnaire C-30 (physical function, fatigue, and appetite loss) and summary QoL scores were mean-dichotomized for the logistic regression analyses. RESULTS: Data were available for 1027 patients (51% men; median age, 66 years). Gastrointestinal cancer was most prevalent (40%), followed by lung cancer (26%) and breast cancer (9%). Distant metastatic disease was present in 87% of patients. The %WL, ECOG-PS, and mGPS were significantly correlated with deteriorating QoL functional and symptom scales (all P < .001). On multivariate regression analysis, >10% WL (odds ratio [OR], 2.69; 95% CI, 1.63-4.42), an ECOG-PS of 3 or 4 (OR, 14.33; 95% CI, 6.76-30.37), and an mGPS of 2 (OR, 1.58; 95% CI, 1.09-2.29) were independently associated with poorer summary QoL scores. These parameters were also independently associated with poorer physical function, fatigue, and appetite loss (all P < .05). Low skeletal muscle attenuation was independently associated with poorer physical functioning (OR, 1.67; 95% CI, 1.09-2.56), but muscle parameters were not independently associated with fatigue, appetite loss, or QoL summary scores. CONCLUSIONS: The current findings indicate that QoL is determined (at least in part) by WL, ECOG-PS, and the systemic inflammatory response in patients with advanced cancer. Identifying early predictors of poor QoL may allow the identification of patients who may benefit from early referral to palliative and supportive care, which has been shown to improve QoL.

Prognostic factors in patients admitted to an urban teaching hospital with COVID-19 infection.

BACKGROUND: Severe COVID-19 infection results in a systemic inflammatory response (SIRS). This SIRS response shares similarities to the changes observed during the peri-operative period that are recognised to be associated with the development of multiple organ failure. METHODS: Electronic patient records for patients who were admitted to an urban teaching hospital during the initial 7-week period of the COVID-19 pandemic in Glasgow, U.K. (17th March 2020-1st May 2020) were examined for routine clinical, laboratory and clinical outcome data. Age, sex, BMI and documented evidence of COVID-19 infection at time of discharge or death certification were considered minimal criteria for inclusion. RESULTS: Of the 224 patients who fulfilled the criteria for inclusion, 52 (23%) had died at 30-days following admission. COVID-19 related respiratory failure (75%) and multiorgan failure (12%) were the commonest causes of death recorded. Age ≥ 70 years (p < 0.001), past medical history of cognitive impairment (p ≤ 0.001), previous delirium (p < 0.001), clinical frailty score > 3 (p < 0.001), hypertension (p < 0.05), heart failure (p < 0.01), national early warning score (NEWS) > 4 (p < 0.01), positive CXR (p < 0.01), and subsequent positive COVID-19 swab (p ≤ 0.001) were associated with 30-day mortality. CRP > 80 mg/L (p < 0.05), albumin < 35 g/L (p < 0.05), peri-operative Glasgow Prognostic Score (poGPS) (p < 0.05), lymphocytes < 1.5 109/l (p < 0.05), neutrophil lymphocyte ratio (p ≤ 0.001), haematocrit (< 0.40 L/L (male)/ < 0.37 L/L (female)) (p ≤ 0.01), urea > 7.5 mmol/L (p < 0.001), creatinine > 130 mmol/L (p < 0.05) and elevated urea: albumin ratio (< 0.001) were also associated with 30-day mortality. On multivariate analysis, age ≥ 70 years (O.R. 3.9, 95% C.I. 1.4-8.2, p < 0.001), past medical history of heart failure (O.R. 3.3, 95% C.I. 1.2-19.3, p < 0.05), NEWS > 4 (O.R. 2.4, 95% C.I. 1.1-4.4, p < 0.05), positive initial CXR (O.R. 0.4, 95% C.I. 0.2-0.9, p < 0.05) and poGPS (O.R. 2.3, 95% C.I. 1.1-4.4, p < 0.05) remained independently associated with 30-day mortality. Among those patients who tested PCR COVID-19 positive (n = 122), age ≥ 70 years (O.R. 4.7, 95% C.I. 2.0-11.3, p < 0.001), past medical history of heart failure (O.R. 4.4, 95% C.I. 1.2-20.5, p < 0.05) and poGPS (O.R. 2.4, 95% C.I. 1.1-5.1, p < 0.05) remained independently associated with 30-days mortality. CONCLUSION: Age ≥ 70 years and severe systemic inflammation as measured by the peri-operative Glasgow Prognostic Score are independently associated with 30-day mortality among patients admitted to hospital with COVID-19 infection.

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

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

"How Long Have I Got?"-A Prospective Cohort Study Comparing Validated Prognostic Factors for Use in Patients with Advanced Cancer.

BACKGROUND: The optimal prognostic factors in patients with advanced cancer are not known, as a comparison of these is lacking. The aim of the present study was to determine the optimal prognostic factors by comparing validated factors. MATERIALS AND METHODS: A multicenter, prospective observational cohort study recruited patients over 18 years with advanced cancer. The following were assessed: clinician-predicted survival (CPS), Eastern Cooperative Oncology Group performance status (ECOG-PS), patient reported outcome measures (anorexia, cognitive impairment, dyspnea, global health), metastatic disease, weight loss, modified Glasgow Prognostic Score (mGPS) based on C-reactive protein and albumin, lactate dehydrogenase (LDH), and white (WCC), neutrophil (NC), and lymphocyte cell counts. Survival at 1 and 3 months was assessed using area under the receiver operating curve and logistic regression analysis. RESULTS: Data were available on 478 patients, and the median survival was 4.27 (1.86-7.03) months. On univariate analysis, the following factors predicted death at 1 and 3 months: CPS, ECOG-PS, mGPS, WCC, NC (all p < .001), dyspnea, global health (both p ≤ .001), cognitive impairment, anorexia, LDH (all p < .01), and weight loss (p < .05). On multivariate analysis ECOG-PS, mGPS, and NC were independent predictors of survival at 1 and 3 months (all p < .01). CONCLUSION: The simple combination of ECOG-PS and mGPS is an important novel prognostic framework which can alert clinicians to patients with good performance status who are at increased risk of having a higher symptom burden and dying at 3 months. From the recent literature it is likely that this framework will also be useful in referral for early palliative care with 6-24 months survival. IMPLICATIONS FOR PRACTICE: This large cohort study examined all validated prognostic factors in a head-to-head comparison and demonstrated the superior prognostic value of the Eastern Cooperative Oncology Group performance status (ECOG-PS)/modified Glasgow Prognostic Score (mGPS) combination over other prognostic factors. This combination is simple, accurate, and also relates to quality of life. It may be useful in identifying patients who may benefit from early referral to palliative care. It is proposed ECOG-PS/mGPS as the new prognostic domain in patients with advanced cancer.

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

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

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.

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 .

A cross-sectional study examining the prevalence of cachexia and areas of unmet need in patients with cancer.

PURPOSE: The semantics of defining cancer cachexia over the last decade has resulted in uncertainty as to the prevalence. This has further hindered the recognition and subsequent treatment of this condition. Following the consensus definition for cancer cachexia in 2011, there is now a need to establish estimates of prevalence. Therefore, the primary aim of the present study was to assess the prevalence of cachexia in an unselected cancer population. A secondary aim was to assess patient-perceived need of attention to cachexia. METHODS: A cross-sectional study in hospital patients was undertaken. Key inclusion criteria were the following: age > 18 years, cancer diagnosis, and no surgery the preceding 24 h. Data on demographics, disease, performance status, symptoms, cachexia, and patients' perceived need of attention to weight loss and nutrition were registered. RESULTS: Data were available on 386 of 426 eligible patients. Median age (IQR) was 65 years (56-72), 214 (55%) were male and 302 (78%) had a performance status of 0-1 (Eastern Cooperative Oncology Group). Prevalence of cachexia (inpatients/outpatients) was 51/22%. Prevalence was highest in patients with gastrointestinal cancer (62/42%) and lung cancer (83/36%). There was no major difference in prevalence between patients with metastatic (55/24%) and localized disease (47/19%). Twenty percent of inpatients and 15% of outpatients wanted more attention to weight loss and nutrition. Cachexia (p < 0.001), symptoms of mood disorder (p < 0.001), and male gender (p < 0.01) were independently associated with increased need of attention. CONCLUSION: Cachexia is a prevalent condition, affecting both patients with localized and metastatic cancer. Clinical attention to the condition is a sizeable unmet need.

The Palliative Radiotherapy and Inflammation Study (PRAIS) - protocol for a longitudinal observational multicenter study on patients with cancer induced bone pain.

BACKGROUND: Radiation therapy (RT) results in pain relief for about 6 of 10 patients with cancer induced bone pain (CIBP) caused by bone metastases. The high number of non-responders, the long median time from RT to pain response and the risk of adverse effects, makes it important to determine predictors of treatment response. Clinical features such as cancer type, performance status and pain intensity, and biomarkers for osteoclast activity are proposed as predictors of response to RT. However, results are inconsistent and there is a need for better predictors of RT response. A similar argument can be stated for the development of cachexia; there are currently no predictors that can identify patients who will develop cachexia later in the cancer disease trajectory. Experimental and preclinical studies show that pain, depression and cachexia are related to inflammation. However, it is not known if inflammatory biomarkers can predict CIBP, depression or development of cachexia. METHODS: This multicenter, multinational longitudinal observational study will include 600 adult patients receiving RT for CIBP. Demographic data, clinical variables, osteoclast and inflammatory biomarkers will be assessed before start of RT, and 3, 8, 16, 24 and 52 weeks after last course of RT. The primary aim of the study is to identify potential predictors for pain relief from RT. Secondary aims are to explore potential predictors for development of cachexia, the longitudinal relationship between pain intensity and depression, and if inflammatory biomarkers are associated with changes in pain intensity, cachexia and depression during one-year follow up. DISCUSSION: The immediate clinical implication of the PRAIS study is to identify potential predictive factors for a RT response on CIBP, and thereby reduce non-efficacious RT. Patient benefits are fewer hospital visits, reduced risk of adverse effects and more individualized pain treatment. The long-term clinical implication of the PRAIS study is to improve the knowledge about inflammation in relation to CIBP, cachexia and depression and potentially identify associations and mechanisms that can be targeted for treatment. TRIAL REGISTRATION: ClinicalTrials.gov NCT02107664 , date of registration April 8, 2014 (retrospectively registered). TRIAL SPONSOR: The European Palliative Care Research Centre (PRC), Department of Clinical and Molecular Medicine, NTNU, Faculty of medicine and Health Sciences, Trondheim, N-7491, Norway.

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.

Pain in Malignant Pleural Mesothelioma: A Prospective Characterization Study.

INTRODUCTION: Malignant pleural mesothelioma (MPM) is associated with severe pain. The underlying neurobiology of this is complex. The primary aim of this study was to characterize pain in MPM. METHODS: This study was undertaken as part of a trial examining radiotherapy for the treatment of pain in MPM (ISRCTN 10644347). Patients had MPM with associated pain for which radiotherapy was planned and a worst pain score ≥ 4/10. The following assessments were undertaken: clinical neuropathic pain assessment, Brief Pain Inventory (BPI), Leeds Assessment of Neuropathic Symptoms and Signs (LANSS), Short form of the McGill Pain Questionnaire (SF-MPQ), and Quantitative Sensory Testing (QST). The relationship of these characteristics and response to radiotherapy was assessed. Unless stated, medians and interquartile range (IQR) are used. RESULTS: Thirty-seven patients were recruited. Average pain and worst pain was 4 (4-6) and 8 (6-8), respectively. Higher average pain and higher worst pain scores were associated with higher interference scores on the BPI, P < 0.001 and P < 0.0005. Twenty patients (54%) had a clinical diagnosis of neuropathic pain, and of these, only six patients (40%) screened positively for neuropathic pain using the LANSS. Patients with a high LANSS also had higher BPI and SF-MPQs. The presence of neuropathic pain (clinically or by LANSS) did not predict response to radiotherapy, P < 0.05. The SF-MPQ scores were higher in those with abnormal cool sensation on QST (P = 0.016). CONCLUSION: Pain in mesothelioma varies among patients and may have neuropathic components. An adequate pain assessment is necessary to guide the clinician in the appropriate choice of analgesics.