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.

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.

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.

Malnutrition in cancer patients: Causes, consequences and treatment options.

Cancer patients are at a high risk of malnutrition and disease-associated catabolic derangements. It is important to differentiate between 'simple' - voluntary or involuntary - caloric restriction with protein-sparing ketogenic metabolic adaptation and cachexia, characterized by the combination of weight loss and dysmetabolism, most prominently systemic inflammation. While both conditions result in the sacrifice of fat and protein stores and thus impact on treatment tolerance, complication rates and survival, the presence of metabolic derangements is especially dangerous by straining multiple organ functions. To avoid underdiagnosing and undertreating malnutrition, all cancer patients should be routinely screened for nutritional risk. At-risk patients require comprehensive assessment for contributing and treatable causes and, if available, multi-professional efforts to improve food intake, support anabolism, alleviate distress and antagonize pro-inflammatory processes. In curative settings, anabolic support should accompany or even precede anticancer treatments. Prehabilitation before major surgery, has been studied extensively, including muscle training as well as nutritional and/or psychological support. Recent meta-analyses report a consistent benefit on functional capacity and possible improvement in postoperative complications and length of hospital stay. In palliative settings, prevailing catabolic derangements require careful assessment of the individual constellation of disturbed functions and an empathic evaluation of benefits and risks of nutritional interventions. This is of special relevance in patients with an expected survival of less than a few months. Due to the complex interactions of mechanical, metabolic and psychological factors, multi-professional teams should be involved.

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.

Current practice in assessment and management of malnutrition in surgical oncology practice - An ESSO-EYSAC snapshot analysis.

INTRODUCTION: Malnutrition is common in patients suffering from malignant diseases and has a major impact on patient outcomes. Prevention and early detection are crucial for effective treatment. This study aimed to investigate current international practice in the assessment and management of malnutrition in surgical oncology departments. MATERIAL AND METHODS: The survey was designed by European Society of Surgical Oncology (ESSO) and ESSO Young Surgeons and Alumni Club (EYSAC) Research Academy as an online questionnaire with 41 questions addressing three main areas: participant demographics, malnutrition assessment, and perioperative nutritional standards. The survey was distributed from October to November 2021 via emails, social media and the ESSO website to surgical networks focussing on surgical oncologists. Results were collected and analysed by an independent team. RESULTS: A total of 156 participants from 39 different countries answered the survey, reflecting a response rate of 1.4%. Surgeons reported treating a mean of 22.4 patients per month. 38% of all patients treated in surgical oncology departments were routinely screened for malnutrition. 52% of patients were perceived as being at risk for malnutrition. The most used screening tool was the "Malnutrition Universal Screening Tool" (MUST). 68% of participants agreed that the surgeon is responsible for assessing preoperative nutritional status. 49% of patients were routinely seen by dieticians. In cases of severe malnutrition, 56% considered postponing the operation. CONCLUSIONS: The reported rate of malnutrition screening by surgical oncologists is lower than expected (38%). This indicates a need for improved awareness of malnutrition in surgical oncology, and nutritional screening.

Caloric restriction and fasting-mimicking diets in the treatment of cancer patients.

PURPOSE OF REVIEW: Different forms of caloric restriction for patients with cancer are widely advertised in lay circles, based mainly on promising preclinical experiments, while evidence from clinical trials is still preliminary. This review aims to present physiological responses to fasting and update knowledge on recently accumulated evidence from preclinical models and clinical trials. RECENT FINDINGS: Like other mild stressors, caloric restriction induces hormetic changes in healthy cells, which increase the tolerance to subsequent more severe stressors. While protecting healthy tissues, caloric restriction sensitizes malignant cells to toxic interventions because of their deficiencies in hormetic mechanisms, especially control of autophagy. In addition, caloric restriction may activate anticancer-directed immune cells and deactivate suppressive cells, thus increasing immunosurveillance and anticancer cytotoxicity. These effects may combine to increase the effectivity of cancer treatments while limiting adverse events. Though evidence obtained from preclinical models is promising, clinical trials in cancer patients so far have been preliminary. In clinical trials it will remain essential to avoid inducing or aggravating malnutrition. SUMMARY: Based on physiology and evidence from preclinical models, caloric restriction is a promising candidate as a potential combination partner for clinical anticancer treatment. However, large randomized clinical trials investigating effects on clinical outcome in patients with cancer are still lacking.

Overcoming barriers to timely recognition and treatment of cancer cachexia: Sharing Progress in Cancer Care Task Force Position Paper and Call to Action.

Cachexia is a life-threatening disorder affecting an estimated 50-80% of cancer patients. The loss of skeletal muscle mass in patients with cachexia is associated with an increased risk of anticancer treatment toxicity, surgical complications and reduced response. Despite international guidelines, the identification and management of cancer cachexia remains a significant unmet need owing in part to the lack of routine screening for malnutrition and suboptimal integration of nutrition and metabolic care into clinical oncology practice. In June 2020, Sharing Progress in Cancer Care (SPCC) convened a multidisciplinary task force of medical experts and patient advocates to examine the barriers preventing the timely recognition of cancer cachexia, and provide practical recommendations to improve clinical care. This position paper summarises the key points and highlights available resources to support the integration of structured nutrition care pathways.

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.

[Nutrition and dietary supplements]. / Ernährung und Nahrungsergänzungsmittel.

Nutritional problems occur very frequently in patients with cancer and different problems are associated with separate phases of the disease. Therefore, it is principally recommended to regularly screen all patients with cancer for nutritional disorders and in the case of conspicuous results meticulous diagnostics should be carried to clarify the underlying causes. The focus is on food intake and possible disturbing complaints, the physical performance index, nutritional status including weight change and body composition, the metabolic pattern and the presence of a systemic inflammatory reaction. As anti-cancer treatments frequently induce gastrointestinal derangements which endanger adequate food intake, individualized nutritional care should be offered routinely. After successful curative treatment patients are at risk of developing a metabolic syndrome; therefore, a balanced diet and regular physically activity are recommended. During palliative treatment special attention should be paid to the development of malnutrition. Patients are particularly endangered by cachexia with the combination of inadequate food intake, inactivity and prevailing catabolism. The treatment of cachexia requires a multiprofessional approach to ensure adequate food intake, guiding and supporting physical activity and interventions for normalization of the metabolic situation. In addition, the need for psychological and social support should be discussed. Dietary supplements are of minor relevance; however, deficits in micronutrients, such as vitamins and trace elements need to be balanced. At the end of life, care should primarily be focused on alleviating debilitating symptoms. To reliably support all patients affected by nutritional disorders, clear structures need to be established, responsibilities assigned and standardized procedures codified.

The importance of protein sources to support muscle anabolism in cancer: An expert group opinion.

This opinion paper presents a short review of the potential impact of protein on muscle anabolism in cancer, which is associated with better patient outcomes. Protein source is a topic of interest for patients and clinicians, partly due to recent emphasis on the supposed non-beneficial effect of proteins; therefore, misconceptions involving animal-based (e.g., meat, fish, dairy) and plant-based (e.g., legumes) proteins in cancer are acknowledged and addressed. Although the optimal dietary amino acid composition to support muscle health in cancer is yet to be established, animal-based proteins have a composition that offers superior anabolic potential, compared to plant-derived proteins. Thus, animal-based foods should represent the majority (i.e., ≥65%) of protein intake during active cancer treatment. A diet rich in plant-derived proteins may support muscle anabolism in cancer, albeit requiring a larger quantity of protein to fulfill the optimal amino acid intake. We caution that translating dietary recommendations for cancer prevention to cancer treatment may be inadequate to support the pro-inflammatory and catabolic nature of the disease. We further caution against initiating an exclusively plant-based (i.e., vegan) diet upon a diagnosis of cancer, given the presence of elevated protein requirements and risk of inadequate protein intake to support muscle anabolism. Amino acid combination and the long-term sustainability of a dietary pattern void of animal-based foods requires careful and laborious management of protein intake for patients with cancer. Ultimately, a dietary amino acid composition that promotes muscle anabolism is optimally obtained through combination of animal- and plant-based protein sources.

ESPEN practical guideline: Clinical nutrition in chronic intestinal failure.

BACKGROUND: This practical guideline is based on the ESPEN Guidelines on Chronic Intestinal Failure in Adults. METHODOLOGY: ESPEN guidelines have been shortened and transformed into flow charts for easier use in clinical practice. The practical guideline is dedicated to all professionals including physicians, dieticians, nutritionists, and nurses working with patients with chronic intestinal failure. RESULTS: This practical guideline consists of 112 recommendations with short commentaries for the management and treatment of benign chronic intestinal failure, including home parenteral nutrition and its complications, intestinal rehabilitation, and intestinal transplantation. CONCLUSION: This practical guideline gives guidance to health care providers involved in the management of patients with chronic intestinal failure.

COVID-19 in Patients with Cancer.

With more than 5 million cases and 333,212 deaths, COVID-19 (or SARS-CoV-2) continues to spread. General symptoms of this disease are similar to that of many other viral respiratory diseases, including fever, cough, dyspnea, and fatigue, with a chance of progression to more severe complications. However, the virus does not affect all people equally, and cases with comorbidities such as malignancies, cardiovascular diseases, respiratory diseases, and kidney diseases are at higher risk of developing severe events, including requiring intensive ventilation, intensive care unit (ICU) admission, and death. Patients with cancer are more likely to be infected with COVID-19, which is possibly due to their immunological dysfunction or frequent clinic visits. Also, there is a higher chance that these patients experience severe events because of the medication they receive. In this chapter, we will review the main clinical manifestations of COVID-19 in patients with cancer. Recommendations and challenges for managing resources, organizing cancer centers, treatment of COVID-19-infected cancer patients, and performing cancer research during this pandemic will also be discussed.

ESPEN practical guideline: Clinical Nutrition in cancer.

BACKGROUND: This practical guideline is based on the current scientific ESPEN guidelines on nutrition in cancer patients. METHODS: ESPEN guidelines have been shortened and transformed into flow charts for easier use in clinical practice. The practical guideline is dedicated to all professionals including physicians, dieticians, nutritionists and nurses working with patients with cancer. RESULTS: A total of 43 recommendations are presented with short commentaries for the nutritional and metabolic management of patients with neoplastic diseases. The disease-related recommendations are preceded by general recommendations on the diagnostics of nutritional status in cancer patients. CONCLUSION: This practical guideline gives guidance to health care providers involved in the management of cancer patients to offer optimal nutritional care.

Supportive Care: Low Cost, High Value.

Supportive care aims to prevent and manage adverse effects of cancer and its treatment across the entire disease continuum. Research and clinical experience in dedicated centers have demonstrated that early appropriate supportive care interventions improve symptoms, quality of life, and overall survival in a cost-effective manner. The challenge is to assess symptoms and needs with validated tools regularly and, ideally, between clinic appointments; electronic patient-reported outcome measures and dedicated easily accessible supportive care units can help. As management of certain problems improves, others come to the fore. Cancer-related fatigue and malnutrition are very frequent and need regular screening, assessment of treatable causes, and early intervention to improve. Pharmacologic agents and phytopharmaceuticals are of little use, but other interventions are valuable: physical exercise, counseling on fatigue, and cognitive behavioral therapy/mind-body interventions (e.g., for fatigue). Nutrition should be oral, rich in proteins, and accompanied by muscle training adapted to the patient's condition. Psychological and societal counseling is often useful; nausea or other problems such as gastrointestinal dysmotility or metabolic derangements must be tackled. Chemotherapy-induced peripheral neuropathy frequently worsens quality of life and has no established prevention strategy (notwithstanding current interest in cryotherapy and compression therapy) and thus requires careful assessment of patient predisposition to develop it with the consideration of feasible dose and treatment alternatives. When painful, duloxetine helps. Nonpharmacologic strategies, including acupuncture, physical exercise, cryotherapy/compression, and scrambler therapy, are promising but require large phase III trials to become the accepted standard. Personalization of chemotherapy, dependent on realistic goals, is key.

Physical activity is associated with less comorbidity, better treatment tolerance and improved response in patients with multiple myeloma undergoing stem cell transplantation.

OBJECTIVES: Multiple myeloma (MM) is the second most common hematological malignancy. Progression free survival (PFS) and overall survival (OS) have substantially improved, nonetheless MM usually remains incurable. Patients with active disease may be affected by numerous comorbidities, including fatigue, depression and osteolytic lesions, which influence their quality of life (QoL). Albeit, it is known that exercising is beneficial for patients' QoL, few clinical trials are available in patients with MM. We therefore aimed to compare comorbidities and clinical outcome in physically active and inactive patients with MM. MATERIAL AND METHODS: We defined physical activity according to WHO criteria (150 min of moderate activity and two sessions of resistance training/week). We matched 53 physically active patients with 53 controls (for age, gender, cytogenetics, disease stage, and therapy) and compared the cohorts for incidence of comorbidities/MM symptoms (osteolytic lesions, anemia, infections, fatigue, depression, Revised-Myeloma Comorbidity Index [R-MCI]) and clinical outcome (treatment tolerance, responses to therapy, PFS and OS) in a retrospective audit. All patients were newly diagnosed with MM and received autologous stem cell transplantations (ASCT) between 2001 and 2017. RESULTS: Physically active patients showed superior outcomes in R-MCI (p = 0.0005), fatigue (p = 0.0063), treatment tolerance (p = 0.0258) and hospital stays (p = 0.0072). Furthermore, they showed better treatment responses (p = 0.0366), especially complete remission (CR; p = 0.0018) as well as better OS and PFS. CONCLUSION: Physical activity in patients with MM undergoing ASCT seemed associated with better overall clinical outcome. Randomized clinical trials are required to understand the benefits and devise strategies for improving exercising among patients with MM.

[Nutrition in Cancer: Effective in Prevention and Treatment?] / Ernährung bei Krebs: Geeignet zur Vorbeugung und Therapie?

Nutritional effects on cancer occurrence and on treatment outcome in cancer patients may depend on food preferences and on the quantity of foods supplied. However, it has been difficult to reliably show beneficial effects of specific dietary concepts on cancer incidence. On the other hand, obesity as a result of chronic overfeeding has been linked firmly to an increased risk of a number of cancers as well as on cancer recurrence after treatment. Metabolic consequences of obesity and other components of the metabolic syndrome may be responsible for inducing and/or promoting cancer growth and should be antagonized by regular moderate physical activity in healthy subjects and in cancer survivors. During cancer treatment and in patients with advanced disease, inadequate food intake and physical inactivity may lead to malnutrition, while recurrent and chronic systemic inflammatory reactions induce chronic catabolism with a preferential loss of muscle and cell mass, condition referred to as cachexia.