Mediators and clinical treatment for cancer cachexia: a systematic review

Abstract

Background Cachexia, a complex multi-organ syndrome, shortens survival time of patients, particularly those with cancer. Many studies and clinical trials have been carried out to identify cachexia-inducing factors and potential treatments for cancer cachexia over the last 20 years. Of these factors, some are promising targets for treatment in humans, owing to their expression profiles in patients. Several clinical interventions, which act on either cachexia-inducing factors or tissues affected by cachexia, have been developed. Some have had positive effects in the treatment of cancer cachexia; however, the question remains whether these interventions reverse cancer cachexia and could be used as standard interventions for disease treatment. The aim of this review is to understand the basic mechanisms and factors that induce cancer cachexia and their efficacies in clinical trials, providing a better outlook for future studies of cancer cachexia. Methods A systematic search was performed using PubMed and ClinicalTrials.gov databases for cachexia mediators and clinical trials. Results Of all databases and peer-reviewed facts considered, 256 papers and 35 clinical trials were included in this systematic review. Twenty-one mediators were identified, and 17 clinical interventions were reported in these studies. Outcomes of these clinical trials were assessed on changes in overall survival, body weight, lean body mass, appetite, muscle strength, muscle function, quality of life, and cytokine levels. Conclusions There is no current standard or successful intervention for treating cancer cachexia. Further research is needed to improve our understanding of initiators of cachexia to achieve successful outcomes in cachexia clinical trials.

Cancer cachexia as a multiorgan failure: Reconstruction of the crime scene

“…The inflammatory mediators can be released both from tumor and host cells and are frequently elevated in cancer cachexia. Among them, IL-6, TNF-α, IL-1β, CRP, and albumin are the most investigated, but the correlation between them and cancer cachexia is elusive in humans ( Cao et al, 2021 ). The Glasgow Prognostic Score, an inflammation-based cancer-prognostic marker composed of serum elevation of CRP and decrease in albumin concentration, predicts patients with systemic inflammation as part of cancer cachexia and has been shown to have independent prognostic value ( Laird et al, 2013 ).…”

“…Other factors related to the immune system have been proposed as biomarkers such as the neutrophil-to-lymphocyte ratio, which is a prognostic indicator in cancer, and has been recently associated with weight loss and cachexia in a retrospective study in advanced colon, lung, and prostate cancer patients ( Barker et al, 2020 ). Beside inflammatory factors, several other circulating proteins have been linked to cachexia development and thus proposed as potential biomarkers: ZAG is a lipid mobilizing factor promoting WAT browning and lipolysis; Activin A, Myostatin, and GDF15 are TGFβ-family members involved in skeletal muscle atrophy (Activin A and Myostatin) and anorexia and lipolysis (GDF15); PTHrP induces WAT browning and correlates with lower lean body mass in lung and colorectal cancer patients; Angiotensin II induces muscle wasting and is upregulated in cancer patients in both pre-cachexia and cachexia conditions; LPS-binding protein is a marker of gut barrier dysfunction and shows interesting prognostic value for cachexia development and overall survival in patients; Lipocalin 2 regulates food intake and correlates with neutrophil expansion, muscle wasting and survival in pancreatic cancer patients; INSL3 promotes anorexia and its plasma levels correlate with anorexia severity in pancreatic cancer patients ( Sanders, Russell and Tisdale, 2005 ; Fearon, Glass and Guttridge, 2012 ; Kir et al, 2014 ; Ebadi and Mazurak, 2015 ; Loumaye et al, 2017 ; Loumaye and Thissen, 2017 ; Bindels et al, 2018 ; Olson, et al, 2021a ; Cao et al, 2021 ; Sohail Ahmed et al, 2021 ; Yeom et al, 2021 ; Talbert and Guttridge, 2022 ).…”

“…The inflammatory mediators can be released both from tumor and host cells and are frequently elevated in cancer cachexia. Among them, IL-6, TNF-α, IL-1β, CRP, and albumin are the most investigated, but the correlation between them and cancer cachexia is elusive in humans (Cao et al, 2021).…”

Targeting cancer cachexia: Molecular mechanisms and clinical study

“…Related treatments are under study currently. 13 , 25 , 31 , 72 , 74 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 …”

Decreased miR-497-5p Suppresses IL-6 Induced Atrophy in Muscle Cells

“…In addition, inhibition of IL-6 using soluble receptor antibody (sIL-6R) reduced muscle atrophy in a mouse model of intestinal cancer [ 27 ]. Although preclinical studies with IL-6 have shown some efficiency, there is no consensus about anti-IL 6 therapies in patients [ 28 ]. For example, cachectic patients with non-small cell lung cancer treated with an anti-IL-6 antibody ameliorated weight loss while decreasing anemia and anorexia [ 29 , 30 ].…”