Vera C. Mazurak

Understanding and managing cancer cachexia

Mrs MJ is a 56-year-old architect with a husband and two children. You performed a mastectomy and axillary dissection on her after neoadjuvant chemotherapy for locally advanced breast cancer 2 years ago. Unfortunately, she developed widespread disease with metastases to liver, lung, and bone. After several more rounds of chemotherapy, she is currently on antiestrogen therapy. Her disease appears stable. You have continued to follow her and she comes to see you for her routine visit. You notice that she is much thinner than you remember, but otherwise looks well. You ask her about her weight loss. She says: “I don’t really know what it is! I can eat, my bowels are working, but I simply don’t want to. I force myself to swallow food, but I keep losing weight anyway.” On clinical examination, you notice her muscle wasting and recognize the signs of cancer cachexia. You want to know more about how to manage this phenomenon.

Supplementation with fish oil increases first‐line chemotherapy efficacy in patients with advanced nonsmall cell lung cancer

Palliative chemotherapy is aimed at increasing survival and palliating symptoms. However, the response rate to first‐line chemotherapy in patients with nonsmall cell lung cancer (NSCLC) is less than 30%. Experimental studies have shown that supplementation with fish oil (FO) can increase chemotherapy efficacy without negatively affecting nontarget tissue. This study evaluated whether the combination of FO and chemotherapy (carboplatin with vinorelbine or gemcitabine) provided a benefit over standard of care (SOC) on response rate and clinical benefit from chemotherapy in patients with advanced NSCLC.

Nutritional intervention with fish oil provides a benefit over standard of care for weight and skeletal muscle mass in patients with nonsmall cell lung cancer receiving chemotherapy

Involuntary weight loss is a major contributor to mortality and morbidity in patients with advanced cancer. Nutritional intervention with fish oil (FO)‐derived eicosapentaenoic acid (EPA) may prevent deterioration of body composition. This study compared intervention with FO with standard of care (SOC; no intervention) with regard to weight, skeletal muscle, and adipose tissue in newly referred patients with nonsmall cell lung cancer from the time of initiation to completion of first‐line chemotherapy.

Measurement of skeletal muscle radiation attenuation and basis of its biological variation.

Skeletal muscle contains intramyocellular lipid droplets within the cytoplasm of myocytes as well as intermuscular adipocytes. These depots exhibit physiological and pathological variation which has been revealed with the advent of diagnostic imaging approaches: magnetic resonance (MR) imaging, MR spectroscopy and computed tomography (CT). CT uses computer‐processed X‐rays and is now being applied in muscle physiology research. The purpose of this review is to present CT methodologies and summarize factors that influence muscle radiation attenuation, a parameter which is inversely related to muscle fat content. Pre‐defined radiation attenuation ranges are used to demarcate intermuscular adipose tissue [from −190 to −30 Hounsfield units (HU)] and muscle (−29 HU to +150 HU). Within the latter range, the mean muscle radiation attenuation [muscle (radio) density] is reported. Inconsistent criteria for the upper and lower HU cut‐offs used to characterize muscle attenuation limit comparisons between investigations. This area of research would benefit from standardized criteria for reporting muscle attenuation. Available evidence suggests that muscle attenuation is plastic with physiological variation induced by the process of ageing, as well as by aerobic training, which probably reflects accumulation of lipids to fuel aerobic work. Pathological variation in muscle attenuation reflects excess fat deposition in the tissue and is observed in people with obesity, diabetes type II, myositis, osteoarthritis, spinal stenosis and cancer. A poor prognosis and different types of morbidity are predicted by the presence of reduced mean muscle attenuation values in patients with these conditions; however, the biological features of muscle with these characteristics require further investigation.

Loss of adipose tissue and plasma phospholipids: relationship to survival in advanced cancer patients.

BACKGROUND & AIMS Extensive loss of adipose tissue is a key feature of cancer cachexia. Advanced cancer patients also exhibit low plasma phospholipids. It is not known whether these processes coincide across the cancer trajectory nor has their relationship with survival been defined. Changes in adipose tissue mass and plasma phospholipids were characterized within 500days prior to death and prognostic significance assessed. METHODS Adipose tissue rate of change was determined in a retrospective cohort of patients who died of colorectal and lung cancers (n=108) and who underwent >2 computed tomography scans in the last 500days of life. Plasma phospholipid fatty acids were measured prospectively in a similar cohort of patients with metastatic cancer (n=72). RESULTS Accelerated loss of adipose tissue begins at 7months from death reaching an average loss of 29% of total AT 2months from death. Plasma phospholipid fatty acids were 35% lower in patients closest to death versus those surviving >8months. Losses of phospholipid fatty acids and adipose tissue occur in tandem and are predictive of survival. CONCLUSIONS Depletion of plasma phospholipids likely indicates a deficit of essential fatty acids in the periphery which may contribute to loss of adipose tissue.

Inflammation, obesity, and fatty acid metabolism: influence of n-3 polyunsaturated fatty acids on factors contributing to metabolic syndrome

Metabolic syndrome (MetS) comprises an array of metabolic risk factors including abdominal obesity, dyslipidemia, hypertension, and glucose intolerance. Individuals with MetS are at elevated risk for diabetes and cardiovascular disease. Central to the etiology of MetS is an interrelated triad comprising inflammation, abdominal obesity, and aberrations in fatty acid metabolism, coupled with the more recently recognized changes in metabolism during the postprandial period. We review herein preliminary evidence regarding the role of dietary n-3 polyunsaturated fatty acids in modulating each of the components of the triad of adiposity, inflammation, and fatty acid metabolism, with particular attention to the role of the postprandial period as a contributor to the pathophysiology of MetS.

Influence of eicosapentaenoic acid supplementation on lean body mass in cancer cachexia

Cancer cachexia is characterised by a progressive loss of muscle, resulting in functional impairment and shorter survival. Eicosapentaenoic acid, an n-3 polyunsaturated fatty acid found in fish, has been studied for its role as an anti-cachexia therapy. Initial results of eicosapentaenoic supplementation in advanced cancer were promising with improvements in lean body mass (LBM), appetite and quality of life. However, subsequent larger phase III clinical trials reported minimal benefits of supplementation. Recently, several studies have used different study designs, which may provide insight on the effectiveness of eicosapentaenoic in cancer cachexia and also on potential sources of divergent results in previous trials. This review examines the potential benefit of eicosapentaenoic supplementation on LBM and discusses limitations with current studies to identify methods which may aid in progressing the research of future clinical trials.

Skeletal Muscle Depletion Is Associated with Reduced Plasma (n-3) Fatty Acids in Non-Small Cell Lung Cancer Patients

Upwards of 50% of newly diagnosed advanced lung cancer patients have severe muscle wasting (sarcopenia). Supplementation with eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in advanced cancer has been shown to attenuate lean tissue wasting. However, the relationship between muscle mass and plasma (n-3) fatty acids in the absence of supplementation is unclear. We aimed to determine how plasma phospholipid (n-3) fatty acids relate to sarcopenia and change in muscle mass in non-small cell lung cancer patients receiving chemotherapy. Computed tomography images were used to measure muscle mass. Patients were classified as sarcopenic or nonsarcopenic based on sex-specific cutpoints. Change in muscle mass during chemotherapy (2.5 mo) was calculated and patients were divided into quartiles based on the rate of muscle loss or gain. Patients with sarcopenia had lower plasma EPA (16.7 +/- 2.1 micromol/L vs. 31.6 +/- 4.4 micromol/L; P = 0.001), DHA (36.6 +/- 4.0 micromol/L vs. 55.3 +/- 4.0 micromol/L; P = 0.003), and Sigma(n-3) fatty acids (63.6 +/- 5.6 micromol/L vs. 95.0 +/- 7.7 micromol/L; P = 0.002) than nonsarcopenic patients. Patients with maximal muscle loss (mean - 3.5 kg) had lower plasma EPA (12.2 +/- 3.3 micromol/L vs. 35.0 +/- 7.1 micromol/L; P = 0.03), DHA (26.9 +/- 8.7 micromol/L vs. 59.6 +/- 5.3 micromol/L; P = 0.01), and Sigma(n-3) fatty acids (57.8 +/- 13.5 micromol/L vs. 104.6 +/- 11.1 micromol/L; P = 0.005) compared with patients who were gaining muscle (mean +1 kg). Plasma (n-3) fatty acids are depleted in cancer patients with sarcopenia, which may contribute to accelerated rates of muscle loss.

Computed tomography-defined muscle and fat wasting are associated with cancer clinical outcomes

Cancer cachexia (i.e., skeletal muscle wasting with or without fat loss) relates to several adverse outcomes. Computed tomography (CT) cross-sectional images serve as an efficient biomarker for assessment of cachexia in cancer patients. We systematically reviewed literature reporting quantitative evaluation of the cross sectional area of the main tissues implicated in cancer cachexia, muscle and visceral, subcutaneous and inter-muscular fat in CT scans at the 3rd lumbar vertebra. Our main goal was to summarize CT-defined variation of muscle and fat and the relationship between these features and cancer outcomes such as chemotherapy toxicity, post-surgery complications and survival.

n -3 Polyunsaturated fatty acids throughout the cancer trajectory: influence on disease incidence, progression, response to therapy and cancer-associated cachexia

Evidence from epidemiological studies suggests that diets rich in n-3 PUFA may be associated with reduced cancer risk. These observations have formed the rationale for exploring the mechanisms by which n-3 PUFA may be chemoprotective and have resulted in significant advances in our mechanistic understanding of n-3 PUFA action on tumour growth. Various interrelated and integrated mechanisms may be at work by which n-3 PUFA influence cancer at all stages of initiation, promotion, progression, and neoplastic transformation. More recently, experimental studies have reported enhanced tumour cell death with chemotherapy when fish oil is provided while toxic side effects to the host are reduced. Furthermore, cancer-associated wasting has been shown to be attenuated by fish oil supplementation. Clinical evidence suggests that the n-3 PUFA status of newly diagnosed cancer patients and individuals undergoing chemotherapy is low. Therefore, both the disease itself and therapeutic treatments may be contributing factors in the decline of n-3 PUFA status. Dietary supplementation to maintain and replenish n-3 PUFA status at key points in the cancer disease trajectory may provide additional health benefits and an enhanced quality of life. The present review will focus on and critically examine current research efforts related to the putative anti-cancer effects of n-3 PUFA and their suggested ability to palliate cancer-associated and treatment-associated symptoms.