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Category Cachexia

Cancer Cachexia: Molecular Mechanisms and Therapeutic Strategies

Cancer cachexia (CC) is a feature of cancer-related muscle wasting characterised by reduced energy intake and heightened activation of skeletal muscle catabolic pathways. CC is particularly prevalent amongst older individuals and significantly contributes to increased morbidity and mortality, with approximately 20-30% of cancer patient deaths attributed to this condition. Effectively addressing cancer-associated wasting, which includes interconnected pathologies such as anorexia, cachexia, and sarcopenia, in affected older patients is thus paramount to preserving their independence, improving their quality of life, and enhancing their ability to endure and respond to cancer treatments. This review aims to investigate the molecular mechanisms underlying CC as well as the pharmacological and non-pharmacological strategies to alleviate it, with a particular focus on the unique needs of older demographics.

The Path to Holistic Multimodal Care for Cancer Cachexia Patients

Cancer cachexia (CC) is a pathophysiologically complex and multifactorial wasting disorder prevalent in cancer patients. Physical symptoms include fever, hyperalgesia, nausea, and oral mucositis. Patients often also present with exhaustion, anxiety, depression, and disorientation. Despite its high prevalence and detrimental impact on the quality of life of affected patients and family caregivers, no established standard care for CC management yet exists. In response to this unmet need, emerging research has highlighted the potential of holistic multimodal care - a comprehensive approach integrating medical, pharmacological, nutritional, and rehabilitative interventions as well as psychological, emotional, and social well-being issues in line with the specific needs of patients and family caregivers. This review aims to provide an overview of existing knowledge on holistic multimodal care for CC.

Cancer cachexia risk score for digestive tract cancer: a review

Cancer cachexia, a form of malnutrition, can be viewed as a determinant of prognosis. However, there are no effective therapies or treatments for this condition. Hence, the identification of high-risk patients remains crucial for the assessment and management of cancer cachexia. The cancer cachexia risk score was validated to show good performance; it successfully identified at-risk digestive tract cancer patients before abdominal surgery. This risk score can provide vital help to clinicians in their cancer cachexia screening process, allowing them to understand a patient’s prognosis and build better-informed decisions for abdominal surgery. This review by Tan S et al. aimed to discuss the cancer cachexia risk score in relation to digestive tract cancer patients, to understand whether survival risks can be identified prior to surgery.

Nutrition in nasopharyngeal carcinoma: a review

Locoregionally advanced nasopharyngeal carcinoma is a type of head and neck cancer. Induction chemotherapy and concurrent chemoradiotherapy is the most common standard of care. However, due to the toxicity and intensity of these treatments, patients’ nutritional statuses are often negatively impacted. Weight loss and malnutrition are often overlooked in head and neck cancer patients, despite the fact that around half of all head and neck cancer patients suffer from malnutrition. This negatively affects their quality of life, affecting physical functioning, nausea and vomiting and can even affect emotional and cognitive functioning. This study supports the need to monitor patients’ nutritional statuses during the later phase of treatments and work on nutritional interventions. This review by Miao J et al. aimed to explore the need for nutritional interventions in nasopharyngeal carcinoma.

Immunology and cachexia: a review

Many types of conditions and diseases are associated with wasting syndromes such as cachexia. However, despite its prevalence, there is limited knowledge regarding the diagnosis and treatment of cachexia due to our lack of understanding of the causative molecular mechanisms. Cachexia must be viewed through an immunological context to understand its full consequences on patient prognosis. For example, it is known that cytokines such as tumour necrosis factor, IL-1β, IL-6 and IFNγ are consistently upregulated in cases of cachexia in both immune and non-immune cells. This appears to lead to the changes in transcriptional regulation, inducing catabolic pathways in muscles and adipose tissue. Yet, despite this understanding, targeting such cytokines has not shown successful in clinical settings. Further research has also been done to identify the involvement of immune cells such as macrophages, neutrophils, myeloid-derived suppressor cells and T cells in cachexia. Yet, their full involvement in the condition is not yet understood. Hence, many questions remain about this interplay between cachexia and immune system. It is vital to discover the common and unique properties of cancer cachexia and infection-associated cachexia to develop effective therapeutic strategies for cachexia. This review by Baazim H et al. aimed to highlight the relationship between the immune system and cachexia, as well as our current lack of knowledge surrounding this syndrome.

Cachexia staging score predicts survival: a review

The guidelines most commonly used to diagnose cachexia are the European Palliative Care Research Collaborative (EPCRC) guidelines. Here, cachexia is classified according to weight loss. However, for patients in palliative care with advanced cancer, there are often cases of oedema and ascites. This hampers the ability to detect weight loss, affecting the likelihood to be diagnosed with cachexia. Therefore, this study wished to examine the validity of diagnosing cachexia based upon other items. Alongside weight loss, this includes factors such as fatigue, decreasing muscle mass in the mid-upper arm, abnormal levels of white blood cells, reduced food intake and others. This study validated the CSS, Cachexia Staging Score, which demonstrated that patients without cachexia had a higher survival rate, and that the risk of mortality was higher with more severe cachexia. They also validated that cachexia prevalence was not significantly different compared to previous studies. Hence, such a multidimensional assessment helps to evaluate disorders including cachexia. This review by Ueshima J et al. aimed to validate the Cachexia Staging Score for patients with advanced cancer who are under palliative care.

GDF15 and muscle function in cancer cachexia: a review

In this study, TOV21G cancer cachexia mouse models were used to demonstrate impaired muscle function and performance which is seen in cachexia patients. With growth differentiation factor 15, GDF15, neutralization, the mice were seen to exhibit restored muscle function and performance. GDF15 is a stress-responsive cytokine which is secreted by many cells, including tumour cells and damaged cells. GDF15 functions by activating glial cell line-derived neurotrophic factor, GDNF, receptor GFRAL. This is expressed in the hindbrain and leads to reducing food intake and weight loss. This is relevant to cachexia patients, and patients with chronic diseases such as heart failure, as their GDF15 levels are significantly higher than that of healthy people. In this study, the mice were treated with mAB2, an anti-GDF15 antibody. They demonstrated weight gain in terms of fat mass and lean mass, improved muscle function and physical performance. Hence, it is thought that GDF15-related therapy may be effective for patients with cachexia. However, symptoms of cachexia such as fatigue do not appear to be related to GDF15 levels, so further exploration is necessary. This review by Kim-Muller JY et al. aimed to explore how GDF15 levels are related to weight loss and highlight how GDF15 neutralization could be an option for treating cachexia.

Progressive development of cachexia in different organ systems: a review

Cachexia is defined as an unintentional loss of 5% or more of body weight, a complication which often negatively affects survival rates. Cachexia is caused by circulating cytokines in the body which are produced by cancer cells and immune cells, causing behavioural and systemic changes. However, how cachexia impacts different tissues is unknown; there is a large amount of information missing, as it is likely there are more tissues in the body affected by cachexia than we know. There are known differences in tissue wasting: in the heart, atrophy is seen after 2 weeks of tumour implantation, but very little wasting in any other tissues at this point. The heart and skeletal muscles are the tissues affected first and foremost. This study also discovered that tissues such as the brain which do not undergo wasting, experience functional derangement due to transcriptional changes such as the upregulation of angiotensin-converting enzyme (ACE). Using lisinopril, a drug which inhibits ACE, muscle force can be improved, even if wasting is not prevented. However, this study was completed on mice with no T lymphocytes - this is a limitation as T cells have been seen to induce or protect from cachexia, so more studies are needed to understand the involvement of T cells in cachexia. This review by Graca FA et al. aimed to summarise how cachexia affects different tissue systems in the body.

2022: A year of research in JCSM

The Journal of Cachexia, Sarcopenia and Muscle mainly publishes research on cachexia, sarcopenia and muscle wasting disorders, but also includes papers on cancer, heart failure, ageing and many other conditions. Before November 2022, there were seen to be 775,000 downloads of the articles within the journal, with the top three countries downloading articles being China, the US and Japan. The most downloaded and cited article is entitled, Cachexia as a major underestimated and unmet medical need: facts and numbers. This review by Frohlich A et al. aimed to review the successes of the Journal of Cachexia, Sarcopenia and Muscle in 2022.

The inflammatory response in muscle homeostasis and plasticity: a review

Around half of a healthy person’s body weight is made up of skeletal muscle. This type of muscle is able to demonstrate high levels of plasticity. In muscle homeostasis, as well as repair processes, there are satellite cells and inflammatory cells which play key roles. However, if the recruitment of inflammatory cells is not carefully controlled, muscle atrophy and fibrosis may occur, leading to muscle function impairment. Hence, the inflammation occurring in muscle repair as a double-edged sword. This is because inflammatory mediators play a role in fighting pathogens as well as in the formation of mature myofibres, but may also cause damage to the muscle. For example, inflammation is also associated with cachexia - specifically, there is a correlation between cachexia and high levels of circulating cytokines. This paper also ends with a summary of approaches to treating muscle wasting disorders, such as cachexia, discussing exercise, nutritional interventions and targeting inflammatory pathways. This review by Bouredji Z et al. aimed to discuss inflammation in muscle homeostasis and repair, as well as some management approaches to muscle wasting disorders such as cachexia.

Review of the endocrine organ-like tumour hypothesis of cancer cachexia in pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma, PDAC, is one of the most fatal types of solid tumours. It is also linked to a high prevalence of cachexia, with around 80% of PDAC patients exhibiting cachexia. There is one hypothesis, the endocrine organ–like tumour hypothesis, which aims to explain the reasons behind cancer cachexia occurring during pancreatic ductal adenocarcinoma. Some of the reasons include metabolites, epigenetic changes, hormonal disturbance and genetic instability may be behind the development of cancer cachexia. Generally, the belief is held that metabolic disruption is the process behind cachexia development, but it is also believed there is not one single factor that triggers it. This review by Yu Y et al aimed to synthesise an understanding of cancer cachexia development and the response of cachexia to current available treatments.

Malnutrition risk and frailty in head and neck cancer patients: a review

For patients with head and neck cancer, malnutrition and frailty are linked with adverse treatment outcomes, higher mortality rates, complications post-surgery and generally lower quality of life. However, the relationship between malnutrition and frailty is not fully known. It is, however, clear that these two conditions often coexist, suggesting they may share similar risk factors. In this study on 197 patients, it was found that the risk of malnutrition is strongly positively associated with frailty. However, some other interesting factors were discovered. Alcohol consumption was shown to present a greater risk of developing malnutrition, but on the other hand, alcohol consumption seems protective for being frail. Overall, these conditions often coexist but do not always fully overlap: screening for both conditions is therefore recommended. This review by Dewansingh P et al aimed to understand the relationship between the risk of malnutrition and frailty in patients with head and neck cancer.

Cachexia staging score and cancer survival: a review

Cancer cachexia has no simple criteria to distinguish its severity in patients. Diagnostic criteria generally includes observing factors such as weight loss, fatigue, abnormal levels of albumin, reduced food intake and others. However, this study explored the cachexia staging score, a method of diagnosing cancer cachexia severity. This score explores strength, walking, rising from a chair, climbing up stairs and how often the patients fall. This allows clinicians to understand the patient’s muscle function. In this study, the cachexia staging score was testing in patients with advanced cancer who are receiving palliative care, to assess its usefulness in these patients. Here, the cachexia staging score was excellent at predicting life expectancy in the patients with advancing cancer receiving palliative care, and was able to classify patients according to their different stages of cachexia. This review by Ueshima J et al. aimed to assess whether the cachexia staging score could be applied to patients with advanced cancer under palliative care.

Hand grip strength-based cachexia index: a review

Cancer cachexia can be mainly categorised with the occurrence of muscle loss, malnutrition and systemic inflammation. Its prognosis can be assessed through the cachexia index, but the use of this index is limited due to it being a complicated procedure with high testing costs. This study explored using a hand grip strength-based cachexia index, testing it with 14, 682 cancer patients. A low hand grip strength index score was found to be associated with high systemic inflammation, high levels of malnutrition and co-morbidities, implying that this index may be associated with disease progression. Overall, using the hand grip strength index for cachexia reflects the muscular and inflammatory conditions of cachexia in one assessment, rather than using multiple such as serum albumin testing, in a simple, non-invasive measure. Furthermore, there is a potential that hand grip strength can provide information about the prognosis of other malignancies. This review by Xie H et al. aimed to compare the hand grip strength-based cachexia index to the original cachexia index to understand its benefits.

Sarcopenia and cachexia prevalence in older patients with colorectal cancer

Colorectal cancer (CRC) incidence has been shown to increase with age, an association which is clinically significant in the context of global ageing populations. Frailty, defined as increased vulnerability to stressors like surgery, is a marker associated with poor outcomes in patients with CRC. Sarcopenia, characterised by an age- and disease-related loss in muscle function and mass, has been identified as a major contributor to frailty. Patients with cancer also commonly experience cancer cachexia, i.e., loss of fat and muscle mass. This syndrome has also been associated with poorer survival rates for cancer patients. As such, both sarcopenia and cachexia constitute potentially modifiable risk factors of negative surgical outcomes. This study aimed to examine the prevalence of preoperative sarcopenia and cachexia in a group of older (≥65 years) vulnerable patients undergoing resection for localized CRC.

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