Eicosapentaenoic Acid

Evid Based Integrative Med 2004; 1 (3): 189-194REVIEW ARTICLE 1176-2330/04/0003-0189/$31.00/0

© 2004 Adis Data Information BV. All rights reserved.

Eicosapentaenoic AcidPromising Nutritional Supplement in the Treatment of Cancer Cachexia inElderly Patients

Nagi B. Kumar and Kyle Dalton

H. Lee Moffitt Cancer Center & Research Institute, University of South Florida, Tampa, Florida, USA

Contents

Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189

1. Cancer Cachexia and Implications of Malnutrition in the Elderly Cancer Patient . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190

2. Cancer Cachexia: Potential Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190

3. Efficacy of Current Therapies for Cancer Cachexia in the Elderly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190

4. Eicosapentaenoic Acid as an Anticachectic Agent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191

5. Valid Intermediate Endpoint Biomarkers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191

5.1 Morphological Markers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192

5.2 Biochemical Markers of Protein Status (Serum Albumin and Transferrin) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192

5.3 Molecular Targets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192

5.4 Immune and Inflammatory Markers (Interleukin-6 and Tumour Necrosis Factor-α) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192

5.5 Functional Markers (Karnofsky Performance Score) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193

6. Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193

Cancer cachexia affects about half of all cancer patients and is associated with negative effects on functionalAbstractstatus and quality of life. This condition is also a major contributor to the morbidity and mortality of patients withadvanced malignancy. Although current strategies to improve appetite and lean body mass by administeringappetite stimulants, increasing physical activity and using nutritional supplementation have a scientific rationale,randomised studies have continued to demonstrate that a reduction in the loss of lean body mass is difficult toachieve unless the underlying metabolic abnormalities in cancer cachexia are corrected. Initial studies usinganimal models have demonstrated that nuclear factor-κ B (NF-κB) is upregulated in cancer cachexia, increasingproteolysis and breakdown of myofibrillar proteins, which results in sarcopenia. Laboratory studies have shownthat eicosapentaenoic acid (EPA), an n-3 fatty acid, has anticachectic effects and may attenuate proteindegradation by preventing NF-κB accumulation in the nucleus. EPA is associated with weight stabilisation, gainin lean body mass, and improvement in quality-of-life markers in weight-losing patients with advancedpancreatic cancer. Although animal studies have demonstrated the molecular basis of the effects of EPA, this hasnever been validated in human clinical trials. On the basis of the promising results of the laboratory and clinicalstudies, we hypothesise that selective targeting of proteasome activity by EPA (a polyunsaturated fatty acid)administered to cancer patients, including elderly patients, with cancer cachexia will alter metabolic abnormali-ties by downregulating NF-κB, modulating immune and inflammatory response and thus preventing thebreakdown of myofibrillar proteins. This will result in promotion of anabolism, reduction of weight loss andincrease in lean body mass and physical function, thus establishing a case for future, prospective clinical trials.

190 Kumar & Dalton

1. Cancer Cachexia and Implications of ia.[5,13-15] The transcription factor nuclear factor-κ B (NF-κB) is aMalnutrition in the Elderly Cancer Patient known regulator of the genes that encode cytokines, cytokine

receptors and cell-adhesion molecules that modulate immune andThe complex syndrome of cancer cachexia involves altered inflammatory responses. The cytokines 40–44 tumour necrosis

metabolism of proteins, carbohydrates and lipids, leading to an- factor (TNF)-α and interleukin (IL)-6 have been shown to sup-orexia, weight loss and loss of adipose tissue and skeletal muscle press myogenesis by activating NF-κB in muscle cells through amass manifested in the cardinal feature of emaciation.[1-5] Cancer process that involves disassociation of NF-κB from its inhibitorycachexia affects about half of all cancer patients and occurs protein IκB.[16,17] A key proteolytic pathway is then activatedprimarily in patients with advanced disease. Cachexia is associated leading to degradation of IκB and breakdown of myofibrillarwith negative effects in the patient’s functional status and quality proteins. In cancer cachexia, this dysregulation may induce theof life and is a major contributor to the morbidity and mortality of cellular breakdown of muscle and bone, resulting in sarcopeniapatients with advanced malignancy.[1,2] Twenty percent of deaths and osteopenia. In simple starvation, the body readily adapts toin cancer patients are related to cancer-induced or treatment- calorie deficit by shifting of fatty acids as the major source ofrelated wasting and malnutrition; this number may be as high as energy, thereby preserving lean body mass. In cancer cachexia, the40% in certain populations. Anorexia or lack of appetite resulting body fails to make this adaptation.[18] The cytokines produced byin involuntary decline in food intake is the most common problem the host in response to tumour presence cause metabolic abnor-contributing to malnutrition for individuals with cancer. Malnutri- malities observed in cancer cachexia, including hyperglycaemia,tion can be defined as a nutritional deficit or altered nutritional insulin resistance, increased basal energy expenditure, decreasedstatus associated with increased risk of adverse clinical events, lipoprotein lipase, lipidaemia and proteolysis of muscle.[2,5,19-21]

such as morbidity or death.[1,2,6] Nearly in three senior Americans This results in malnutrition, disproportionate wasting of lean bodymay be at high risk for malnutrition, which amounts to almost 10 mass and loss of strength and functional status, leading to negativemillion Americans today.[7] The prevalence of malnutrition in the outcomes in the cancer patient in addition to profound effects onfree-living elderly is relatively low (5–10%) compared with hos- quality of life.[22,23] These symptoms are accelerated in the elderly,pitalised or institutionalised elderly,[8] where it is estimated that who have relatively lower steroid hormone levels as a result of30–65% are malnourished. Malnutrition is an important predictor ‘hormonal ageing’ and lowered physical activity as a result ofof morbidity and mortality, even more so in the elderly than in treatment-related fatigue, which has been demonstrated to contrib-younger adults.[8-10] Unplanned weight loss, especially in the eld- ute to lowered bone mineral density and muscle mass. These age-erly cancer patient,[8-10] is also identified as a clinically significant related conditions may thus be exacerbated, resulting in falls,independent predictor of morbidity and mortality. Even a weight fractures and general muscle weakness. Although it was initiallyloss of 5% in older persons reflects poor health, hospitalisation and believed that the best way to treat cancer cachexia is to cure thea higher rate of mortality. Research also indicates that the elderly cancer, with our better understanding of the molecular mechanismare particularly at risk for deficiency of vitamins and trace miner- of cancer cachexia based on animal studies, in most cases, theals. Other pre-existing chronic diseases and drug therapies in this consequence of cancer cachexia is what often leads to death andspecial population may increase requirements of certain nutrients not the cancer.[5]

because of changes in absorptive and metabolic capacity. Recentstudies have also shown that advanced malnutrition is much more 3. Efficacy of Current Therapies for Cancerdifficult to treat in the elderly than in younger adults, and failure to Cachexia in the Elderlycorrect malnutrition delays recovery and has a significant impact

Traditional therapies have focused on treating the patient withon functional dependence and quality of life.[11,12]

appetite stimulants and nutritional interventions using high calo-rie-protein supplemental feeding, with limited success in treating2. Cancer Cachexia: Potential Mechanismscancer cachexia. High calorie and high protein supplemental feed-

Based on animal models, several potential mechanisms have ings result in substitution of regular meals and thus a reduction ofbeen proposed to explain the protein catabolism resulting in mus- caloric and protein intake in this patient population.[24-28] Appetitecle wasting observed in cancer cachexia. One of the most plausible stimulants have been shown to ameliorate or slow age-relatedmechanisms of cancer cachexia comes from a group of studies anorexia and unintentional weight loss in other populations butusing rodent models of muscle wasting, which have indicated that have not been shown to increase lean body mass or markers ofaccelerated protein degradation by the proteasome is the principal protein metabolism in cachectic elderly cancer patients. The mostcause of muscle atrophy and wasting induced by cancer cachex- common agents used to enhance patient appetite are orexigenic

© 2004 Adis Data Information BV. All rights reserved. Evid Based Integrative Med 2004; 1 (3)

Eicosapentaenoic Acid in Treatment of Cancer Cachexia 191

agents such as megestrol acetate, which acts by reducing cytokine 4. Eicosapentaenoic Acid as anproduction.[27] However, this is also associated with a reduction in Anticachectic Agentsteroid hormones, which results in decline in muscle mass (which

Evidence from laboratory and clinical studies has demonstratedis already decreased in the elderly) and an increase in fat mass.that eicosapentaenoic acid (EPA), an n-3 fatty acid, has antitumourAnother common agent is dronabinol, a cannabis derivativeand anticachectic effects.[1,23-31] EPA is an essential fatty acid thatdemonstrated to enhance appetite and mood in cancer patients.cannot be synthesised completely by mammalian tissue and has toHowever, the pharmacokinetic profile of this agent in elderlybe consumed in the diet. These polyunsaturated fats are present incancer patients has not been examined. In addition, mood altera-fish oils such as cod liver, sardine and salmon oil. There is notions secondary to drug treatment can be confused with dementia,established dietary reference intake for n-3 fatty acids, yet theespecially in individuals who have never used cannabinoids in theadequate intake (AI) is set at 1.6 g/day and 1.1 g/day for men andpast.[11,12,28] More recently, antidepressants such as Remeron® 1

women, respectively. While intake in the US occurs at much lower(mirtazapine) have been used to treat depression, which may be athan the proposed AI and no signs of deficiency are observed, themajor reversible contributor to weight loss in elderly cancer pa-AI is proposed to provide optimal health benefits associated withtients. Increasing physical activity, aerobic and anaerobic, as aconsuming n-3 fatty acids.non-pharmacological means to improve muscle and bone mass is

As indicated earlier, initial studies using animal models havecurrently being examined.demonstrated that NF-κB is upregulated in cancer cachexia, in-In a recently completed pilot study to determine the prevalencecreasing proteolysis and inducing apoptosis in myotubes. Severaland efficacy of the use of traditional anti-anorectic therapies forrecent laboratory studies have shown that EPA may attenuatethe treatment of cancer cachexia at Moffitt Cancer Center, weprotein degradation, by preventing NF-κB accumulation in thecollected data on elderly cancer patients, all of whom were onnucleus.[14,15] Administration of n-3 fatty acids and EPA capsuleschemotherapy or radiation therapy and were placed on the aboveor supplements with EPA has been shown to be associated totraditional anticachectic therapies at the cancer centre. Using aweight stabilisation, gain in lean body mass, and improvement indata collection instrument, we collected basic, easily available andquality-of-life markers in weight-losing patients with advancedpertinent serial data on markers of nutritional status (anthropome-pancreatic cancer.[29-31] Although the patient population had termi-try and weight) and biochemical data (albumin, protein status,nal illness and a life expectancy of 2 months, promising changes inhaemoglobin/haematocrit [anaemia] and lymphocytes [immuni-net gain in weight, lean body mass and improved quality ofty]) from the start to the end of treatment. Prospective data werelife[1,23,29-31] were noted. Nutritional supplementation alone hasobtained in this pilot study from 17 subjects. Although the mecha-been unable to reverse the process of muscle wasting, since itnism is poorly understood, our pilot study indicated that thearises from the activation of the ubiquitin proteasome pathway,current anticachectic therapies may be effective only in increasingwhich is independent of nutritional intake. It is logical, then, toweight or maintaining the bodyweight of the cancer patient andhypothesise that agents such as EPA that can inhibit NF-κB mightmay produce moderate increases or stable markers of immunitystimulate recovery of muscle mass in this patient population andand protein status. Cannabinoids produced the most significantoffer the most promise for the development of an effective molec-weight gain and corticosteroids and Megace® produced no changeular-based approach for the treatment of cancer cachexia[5] (figurein weight over the 6- to 8-week period of observation. However,1).lymphocyte counts and serum albumin decreased in all three

groups. It is important to note that this was only a pilot study with a 5. Valid Intermediate Endpoint Biomarkerssmall sample size, using easy-to-obtain intermediate endpointbiomarkers (IEBs) to monitor efficacy of treatment and performed The utility of IEBs in the development of agents for treatingin a group of acutely ill cancer patients during treatment. However, cancer cachexia is solidly established. With rigorous attention toit is evident that although these strategies to improve appetite and methodology, identification of high-risk cohorts and validatedlean body mass may have a scientific rationale and merit, IEBs, the evaluation of efficacy, safety and the mechanism ofrandomised studies, including our pilot study, have continued to action of potential agents for the treatment of cancer cachexia indemonstrate that reduction in the loss of lean body mass is difficult clinical trials has become an increasingly critical area of research.to achieve unless the underlying metabolic abnormalities are cor- In addition, EPA may have multiple molecular activities, some ofrected.[12,24-28] which may be interrelated. Also, a single activity, even if it is the

1 The use of trade names is for product identification purposes only and does not imply endorsement.


192 Kumar & Dalton

critical to incorporate these markers in studies, to be measuredserially along with bodyweight.[36-40]

5.2 Biochemical Markers of Protein Status (Serum Albuminand Transferrin)

Assessment of protein status is critical in the identification andtreatment of protein metabolism. Measurements of body composi-tion should be combined with more objective and sensitive mea-sures of protein status such as biochemical assessment of intravas-cular and visceral protein stores. Serum protein level is influencedby hydration status, and rate of synthesis can be altered by liver orrenal dysfunction, sepsis and surgery. It may thus be important tocombine two valid IEBs that represent intravascular and visceral

Prevent loss of lean body mass and weight

Prevention of breakdown of myofibrillar protein

Modulation of immune and Inflammatory responsesDecreases PIF and cytokine production (IL-6, TNFα)

Downregulates NF-κB and PIFUpregulates IκB

Eicosapentaenoic acid

Fig. 1. Molecular-based therapeutic approach in the treatment of cancercachexia in the elderly cancer patient. IκB = inhibitory factor-κ B; lL =interleukin; NF-κB = nuclear factor-κ B; PIF = proteolysis-inducing factor;TNF = tumour necrosis factor.

protein pools – transferrin and albumin, respectively – as thebiochemical indicators of protein status.

agent’s predominant pharmacological activity, may not be theSerum albumin is the most validated as a prognostic index and

most important or the only one effecting the metabolic modula-the most readily available biochemical parameter used to assess

tions. Thus, although observing effects at the morphological andprotein status. However, its relatively long half-life (14–20 days)

biochemical levels is a key approach to identifying potentialmakes it slow to respond to dietary interventions and thus more

agents, it should be complemented by molecular targeting.[32]

suitable for prospective long-term interventions exceeding 25days.

5.1 Morphological Markers Transferrin is a serum β-globulin protein synthesised primarilyin the liver, but in contrast to albumin it is located intravascularly

Morphological markers such as anthropometric measurements (as a transporter of iron), has a shorter half-life (8–10 days) andresponds more rapidly to changes in protein status. Serum transfer-of body mass index (height, weight) and skinfold measurements ofrin, either singly or as part of a multiparameter index, is theupper and lower body compartments to determine body composi-strongest predictor of patient mortality and morbidity.[6,41]tion (lean body mass, percentage of fat)[33] are valid IEBs that can

be used to reliably measure efficacy of treatment. Current weight5.3 Molecular Targetsis useful as an indicator of nutritional risk or depletion only if it is

evaluated in comparison to the patient’s usual weight. Weight lossInitial studies have demonstrated that NF-κB is upregulated inmust also be assessed in relation to its duration and whether it is

cancer cachexia, increasing proteolysis and inducing apoptosis inunintentional or intended weight loss.[34] In addition, weight andmyotubes. Several recent laboratory studies have shown that EPAweight change must be assessed in combination with other anthro-may attenuate protein degradation, by preventing NF-κB accumu-pometric parameters such as body composition, as a marker oflation in the nucleus and upregulating IκB.[14,15] Proteasomes thusagent efficacy.may indeed be the target for EPA, in its role in prevention of

The most widely accepted method of estimating body composi- proteolysis and subsequent sarcopenia in cancer cachexia. It istion changes is the use of standardised equipment and procedures thus relevant to measure serum proteasomes using methods de-for measuring triceps skinfold and mid-arm muscle circumference. scribed and previously validated by our group.[42,43]

These values are then compared with a table of standard measure-ments based on a reference group of healthy individuals. There is 5.4 Immune and Inflammatory Markers (Interleukin-6 andstill controversy regarding the validity of these measurements as Tumour Necrosis Factor-α)part of the initial baseline assessment owing to influences ofinactivity and the disease process on muscle mass and difficulty Unlike anorexia of aging, cancer cachexia features a range ofwith obtaining accurate results in the presence of oedema or metabolic responses triggered by inflammatory and immunologi-obesity.[35] However, there is general agreement that these mea- cal responses. It is believed that the putative mediators of cancersurements can be useful for serial evaluation, as proposed in this cachexia are cytokines, and increased expression of TNFα andstudy, to identify changes in body fat and lean body mass. It is thus IL-6 has been observed in patients with cancer cachexia. It is thus


Eicosapentaenoic Acid in Treatment of Cancer Cachexia 193

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