Cancer Cachexia: Traditional Therapies and Novel Molecular Mechanism-Based Approaches to Treatment

Abstract

Opinion statementThe complex syndrome of cancer cachexia (CC) that occurs in 50% to 80% cancer patients has been identified as an independent predictor of shorter survival and increased risk of treatment failure and toxicity, contributing to the mortality and morbidity in this population. CC is a pathological state including a symptom cluster of loss of muscle (skeletal and visceral) and fat, manifested in the cardinal feature of emaciation, weakness affecting functional status, impaired immune system, and metabolic dysfunction. The most prominent feature of CC is its non-responsiveness to traditional treatment approaches; randomized clinical trials with appetite stimulants, 5-HT3 antagonists, nutrient supplementation, and Cox-2 inhibitors all have failed to demonstrate success in reversing the metabolic abnormalities seen in CC. Interventions based on a clear understanding of the mechanism of CC, using validated markers relevant to the underlying metabolic abnormalities implicated in CC are much needed. Although the etiopathogenesis of CC is poorly understood, studies have proposed that NFkB is upregulated in CC, modulating immune and inflammatory responses induce the cellular breakdown of muscle, resulting in sarcopenia. Several recent laboratory studies have shown that n-3 fatty acid may attenuate protein degradation, potentially by preventing NFkB accumulation in the nucleus, preventing the degradation of muscle proteins. However, clinical trials to date have produced mixed results potentially attributed to timing of interventions (end stage) and utilizing outcome markers such as weight which is confounded by hydration, cytotoxic therapies, and serum cytokines. We propose that selective targeting of proteasome activity with a standardized dose of omega-3-acid ethyl esters, administered to cancer patients diagnosed with early stage CC, in addition to a standard intervention with nutritionally adequate diet and appetite stimulants, will alter metabolic abnormalities by downregulating NFkB, preventing the breakdown of myofibrillar proteins and resulting in increasing serum protein markers, lean body mass, and functional status.

Anti-diabetic Action of 7-<i>O</i>-Galloyl-d-sedoheptulose, a Polyphenol from Corni Fructus, through Ameliorating Inflammation and Inflammation-Related Oxidative Stress in the Pancreas of Type 2 Diabetics

“…These results showing the amelioration of pro-inflammatory markers, i.e., NF-κB p65, COX-2, and TGF-β 1 protein expressions, are in parallel with a recent report showing enhanced COX-2 protein expression due to NF-κB activation. 40) These results also confirm our previous work 18) that the suppression of inflammation by the modulation of NF-κB p65 and COX-2 is a critical factor contributing to an anti-diabetic action.…”

Palliative Nutritional Care for Cancer Patients

“…15,16 Malnutrition has been documented globally among 30-80% of cancer patients. [17][18][19] The consequences of malnutrition may include an increased risk of morbidity, decreased response and tolerance to treatment, a decline in quality of life, higher health-care costs and reduced survival. [20][21][22] Reported dietary intake of advanced cancer patients suggests that their total calorie intake is 1610+686 kcal/d which is 4-53 kcal/kg body weight/d.…”

“…23 Kumar et al also documented a calorie deficit of approximately 250-400 kcal/d among weight losing cancer patients. 18 Anemia is commonly reported in advanced cancer patients, leading to altered energy homeostasis and reduction in physical activity. 24 Advanced cancer patients have deficiency of essential micronutrients like zinc, selenium, vitamin C and vitamin E, which support body's immune response.…”

Nutritional influences on age-related skeletal muscle loss

“…Recent human studies have found that supplementation with long chain n-3 PUFA increases rates of protein synthesis and augments the muscle protein anabolic response, and may also attenuate acute muscle loss (cachexia) (236)(237)(238)(239)(240)(241) . One small observational study found a negative association with appendicular lean mass and saturated fat, and a comprehensive study of dietary fat composition and muscle mass found positive associations with the PUFA:SFA ratio and negative associations with saturated and trans fatty acids (15,81) .…”