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

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

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

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

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

Prevalence, early detection and classification of cancer cachexia

Cancer cachexia is characterized by loss of muscle mass accompanied by a variable loss of fat mass. It leads to a decline in physical function and quality of life, and an increase in psychological distress and mortality. The pathophysiology is complex and characterized by a negative protein and energy balance mediated by inflammation and neuroendocrine changes. Anorexia and lack of exercise contributes to the decay. Estimates of cancer cachexia prevalence vary between 30-85% depending on how it is defined, and the population examined. There is no established treatment of cancer cachexia, and nutrition therapy alone will not fully reverse the condition. Several different pharmacological agents have been tested, but so far, no drug has been licensed. An important barrier against progress in cachexia management has been the absence of a consensus definition, and thus, a common perception of what cachexia is. In the clinical setting, cachexia has most often been recognized by its historical phenotype of severe weight loss and poor physical function and as such not recognized until late in its development. This may have compounded the lack of awareness among health care professionals to the development of cachexia. Criteria for the diagnosis of cachexia in studies have varied; often based on weight loss in varying degrees, but other characteristics of cachexia such as markers of appetite loss and the systemic inflammatory response have also been used. This heterogeneity has made comparison of research results challenging, and the differing estimates of prevalence have led to uncertainty as to the impact and extent of cachexia in the cancer population. Progress was made in 2011 when an international consensus definition incorporating diagnostic criteria for cancer cachexia was published. Fundamental to this was a framework for the classification of the trajectory of cancer cachexia through the stages of ‘pre-cachexia’, ‘cachexia’ and ‘refractory cachexia’. Cachexia is present if 6 months’ weight loss is >5%, or if the patient either has a body mass index 2%. Pre-cachexia is a stage of early metabolic change and appetite loss, and refractory cachexia a stage of variable degree of cachexia, but where the cancer disease is pro-catabolic and no longer responsive to anti-cancer therapy. The ability to classify patients according to where they are in the trajectory may help stratify treatment. To illustrate, where a patient with pre-cachexia or cachexia might be susceptible to treatment aiming to delay or reverse cachexia, such treatment would seem futile in a patient with refractory cachexia. Instead, treatment aiming to provide optimal symptom relief would be more appropriate. Although the consensus definition and classification framework was an important starting point, it was acknowledged that further research was necessary to find objective and reliable criteria for the cachexia stages. Moreover, it was necessary to establish an accurate estimate of cancer cachexia prevalence based on the new definition to better understand the extent of the condition. To this end, the overall aim of the thesis was to gain new knowledge of the prevalence of cancer cachexia and contribute to a better classification system to allow for optimal selection of anti-cachexia treatment for each individual patient in the future. The aims pertaining to paper I were to estimate prevalence of cancer cachexia in an unselected population as well as in cohorts based on demographical and clinical characteristics, and to evaluate patient-perceived importance of clinical attention to cachexia. A cross-sectional study was conducted in patients with cancer at three centers in the Regional Health Authority of Central-Norway. Fifty-one percent (95%CI40-63) of inpatients and 22% (95%CI 17-27) of outpatients had cachexia. Prevalence varied significantly with cancer type and was higher in patients with gastrointestinal (OR 4.4 [95%CI 2.0-9.6]) and lung cancer (OR 5.5 [95%CI 2.0-15.1]) compared to patients with hematologic cancer. Twenty percent of inpatients and 15% of outpatients wanted more clinical attention to cachexia. Having cachexia (p=0.02), symptoms of a mood disorder (p=0.05) or being male (p<0.01) were factors significantly associated with a need for more attention. The aims pertaining to paper II were to confirm the survival prognostic validity of the Weight loss grading system (WLGS), a potential classification system of cancer cachexia; evaluate its relationship with established cachexia characteristics and to explore its ability to predict cachexia progression. An analysis of an international cohort of patients with incurable cancer (European Palliative Care Cancer Symptom study, EPCCS) was conducted. The WLGS significantly predicted survival (p<0.001), and the addition of measurements of performance status (p<0.001), appetite (p=0.005), physical (p<0.001) and emotional functioning (p=0.004) to this model significantly improved the prognostic accuracy. The WLGS was associated with increased severity of all evaluated cachexia characteristics (p<0.001), and patients with weight loss grade 2 were more likely to have cachexia progression than patients with weight loss grade 0 and 1 (descriptive analysis only). The aims pertaining to paper III were to identify predictors of cachexia development and to create and evaluate a predictive model of cancer cachexia based on these predictors. Patients included in the EPCCS cohort that had not developed cachexia at baseline were included in this analysis. Early weight loss (p<0.001), cancer type (p<0.01), appetite loss (p=0.04) and chronic obstructive pulmonary disease (p=0.04) predicted development of cancer cachexia. A five-level model based on these predictors was created where each level was associated with an increasing risk of cachexia development. The accuracy of the model in patients remaining in the study after three months was 76%

Combining optimal nutrition and exercise in a multimodal approach for patients with active cancer and risk for losing weight: Rationale and practical approach

Weight loss and functional decline is a common and detrimental consequence of cancer. The interventions that are offered to patients with weight loss and functional decline often seem haphazard and varying from center to center. The lack of stringent management is probably based both on lack of knowledge of existing treatment guidelines and the current weak level of evidence of clinical effects of different nutritional and exercise interventions. Some studies evaluated multimodal interventions with various treatment combinations, including nutrition and exercise, that report clinically significant effects on cachexia outcomes. As of today, however, there is a paucity of large randomized controlled trials that incorporate both a fully structured exercise program and a well-described nutritional intervention. Studies investigating combinations of several interventions in patients with active cancer and risk for losing weight are too few and too heterogeneous to enable firm conclusions about effect, optimal dose, or timing of interventions. However, data presented in this review suggest an overall benefit, especially if interventions are started before weight loss and loss of function become too severe. Thus, the aim of this review was to examine the evidence for combined treatments targeting weight loss in cancer patients

Is it possible to detect an improvement in cancer pain management? A comparison of two Norwegian cross-sectional studies conducted 5 years apart.

Purpose: Cancer pain (CP) management is challenging. In recent years, efforts were undertaken to achieve better CP management, e.g. clinical research, new treatment modalities, development of guidelines, education, and focus on implementation. The aim of the present study was to compare the prevalence and characteristics of pain and breakthrough pain (BTP) between cross-sectional studies conducted in 2008 and 2014. It was hypothesized that an improvement in pain control would be observed the years in-between. Methods: Two cross-sectional studies were conducted where adult cancer patients answered questions from Brief Pain Inventory and the Alberta Breakthrough Pain Assessment Tool for cancer patients. Physicians reported socio-demographic and medical data. Regression models were applied for analysis. Results: In total, 168 inpatients, 92 in 2008 and 76 in 2014, and 675 outpatients, 301 in 2008 and 374 in 2014, were included. The patient characteristics of the samples were comparable. Prevalence of CP among inpatients was 55% in 2008 and 53% in 2014, and among outpatients 39% and 35%, respectively. Inpatients reported average pain intensity (0-10 NRS) of 3.60 (SD 1.84) (2008) and 4.08 (SD 2.11) (2014), prevalence of BTP was 52% (2008) and 41% (2014). For outpatients, average pain intensity was 3.60 (SD 2.04) (2008) and 3.86 (SD 2.20) (2014), prevalence of BTP was 43% (2008) and 37 % (2014). None of the differences were statistically significant. Conclusion: Unexpectedly, no improvement in pain control was observed. Efforts are still needed to improve cancer pain management

Pain management index (PMI)-does it reflect cancer patients? wish for focus on pain?

Background The pain management index (PMI) was developed to combine information about the prescribed analgesics and the self-reported pain intensity in order to assess physicians’ response to patients’ pain. However, PMI has been used to explore undertreatment of cancer pain. The present study explores prevalence of negative PMI and its associations to clinical variables, including the patient-perceived wish for more attention to pain. Methods A single-center, cross-sectional, observational study of cancer patients was conducted. Data on demographics and clinical variables, as well as patient-perceived wish for more attention to pain, were registered. PMI was calculated. Negative PMI indicates that the analgesics prescribed might not be appropriate to the pain intensity reported by the patient, and associations to negative PMI were explored by logistic regression models. Results One hundred eighty-seven patients were included, 53% had a negative PMI score. Negative PMI scores were more frequent among patients with breast cancer (OR 4.2, 95% CI 1.3, 13.5), in a follow-up setting (OR 12.1, 95% CI 1.4, 101.4), and were inversely associated to low performance status (OR 0.14, 95% CI 0.03, 0.65). Twenty-two percent of patients with negative PMI scores reported that they wanted more focus on pain management, versus 13% among patients with a non-negative PMI score; the difference was not statistically significant. Conclusion A high prevalence of negative PMI was observed, but only 1/5 of patients with a negative PMI wanted more attention to pain by their physician. Our findings challenge the use of PMI as a measure of undertreatment of cancer pain

Top Ten Tips Palliative Care Clinicians Should Know About Cachexia

Cachexia is a multifactorial syndrome that is common in cancer and chronic disease. It is often underdiagnosed and therefore goes untreated or undertreated. Cachexia causes suffering across biopsychosocial domains and affects patients and their loved ones. In this article, a group of clinicians and researchers across cancer care, nutrition, and exercise offers tips about assessment, classification, and management of cachexia, with attention to its stage. The required multimodal management of cachexia mirrors well the interprofessional collaboration that is the mainstay of interdisciplinary palliative care and attention to screening, diagnosis, and management of cachexia is critical to maximize patients' quality of life

Top ten tips palliative care clinicians should know about cachexia

Cachexia is a multifactorial syndrome that is common in cancer and chronic disease. It is often underdiagnosed and therefore goes untreated or undertreated. Cachexia causes suffering across biopsychosocial domains and affects patients and their loved ones. In this article, a group of clinicians and researchers across cancer care, nutrition, and exercise offers tips about assessment, classification, and management of cachexia, with attention to its stage. The required multimodal management of cachexia mirrors well the interprofessional collaboration that is the mainstay of interdisciplinary palliative care and attention to screening, diagnosis, and management of cachexia is critical to maximize patients' quality of life