Cancer cachexia is a multi-factorial syndrome, which negatively affects quality of life, responsiveness to chemotherapy, and survival in advanced cancer patients. Our understanding of cachexia has grown greatly in recent years and the roles of many tumor-derived and host-derived compounds have been elucidated as mediators of cancer cachexia. However, cancer cachexia remains an unmet medical need and attempts towards a standard treatment guideline have been unsuccessful. This review covers the diagnosis, assessment, and treatment of cancer cachexia; the elements impeding the formulation of a standard management guideline; and future directions of research for the improvement and standardization of current treatment procedures.

Cancer cachexia: Diagnosis, assessment, and treatment.

Protein-calorie malnutrition is very frequent in cancer patients and is associated with an increase in morbidity and mortality. Recently, the Global Leadership Initiative on Malnutrition (GLIM) criteria were proposed to standardize the diagnosis of malnutrition. Nevertheless, these criteria were not validated in prospective studies. Our objective is to determine the prevalence of malnutrition in cancer inpatients using different diagnostic classifications, including GLIM criteria, and to establish their association with length of stay and mortality. Hence, we designed a prospective study. Within the first 24 hours of admission to the Inpatient Oncology Unit, subjective global assessment (SGA) was carried out, and anthropometric data (body mass index (BMI), mid-arm circumference (MAC), arm muscle circumference (AMC), fat-free mass index (FFMI)) and hand grip strength (HGS) were obtained to assess the reduction of muscle mass according to GLIM criteria. Length of stay, biomarkers (albumin, prealbumin, C-reactive protein (CRP)), and in-hospital and six-month mortality were evaluated. Regarding the 282 patients evaluated, their mean age was 60.4 ± 12.6 years, 55.7% of them were male, and 92.9% had an advanced-stage tumor (17.7% stage III, 75.2% stage IV). According to SGA, 81.6% of the patients suffered from malnutrition (25.5% moderate malnutrition, and 56.1% severe malnutrition), and, based on GLIM criteria, malnutrition rate was between 72.2 and 80.0% depending on the used tool. Malnourished patients (regardless of the tool used) showed significantly worse values concerning BMI, length of stay, and levels of CRP/albumin, albumin, and prealbumin than normally nourished patients. In logistic regression, adjusted for confounding variables, the odds ratio of death at six months was significantly associated with malnutrition by SGA (odds ratio 2.73, confidence interval (CI) 1.35–5.52, p = 0.002), and by GLIM criteria calculating muscle mass with HGS (odds ratio 2.72, CI 1.37–5.40, p = 0.004) and FFMI (odds ratio 1.87, CI 1.01–3.48, p = 0.047), but not by MAC or AMC. The prevalence of malnutrition in advanced-stage cancer inpatients is very high. SGA and GLIM criteria, especially with HGS, are useful tools to diagnose malnutrition and have a similar predictive value regarding six-month mortality in cancer inpatients.

https://www.mdpi.com/2072-6643/11/9/2043/pdf

GLIM Criteria Using Hand Grip Strength Adequately Predict Six-Month Mortality in Cancer Inpatients.

Many cancer patients suffer from severe fatigue when treated with chemotherapy or radiotherapy; however, the etiology and pathogenesis of this kind of fatigue remains unknown. Fatigue is associated with cancer itself, as well as adjuvant therapies and can persist for a long time. Cancer patients present a high degree of fatigue, which dramatically affects the quality of their everyday life. There are various clinical research studies and reviews that aimed to explore the mechanisms of cancer-related fatigue (CRF). However, there are certain limitations in these studies: For example, some studies have only blood biochemical texts without histopathological examination, and there has been insufficient systemic evaluation of the dynamic changes in relevant indexes. Thus, we present this narrative review to summarize previous studies on CRF and explore promising research directions. Plenty of evidence suggests a possible association between CRF and physiological dysfunction, including skeletal muscular and mitochondrial dysfunction, peripheral immune activation and inflammation dysfunction, as well as central nervous system (CNS) disorder. Mitochondrial DNA (mtDNA), mitochondrial structure, oxidative pressure, and some active factors such as ATP play significant roles that lead to the induction of CRF. Meanwhile, several pro-inflammatory and anti-inflammatory cytokines in the peripheral system, even in the CNS, significantly contribute to the occurrence of CRF. Moreover, CNS function disorders, such as neuropeptide, neurotransmitter, and hypothalamic-pituitary-adrenal (HPA) axis dysfunction, tend to amplify the sense of fatigue in cancer patients through various signaling pathways. There have been few accurate animal models established to further explore the molecular mechanisms of CRF due to different types of cancer, adjuvant therapy schedules, living environments, and physical status. It is imperative to develop appropriate animal models that can mimic human CRF and to explore additional mechanisms using histopathological and biochemical methods. Therefore, the main purpose of this review is to analyze the possible pathogenesis of CRF and recommend future research that will clarify CRF pathogenesis and facilitate the formulation of new treatment options.

https://www.mdpi.com/2073-4409/8/7/738/pdf

A Narrative Review of Cancer-Related Fatigue (CRF) and Its Possible Pathogenesis.

The recent publication of the revised Consensus on definition and diagnosis of sarcopenia (EWGSOP2) and the Global Leadership Initiative on Malnutrition (GLIM) criteria changed the approach to research on sarcopenia and malnutrition. Whilst sarcopenia is a nutrition-related disease, malnutrition and cachexia are nutritional disorders sharing the common feature of low fat-free mass. However, they have differential characteristics and etiologies, as well as specific therapeutic approaches. Applying the current definitions in clinical practice is still a challenge for health professionals and the potential for misdiagnosis is high. This is of special concern in the subgroup of older people with cancer, in which sarcopenia, malnutrition, and cancer cachexia are highly prevalent and can overlap or occur separately. The purpose of this review is to provide an updated overview of the latest research and consensus definitions of sarcopenia, malnutrition, and cachexia and to discuss their implications for clinical practice in older patients with cancer. The overall aim is to improve the quality of nutritional care in light of the latest findings.

Sarcopenia, Malnutrition, and Cachexia: Adapting Definitions and Terminology of Nutritional Disorders in Older People with Cancer.

BACKGROUND Handgrip strength (HGS) is associated with poor clinical outcomes, including all-cause, non-cardiovascular, and cardiovascular mortalities. The published cut-off points for HGS are mostly based on community populations from Western countries, lacking information on cancer patients from China. The objective of this study was to establish sex-specific cut-off points for Chinese cancer patients and investigate the effect of low HGS on cancer mortality. METHODS We did a retrospective cohort study of patients who were diagnosed with malignant cancer from June 2012 to December 2018. HGS was measured using a hand dynamometer in 8257 cancer patients. Optimal stratification was used to solve threshold points. The hazard ratio (HR) of all cancer mortality and cancer-specific mortality was calculated using Cox proportional hazard regression models. RESULTS Among all participants, there were 3902 (47.3%) women and 4355 (52.7%) men. The median age was 58 years old. The cut-off points of HGS to best classify patients with respect to time to mortality were <16.1 kg for women and <22 kg for men. Low HGS was associated with overall cancer mortality in both women and men [HR = 1.339, 95% confidence interval (CI) = 1.170-1.531, P < 0.001; HR = 1.346, 95% CI = 1.176-1.540, P < 0.001, respectively]. For specific cancer types, low HGS was associated with breast cancer (HR = 1.593, 95% CI = 1.230-2.063, P < 0.001) in women, and lung cancer (HR = 1.369, 95% CI = 1.005-1.866, P = 0.047) and colorectal cancer (HR = 1.399, 95% CI = 1.007-1.944, P = 0.045) in men. CONCLUSIONS On the basis of our sex-specific cut-off points, low HGS was strongly associated with cancer mortalities. These results indicate the usefulness of HGS measurement in routine clinical practice for improving patient assessments, cancer prognosis, and intervention.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/jcsm.12614

Associations of low handgrip strength with cancer mortality: a multicentre observational study

Objective This study aimed to provide evidence-based results on differences in overall survival (OS) rate to guide the diagnosis of cancer cachexia. Design Data collection and clinical assessment was performed every 3 months (5 visits): baseline data, muscle strength, nutritional and psychosocial status. 2 definitions on cachexia using different diagnostic criteria were applied for the same patient population. Fearon et al's definition is based on weight loss, body mass index (BMI) and sarcopenia. Evans et al nuances the contribution of sarcopenia and attaches additional attention to abnormal biochemistry parameters, fatigue and anorexia. The mean OS rates were compared between patients with and without cachexia for both definitions. Results Based on the population of 167 patients who enrolled, 70% developed cachexia according to Fearon et al's definition and 40% according to Evans et al's definition. The OS in the cachectic population is 0.97 and 0.55 years, respectively. The difference in OS between pat...

https://bmjopengastro.bmj.com/content/bmjgast/3/1/e000097.full.pdf

Cachexia in cancer: what is in the definition?

We report the case of an 83-year-old woman that presented with progressive dyspnoea due to an intraluminal right atrial metastasis of an endometrial carcinoma that had been diagnosed 4 years earlier. Treatment up to that point consisted of an hysterectomy and resection and radiation of local recurrences. Follow-up had been interpreted as negative, despite a PET-CT 8 months before presentation which had shown increased FDG uptake in the right atrium, but was unfortunately considered benign. After confirmation of metastasis, first-line chemotherapy was started. However, due to poor tolerance and rapid symptom progression, chemotherapy had to be stopped early. She died 2 months later. Cardiac metastasis in endometrial carcinoma is rare. However, the incidence is increasing simultaneously with prolonged cancer survival. Because advances in systemic and radiotherapy now allow curative treatment, more focus should be put on early detection, for example by PET-CT. This way aggressive combined therapy can be started before the burden of cardiac metastasis does not allow it any longer.

Annelies Troch

Papers

Cachexia in cancer: what is in the definition?

Late overlooked intraluminal right atrial metastasis in endometrial carcinoma.