Global Leadership Initiative on Malnutrition cachexia: an inflammation-first approach for the diagnosis of disease-related malnutrition.

PURPOSE OF REVIEW: The following article examines the rationale for an inflammation-first approach for diagnosing cachexia and how the current Global Leadership Initiative on Malnutrition (GLIM) framework may be adapted to facilitate this. RECENT FINDINGS: Recently, the GLIM have published guidance on the measurement of inflammation in the context of cachexia, advocating that C-reactive protein (CRP) should be utilized for quantification. The inclusion of a systemic inflammatory biomarker for the diagnosis of cachexia questions whether it may be more aptly considered a systemic inflammatory syndrome. SUMMARY: The current consensus of the GLIM is that cachexia is 'disease-related malnutrition with inflammation'. In line with this definition, the GLIM proposed a two-step diagnostic framework: screening for malnutrition using validated screening tools and then confirming the presence of disease-related malnutrition with phenotypic (nonvolitional weight loss, low BMI, and reduced muscle mass) and aetiologic criterion reduced food intake/assimilation, and inflammation or disease burden). The GLIM are to be commended for guidance on the measurement of systemic inflammation in their current proposal, given the relative importance to clinical outcomes in patients with cancer. However, the use of CRP is somewhat rudimentary and contrasts other cancer cachexia guidelines and contemporary clinical cancer research.

CT Derived Measurement of Body Composition: Observations from a Comparative Analysis of Patients with Colorectal and Lung Cancer.

BACKGROUND: CT-derived measures of body composition have been shown to have prognostic value in patients with cancer. However, few studies have compared these observations across tumor types and stages of disease. The aim of the present study was to compare body composition measures between two types of cancers, i.e. colorectal cancer (CRC), which is less inflammatory and patients maintain body composition over a longitudinal study period, whereas lung cancer (LC) is proinflammatory and patients lose more fat and muscle mass using a standard methodology. METHODS: Clinicopathological characteristics, including those pertaining to nutritional risk/status and systemic inflammation in patients with colorectal cancer (CRC, n = 1047) and lung cancer (LC, n = 662), were compared. The CT image at L3 was used to assess body composition. Comparison of these cohorts was carried out using the chi-square test. Binary logistic regression analysis was performed to assess the impact of clinico-pathological variables on body composition, and scatter plots were used to examine the relationship between body mass index (BMI) and CT-derived measures of body composition. RESULTS: According to CT-derived body composition, high subcutaneous (SFI) and visceral fat index (VFI) were common (>70%) in both CRC and LC. Also, low skeletal muscle index (SMI) and density (SMD) were approximately 40-50% and 60-70% in both CRC and LC. Compared with CRC, patients with LC had a higher American Society of Anaesthesia (ASA) (P < 0.001), Malnutrition Universal Screening Tool (MUST) (P < 0.001), modified frailty index (mFI) (P < 0.001), modified Glasgow Prognostic Score (mGPS) (P < 0.001), and neutrophil lymphocyte ratio (NLR) (P < 0.001) scores.On binary logistic regression analysis, MUST, mFI, and NLR were predictors of subcutaneous adiposity (P < 0.05); type of cancer, MUST, and mFI were predictors of visceral obesity (P < 0.001); age, type of cancer, MUST, and mGPS were predictors of low SMI (P < 0.001); and age, type of cancer, mFI, and mGPS were predictors of low SMD (P < 0.05). There was a similar relationship between BMI and other measures of CT-derived body composition across two types of cancers. CONCLUSION: Obesity and low skeletal muscle mass were common in both CRC and LC cohorts despite large differences in comorbidity, nutritional risk, systemic inflammation, and survival, even when normalized for TNM stage. These observations would support the hypothesis that, although prognostic, CT derived body composition analysis primarily reflects patient constitution rather than the effect of tumor stage in patients with cancer. The systemic inflammatory response, as evidenced by mGPS, can be considered as an important therapeutic target and loss of muscle mass in patients with advanced cancer is related to the systemic inflammatory response.

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: 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.

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.

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.

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.

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.

Central neural mechanisms of cancer cachexia.

PURPOSE OF REVIEW: Cachexia is a devasting syndrome which impacts a large number of patients with cancer. This review aims to provide a comprehensive overview of the central mechanisms of cancer cachexia. In particular, it focuses on the role of the central nervous system (CNS), the melanocortin system, circulating hormones and molecules which are produced by and act on the CNS and the psychological symptoms of cancer cachexia. RECENT FINDINGS: A growing body of evidence suggests that a central mechanism of action underpins this multi-system disorder. Recent research has focused on the role of neuroinflammation that drives the sickness behaviour seen in cancer cachexia, with emphasis on the role of the hypothalamus. Melanocortin receptor antagonists are showing promise in preclinical studies. There are also new pharmacological developments to overcome the short half-life of ghrelin. GDF-15 has been identified as a core target and trials of compounds that interfere with its signalling or its central receptor are underway. SUMMARY: Understanding the central mechanisms of cancer cachexia is pivotal for enhancing treatment outcomes in patients. While emerging pharmacological interventions targeting these pathways have shown promise, further research is essential.

The prevalence and prognostic value of systemic inflammation in good performance status patients with advanced, inoperable non-small cell lung cancer receiving palliative radiotherapy: Comparison of composite ratios and cumulative scores.

INTRODUCTION: The present study sought to examine the relationships between systemic inflammatory composite ratios/cumulative scores, magnitude of systemic inflammatory response (SIR) and survival in good performance status patients (ECOG-PS 0/1) with advanced NSCLC receiving palliative radiotherapy. METHODS: Systemic inflammatory composite ratios/cumulative scores included the neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), lymphocyte-monocyte ratio (LMR), C-reactive protein, (CRP)-albumin ratio (CAR), neutrophil- lymphocyte score (NLS), platelet-lymphocyte score (PLS), lymphocyte-monocyte score (LMS), neutrophil-platelet score (NPS), modified Glasgow prognostic score (mGPS). The magnitude of SIR was determined by serum CRP concentration, with a median CRP concentration of >10 m mg/L considered to be systemically inflamed. Relationships between systemic inflammatory composite ratios/ cumulative scores and clinicopathological characteristics were examined using chi-square analysis. Relationships between overall survival (OS) and systemic inflammatory composite ratios/ cumulative scores were examined using cox regression analysis. RESULTS: 479 patients were included. 48% (n = 231) of patients were male and 70% (n = 338) were ≥65 years of age. 29% (n = 140) patients were ECOG-PS 0 and 71% (n = 339) were ECOG-PS 1. 98% (n = 469) of patients died during follow-up. The median survival was 5 months (2-11). A similar prevalence of systemic inflammation was noted across the various ratios/scores (NLR >3 68%; LMR <2.4 65%; PLR >150 70%; CAR >0.20 83%; NLS ≥1 66%; LMS ≥1 71%; NPS≥1 50%; PLS≥1 60% and mGPS≥1 75%). Despite not considered to be systemically inflamed, an NLR <3, LMR ≥2.4, PLR ≤150, NLS 0, LMS 0, NPS 0 and PLS 0 all had a median CRP concentration of >10 mg/L. When adjusted for ECOG-PS, CAR>0.40 (p < 0.001) and mGPS 2 (p < 0.05) remained significantly associated with OS. CONCLUSION: Liver-based measures of systemic inflammation (CAR and mGPS) appear more reliable for the quantification of the magnitude of SIR and have prognostic value in patients with advanced NSCLC.

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.