An exploratory study examining the relationship between performance status and systemic inflammation frameworks and cytokine profiles in patients with advanced cancer

The role of cytokines in the systemic inflammatory response (SIR) is now well established. This is in keeping with the role of the SIR in tumorigenesis, malignant spread, and the development of cachexia. However, the relationship between performance status/systemic inflammation frameworks and cytokine profiles is not clear. The aim of the present study was to examine the relationship between the Eastern cooperative oncology group performance status/modified Glasgow prognostic score (ECOG-PS/mGPS) and cooperative oncology group performance status/neutrophil platelet score (ECOG-PS/NPS) frameworks and their cytokine profile in patients with advanced cancer.This was a retrospective interrogation of data already collected as part of a recent clinical trial (NCT00676936). The relationship between the independent variables (ECOG-PS/mGPS and ECOG-PS/NPS frameworks), and dependent variables (cytokine levels) was examined using independent Mann-Whitney U and Kruskal Wallis tests where appropriate.Of the 40 patients included in final analysis the majority had evidence of an SIR assessed by mGPS (78%) or NPS (53%). All patients died on follow-up and the median survival was 91 days (4-933 days). With increasing ECOG-PS there was a higher median value of Interleukin 6 (IL-6, P = .016) and C-reactive protein (CRP, P < .01) and lower albumin (P < .01) and poorer survival (P < .001). With increasing mGPS there was a higher median value of IL-6 (P = .016), Macrophage migration inhibitory factor (MIF, P = .010), erythrocyte sedimentation rate (ESR, P < .01) and poorer survival (P < .01). With increasing NPS there was a higher median value of TGF-β (P < .001) and C-reactive protein (P = .020) and poor survival (P = .001). When those patients with an ECOG-PS 0/1 and mGPS0 were compared with those patients with an ECOG-PS 2 and mGPS2 there was a higher median value of IL-6 (P = .017) and poorer survival (P < .001). When those patients with an ECOG-PS 0/1 and NPS0 were compared with those patients with an ECOG-PS 2 and NPS1/2 there was a higher median value of IL-6 (P = .002), TGF-β (P < .001) and poorer survival (P < .01).In patients with advanced cancer IL-6 was associated with the ECOG-PS/mGPS and ECOG-PS/NPS frameworks and survival in patients with advanced cancer. Therefore, the present work provides supporting evidence that agents targeting IL-6 are worthy of further exploration

Randomized double-blind trial of pregabalin versus placebo in conjunction with palliative radiotherapy for cancer-induced bone pain

Purpose Cancer-induced bone pain (CIBP) affects one third of patients with cancer. Radiotherapy remains the gold-standard treatment; however, laboratory and clinical work suggest that pregabalin may be useful in treating CIBP. The aim of this study was to examine pregabalin in patients with CIBP receiving radiotherapy. Patients and Methods A multicenter, double-blind randomized trial of pregabalin versus placebo was conducted. Eligible patients were age ≥ 18 years, had radiologically proven bone metastases, were scheduled to receive radiotherapy, and had pain scores ≥ 4 of 10 (on 0-to-10 numeric rating scale). Before radiotherapy, baseline assessments were completed, followed by random assignment. Doses of pregabalin and placebo were increased over 4 weeks. The primary end point was treatment response, defined as a reduction of ≥ 2 points in worst pain by week 4, accompanied by a stable or reduced opioid dose, compared with baseline. Secondary end points assessed average pain, interference of pain with activity, breakthrough pain, mood, quality of life, and adverse events. Results A total of 233 patients were randomly assigned: 117 to placebo and 116 to pregabalin. The most common cancers were prostate (n = 88; 38%), breast (n = 77; 33%), and lung (n = 42; 18%). In the pregabalin arm, 45 patients (38.8%) achieved the primary end point, compared with 47 (40.2%) in the placebo arm (adjusted odds ratio, 1.07; 95% CI, 0.63 to 1.81; P = .816). There were no statistically significant differences in average pain, pain interference, or quality of life between arms. There were differences in mood (P = .031) and breakthrough pain duration (P = .037) between arms. Outcomes were compared at 4 weeks. Conclusion Our findings do not support the role of pregabalin in patients with CIBP receiving radiotherapy. The role of pregabalin in CIBP with a clinical neuropathic pain component is unknown

REVOLUTION (Routine EValuatiOn of people LivIng with caNcer)—protocol for a prospective characterisation study of patients with incurable cancer

Introduction: There is a pressing need for a holistic characterisation of people with incurable cancer. In this group, where quality of life and improvement of symptoms are therapeutic priorities, the physical and biochemical manifestations of cancer are often studied separately, giving an incomplete picture. In order to improve care, spur therapeutic innovation, provide meaningful endpoints for trials and set priorities for future research, work must be done to explore how the tumour influences the clinical phenotype. Characterisation of the host-tumour interaction may also provide information regarding prognosis, allowing appropriate planning of investigations, treatment and referral to palliative medicine services. Methods: Routine EValuatiOn of people LivIng with caNcer (REVOLUTION) is a prospective observational study that aims to characterise people with incurable cancer around five key areas, namely body composition, physical activity, systemic inflammatory response, symptoms, and quality of life by developing a bio-repository. Participants will initially be recruited from a single centre in the UK and will have assessments of body composition (bio-impedance analysis [BIA] and computed tomography [CT]), assessment of physical activity using a physical activity monitor, measurement of simple markers of inflammation and plasma cytokine proteins and three symptom and quality of life questionnaires. Discussion: This study aims to create a comprehensive biochemical and clinical characterisation of people with incurable cancer. Data in this study can be used to give a better understanding of the ‘symptom phenotype’ and quality of life determinants, development of a profile of the systemic inflammatory response and a detailed characterisation of body composition

Quality of Life in Patients With Advanced Cancer: Differential Association With Performance Status and Systemic Inflammatory Response

Purpose: Quality of life is a key component of cancer care; however, the factors that determine quality of life are not well understood. The aim of this study was to examine the relationship between quality of life parameters, performance status (PS), and the systemic inflammatory response in patients with advanced cancer. Methods: An international biobank of patients with advanced cancer was analyzed. Quality of life was assessed at a single time point by using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C-30 (EORTC QLQ-C30). PS was assessed by using the Eastern Cooperative Oncology Group (ECOG) classification. Systemic inflammation was assessed by using the modified Glasgow Prognostic Score (mGPS), which combines C-reactive protein and albumin. The relationship between quality of life parameters, ECOG PS, and the mGPS was examined. Results: Data were available for 2,520 patients, and the most common cancers were GI (585 patients [22.2%]) and pulmonary (443 patients [17.6%]). The median survival was 4.25 months (interquartile range, 1.36 to 12.9 months). Increasing mGPS (systemic inflammation) and deteriorating PS were associated with deterioration in quality-of-life parameters (P < .001). Increasing systemic inflammation was associated with deterioration in quality-of-life parameters independent of PS. Conclusion: Systemic inflammation was associated with quality-of-life parameters independent of PS in patients with advanced cancer. Further investigation of these relationships in longitudinal studies and investigations of possible effects of attenuating systemic inflammation are now warranted

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

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

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

An exploratory study examining the relationship between performance status and systemic inflammation frameworks and cytokine profiles in patients with advanced cancer

The role of cytokines in the systemic inflammatory response (SIR) is now well established. This is in keeping with the role of the SIR in tumorigenesis, malignant spread, and the development of cachexia. However, the relationship between performance status/systemic inflammation frameworks and cytokine profiles is not clear. The aim of the present study was to examine the relationship between the Eastern cooperative oncology group performance status/modified Glasgow prognostic score (ECOG-PS/mGPS) and cooperative oncology group performance status/neutrophil platelet score (ECOG-PS/NPS) frameworks and their cytokine profile in patients with advanced cancer.This was a retrospective interrogation of data already collected as part of a recent clinical trial (NCT00676936). The relationship between the independent variables (ECOG-PS/mGPS and ECOG-PS/NPS frameworks), and dependent variables (cytokine levels) was examined using independent Mann-Whitney U and Kruskal Wallis tests where appropriate.Of the 40 patients included in final analysis the majority had evidence of an SIR assessed by mGPS (78%) or NPS (53%). All patients died on follow-up and the median survival was 91 days (4-933 days). With increasing ECOG-PS there was a higher median value of Interleukin 6 (IL-6, P = .016) and C-reactive protein (CRP, P < .01) and lower albumin (P < .01) and poorer survival (P < .001). With increasing mGPS there was a higher median value of IL-6 (P = .016), Macrophage migration inhibitory factor (MIF, P = .010), erythrocyte sedimentation rate (ESR, P < .01) and poorer survival (P < .01). With increasing NPS there was a higher median value of TGF-β (P < .001) and C-reactive protein (P = .020) and poor survival (P = .001). When those patients with an ECOG-PS 0/1 and mGPS0 were compared with those patients with an ECOG-PS 2 and mGPS2 there was a higher median value of IL-6 (P = .017) and poorer survival (P < .001). When those patients with an ECOG-PS 0/1 and NPS0 were compared with those patients with an ECOG-PS 2 and NPS1/2 there was a higher median value of IL-6 (P = .002), TGF-β (P < .001) and poorer survival (P < .01).In patients with advanced cancer IL-6 was associated with the ECOG-PS/mGPS and ECOG-PS/NPS frameworks and survival in patients with advanced cancer. Therefore, the present work provides supporting evidence that agents targeting IL-6 are worthy of further exploration

Results from a randomised, open-label trial of a multimodal intervention (exercise, nutrition and anti-inflammatory medication) plus standard care versus standard care alone to attenuate cachexia in patients with advanced cancer undergoing chemotherapy.

Background: Cancer cachexia arises from the interaction between the host and the tumour, triggering an inflammatory response that leads to weight and appetite loss, diminished physical activity, reduced treatment efficacy and survival. Combining interventions to address inflammation, weight loss, and physical activity is proposed as an effective strategy. Building on a promising pilot study, we conducted the MENAC (Multimodal Exercise Nutrition Anti-inflammatory Cachexia) trial to comprehensively evaluate this approach in patients with lung and pancreatic cancer undergoing systemic anti-cancer treatment (SACT). Methods: MENAC was an investigator-initiated, multicentre, open label, randomised phase 3 trial conducted at 17 sites in 4 countries. Patients with stage III or IV lung or pancreatic cancer receiving SACT with non-curative intent were randomly assigned (1:1) to a multimodal intervention consisting of nutritional counselling plus fish oil containing oral nutritional supplements, physical exercise [endurance and strength] and non-steroidal anti-inflammatory drugs [NSAIDs]) versus standard care. Randomisation was stratified by country, cancer type and stage. Primary Objective: To assess differences between arms in change in body weight. Secondary Objectives: To assess differences in muscle mass (measured by CT L3 technique) and physical activity (assessed through step counts using ActivPAL activity meter) between arms. Assessments were conducted at basline (pre-randomisation) and at endpoint (after 6 weeks). Results: From May 2015 to February 2022, 212 patients were enrolled (105 to multimodal treatment, 107 standard care). Over 6 weeks, weight stabilised in patients assigned to multimodal treatment compared with those assigned to standard care (mean weight change [SD] 0.05 kg [3.8] vs – 0.99 kg [3.2], respectively) with a mean difference in weight change of -1.04, 95 % CI -2.02 to -0.06, p=0.04. There was no conclusive difference in muscle mass (mean change [SD] -6.5cm2 [ 10.1] vs -6.3cm2 [11.9], p=0.93) or in mean step counts [SD] (-377.7 [2075] vs -458 [1858], p=0.89). There were 28 and 24 reported SAEs in the intervention and control arm respectively, no SUSARs were reported. Conclusions: A multimodal cachexia intervention stabilised weight compared to standard care at six weeks. There was no difference in physical activity or muscle mass between trial arms. Clinical trial information: NCT02330926