Cachexia index for prognostication in surgical patients with locally advanced oesophageal or gastric cancer: multicentre cohort study.

BACKGROUND: Features of cancer cachexia adversely influence patient outcomes, yet few currently inform clinical decision-making. This study assessed the value of the cachexia index (CXI), a novel prognostic marker, in patients for whom neoadjuvant chemotherapy and surgery for oesophagogastric cancer is planned. METHODS: Consecutive patients newly diagnosed with locally advanced (T3-4 or at least N1) oesophagogastric cancer between 1 January 2010 and 31 December 2015 were identified through the West of Scotland and South-East Scotland Cancer Networks. CXI was calculated as (L3 skeletal muscle index) × (serum albumin)/(neutrophil lymphocyte ratio). Sex-stratified cut-off values were determined based on the area under the curve (AUC), and patients were divided into groups with low or normal CXI. Primary outcomes were disease progression during neoadjuvant chemotherapy and overall survival (at least 5 years of follow-up). RESULTS: Overall, 385 patients (72% men, median age 66 years) were treated with neoadjuvant chemotherapy for oesophageal (274) or gastric (111) cancer across the study interval. Although patients with a low CXI (men: CXI below 52 (AUC 0.707); women: CXI below 41 (AUC 0.759)) were older with more co-morbidity, disease characteristics were comparable to those in patients with a normal CXI. Rates of disease progression during neoadjuvant chemotherapy, leading to inoperability, were higher in patients with a low CXI (28 versus 12%; adjusted OR 3.07, 95% c.i. 1.67 to 5.64; P < 0.001). Low CXI was associated with worsened postoperative mortality (P = 0.019) and decreased overall survival (median 14.9 versus 56.9 months; adjusted HR 1.85, 1.42 to 2.42; P < 0.001). CONCLUSION: CXI is associated with disease progression, worse postoperative mortality, and overall survival, and could improve prognostication and decision-making in patients with locally advanced oesophagogastric cancer.

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.

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.

Temporal Trends in the Investigation, Management and Outcomes of Acute Appendicitis over 15 Years in the North of England: A Retrospective Cohort Study.

BACKGROUND: Acute appendicitis is a common surgical emergency with an estimated lifetime prevalence of 8.6% for males and 6.7% for females. Despite the frequency of presentation, considerable variation in clinical practice exists. Our study aimed to explore temporal trends in the investigation, treatment and outcomes for patients with appendicitis between 2002 and 2016. METHODS: Data collected included all patients aged ≥16 years across the NHS trusts in Northern England between 01/01/2002 and 31/12/2016 diagnosed with appendicitis. Patient demographics, co-morbidity and management strategies were included. Outcomes of interest were length of stay and inpatient mortality. RESULTS: Over a 15 years period, 22,137 patients were admitted with acute appendicitis. A consistent male preponderance (n = 11,952, 54%) was observed, and median age increased over time (2002-2006: 36.4 vs. 2012-2016: 39.5, p < 0.001). Comorbidity of patients also increased (p < 0.001) in recent years. Computed tomography (CT) use increased from 0.8 to 21.9% (p < 0.001) over the study period. Following CT scanning, there was a longer time to theatre (1.22 vs. 0.70 days, p < 0.001), and patients were more frequently managed non-operatively (23.8% vs. 5.7%, p < 0.001). The utilisation of laparoscopic approaches significantly increased from 4.1 to 70.4% (p < 0.001). Laparoscopic patients had a shorter median length of stay (2.97 days) when compared with open surgery (4.44 days) or non-operative (6.19 days) patients. The 30-day mortality rate was 0.33% overall and decreased with time (p = 0.004). CONCLUSIONS: CT and laparoscopic surgery are increasingly utilised in the management of appendicitis. Along with other advances in clinical practice, they have led to reduced lengths of stay and mortality.

The impact of surgical subspecialization on patient outcomes following emergency colorectal resections in the north of England: a retrospective cohort study.

AIM: Emergency colorectal surgery is associated with significant morbidity and mortality. Most general surgeons have a subspecialty, which forms the focus of their elective work, allowing development of specialist skill sets. The aim of this study was to assess the impact of consultant subspecialization on patient outcomes following emergency colorectal resections. METHODS: Data were requested for all emergency admissions under a general surgeon between 1 January 2002 and 31 December 2016 within the north of England. These were acquired from individual Trusts following Caldicott approval. Data included demographics, diagnoses and any procedures undertaken. Patients were assigned to cohorts based on the subspecialist interest of the consultant they were under the care of. The primary outcome of interest was 30-day postoperative mortality. Categorical data were compared with the chi-squared test, and continuous data with the t test or ANOVA. A logistic regression model determined factors associated with 30-day in-hospital mortality. RESULTS: Overall, 7648 emergency colorectal resections were performed with a 30-day postoperative mortality of 13.8%. This was significantly lower if the responsible consultant was a colorectal surgeon compared with other general surgery subspecialties (11.8% vs. 15.2%, P < 0.001). This was significant on univariate analysis (OR 0.75, P < 0.001); however, following multivariable adjustment, this was not statistically significant (P = 0.380). The colorectal specialists had a higher laparoscopy rate than their colleagues-9.8% versus 6.8% (P < 0.001). Stoma rates were also lower (46.9% vs. 51.0%, P = 0.001) and anastomosis rates higher (55.9% vs. 49.3%, P < 0.001) amongst colorectal surgeons. CONCLUSION: These findings add to the growing body of evidence that patient outcomes may be improved by involving subspecialists in colorectal emergencies.

Decision analysis of minimally invasive management options for cholecysto-choledocholithiasis.

BACKGROUND: The management of cholecysto-choledocholithiasis is controversial with the risks and benefits of one versus two-stage approaches debated. This study aims to perform decision analysis of minimally invasive laparo-endoscopic approaches. METHODS: An advanced decision tree was constructed to compare pre, intra and post-operative ERCP and laparoscopic common bile duct exploration in terms of primary ductal clearance and significant complications for patients intended to undergo laparoscopic cholecystectomy. Transition probabilities were calculated from randomised controlled trials following a comprehensive literature search. Model uncertainties were extensively tested through deterministic and probabilistic Monte Carlo sensitivity analysis. Utility outcomes were 1 and 0.5 for successful primary clearance without and with complications, respectively, and 0 for failure of primary clearance of the duct. RESULTS: Twenty-one studies (n = 2697) were included in the analysis. At base case analysis, a laparo-endoscopic rendezvous approach had the highest utility output (0.90; no complication probability: 0.87/complication probability 0.06). Laparoscopic common bile duct exploration was ranked second with a utility output 0.87 (no complication probability: 0.82/complication probability 0.10). Pre-operative ERCP utility score was 0.84 (no complication probability: 0.78/ complication probability 0.11) and post-operative ERCP utility score was 0.78 (no complication probability: 0.71/complication probability 0.13). Monte Carlo analysis showed that laparo-endoscopic rendezvous and laparoscopic common bile duct exploration had an equal mean utility output of 0.57 (standard deviation 0.36; variance 0.13; 95% confidence interval 0.00-0.99 versus standard deviation 0.34; variance 0.12; 95% confidence interval 0.01-0.98). Laparo-endoscopic rendezvous had a superior treatment selection frequency of 39.93% followed by laparoscopic bile duct exploration (36.11%), pre-operative ERCP (20.67%) and post-operative ERCP (2.99%). CONCLUSION: One-stage approach to the management of cholecysto-choledocholithiasis is superior to two-stage, in terms of primary clearance of the duct and risk of operative morbidity. Laparo-endoscopic rendezvous approach could offer marginal additional benefit but more high-quality randomised controlled trials are needed.

The prospects of sitting 'end of year' open book exams in the light of COVID-19: A medical student's perspective.

Medical schools in the UK have been forced to dramatically restructure teaching and assessment amidst the Coronavirus (COVID-19) pandemic. As part of this, some have opted to assess progression through open book examinations (OBE). I aim to share my thoughts as an unsettled 4th year medical student about to embark on my first set of clinical exams conducted in this format. The difficulties associated with preparing for examinations under such unique and challenging circumstances cannot be underestimated. Working from home, during social distancing, surrounds students with the extra family stresses that we are all facing during this pandemic. This combined with a new, unfamiliar examination format will inevitably lead to students feeling daunted. While some would argue that an OBE may reward good problem solvers, students still require a strong foundation of knowledge. The luxury of reference will not be afforded in all clinical settings thus leading to concerns regarding students skimming over essential learning points. Furthermore, we cannot ignore the increased opportunity for academic misconduct resulting from an open book assessment format. Why are medical schools placing undue stress on students who could instead focus their attention on living compassionately for others during this difficult time?

The survivorship of the link endo-rotational hinge total knee arthroplasty: 5-12-year follow-up of 100 patients.

INTRODUCTION: There is a paucity of survival data reporting the medium to long-term outcome of the LINK® Endo-Model® rotational hinge total knee arthroplasty (ERH-TKA). Such information is essential when counselling patients and predictors of survival would help inform patients of their likely outcome. MATERIALS AND METHODS: A series of patients, who received an ERH-TKA, with a minimum follow-up of 5 years, were retrospectively identified from an established arthroplasty database. Data were collected from paper and electronic patient records. This included patient demographics, indication for surgery, complication rates and revision status. Our primary outcome of interest was joint implant survival. RESULTS: One hundred patients underwent an ERH-TKA over an 11-year period. There were 66 females and 34 males, with a mean age of 73.8 years and 67.6 years, respectively. Indications were classified into primary (n = 41), aseptic revision (n = 47) and two-stage infective revision (n = 12). The median follow-up was 8.2 (range 5-12) years. One-year implant survival amongst the cohort was 99%, falling to 95% at 5 years. Overall, there were eight revisions during the follow-up period. Considering only cases of aseptic failure, survival was 97% at 5 years and all failures occurred amongst revision cases. Implant failure was greater following revision arthroplasty but this was not statistically significant (p = 0.97). Cox regression analysis identified male sex to be the only independent predictor of failure (hazard ratio 1.75, 95% CI 1.04-31.82, p = 0.04) after adjusting for confounding variables. CONCLUSIONS: The ERH-TKA has a good medium- to long-term survival rate but male patients are nearly twice as likely to undergo revision, compared to females, and should be made aware of this preoperatively.

Prognostic Biomarkers of Systemic Inflammation in Non-Small Cell Lung Cancer: A Narrative Review of Challenges and Opportunities.

Non-small cell lung cancer (NSCLC) is a common malignancy and is associated with poor survival outcomes. Biomarkers of systemic inflammation derived from blood tests collected as part of routine clinical care offer prognostic information for patients with NSCLC that may assist clinical decision making. They are an attractive tool, as they are inexpensive, easily measured, and reproducible in a variety of healthcare settings. Despite the wealth of evidence available to support them, these inflammatory biomarkers are not yet routinely used in clinical practice. In this narrative review, the key inflammatory indices reported in the literature and their prognostic significance in NSCLC are described. Key challenges limiting their clinical application are highlighted, including the need to define the optimal biomarker of systemic inflammation, a lack of understanding of the systemic inflammatory landscape of NSCLC as a heterogenous disease, and the lack of clinical relevance in reported outcomes. These challenges may be overcome with standardised recording and reporting of inflammatory biomarkers, clinicopathological factors, and survival outcomes. This will require a collaborative approach, to which this field of research lends itself. This work may be aided by the rise of data-driven research, including the potential to utilise modern electronic patient records and advanced data-analysis techniques.

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.

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.

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

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

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.

Environmentally dependent and independent control of 3D cell shape.

How cancer cells determine their shape in response to three-dimensional (3D) geometric and mechanical cues is unclear. We develop an approach to quantify the 3D cell shape of over 60,000 melanoma cells in collagen hydrogels using high-throughput stage-scanning oblique plane microscopy (ssOPM). We identify stereotypic and environmentally dependent changes in shape and protrusivity depending on whether a cell is proximal to a flat and rigid surface or is embedded in a soft environment. Environmental sensitivity metrics calculated for small molecules and gene knockdowns identify interactions between the environment and cellular factors that are important for morphogenesis. We show that the Rho guanine nucleotide exchange factor (RhoGEF) TIAM2 contributes to shape determination in environmentally independent ways but that non-muscle myosin II, microtubules, and the RhoGEF FARP1 regulate shape in ways dependent on the microenvironment. Thus, changes in cancer cell shape in response to 3D geometric and mechanical cues are modulated in both an environmentally dependent and independent fashion.

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.

Longitudinal characterisation of cachexia in patients undergoing surgical resection for cancer.

PURPOSE OF REVIEW: The complexity of the cancer cachexia phenotype has undoubtedly hindered researchers' understanding of this devastating syndrome. The presence and magnitude of host-tumour interactions are rarely considered during clinical decision-making within the current staging paradigm. Furthermore, treatment options for those patients who are identified as suffering from cancer cachexia remain extremely limited. RECENT FINDINGS: Previous attempts to characterise cachexia have largely focussed on individual surrogate disease markers, often studied across a limited timeframe. While the adverse prognostic value of clinical and biochemical features is evident, the relationships between these are less clear. Investigation of patients with earlier-stage disease could allow researchers to identify markers of cachexia that precede the refractory stage of the wasting process. Appreciation of the cachectic phenotype within 'curative' populations may aid our understanding of the syndrome's genesis and provide potential routes for prevention, rather than treatment. SUMMARY: Holistic, longitudinal characterisation of cancer cachexia, across all at-risk and affected populations, is of vital importance for future research in the field. This paper presents the protocol for an observational study aiming to create a robust and holistic characterisation of surgical patients with, or at risk of, cancer cachexia.