Nutrition 31 (2015) 549–555
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Applied nutritional investigation
Eicosapentaenoic acid in cancer improves body composition and modulates metabolism Giulia Pappalardo R.D., Ana Almeida R.D., Paula Ravasco M.D., Ph.D., M.Sc., R.D. * ~o da Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal rio de Nutric¸a Laborato
a r t i c l e i n f o
a b s t r a c t
Article history: Received 8 August 2014 Accepted 2 December 2014
Objectives: The objective of this review article is to present the most recent intervention studies with EPA on nutritional outcomes in cancer patients, e.g. nutritional status, weight & lean body mass. Methods: For this purpose a PubMedÒ and MedLineÒ search of the published literature up to and including January 2014 that contained the keywords: cancer, sarcopenia, EPA, u-3 fatty acids, weight, intervention trial, muscle mass was conducted. The collected data was summarized and written in text format and in tables that contained: study design, patient’ population, sample size, statistical significance and results of the intervention. The paper will cover malignancy, body composition, intervention with EPA, physiological mechanisms of action of EPA, effect of EPA on weight and body composition, future research. Results: In cancer patients deterioration of muscle mass can be present regardless of body weight or Body Mass Index (BMI). Thus, sarcopenia in cancer patients with excessive fat mass (FM), entitled sarcopenic obesity, has gained greater relevance in clinical practice; it can negatively influence patients’ functional status, tolerance to treatments & disease prognosis. The search for an effective nutritional intervention that improves body composition (preservation of muscle mass and muscle quality) is of utmost importance for clinicians and patients. The improvement of muscle quality is an even more recent area of interest because it has probable implications in patients’ prognosis. Eicosapentaenoic acid (EPA) has been identified as a promising nutrient with the wide clinical benefits. Several mechanisms have been proposed to explain EPA potential benefits on body composition: inhibition of catabolic stimuli by modulating pro-inflammatory cytokines production and enhancing insulin sensitivity that induces protein synthesis; also, EPA may attenuate deterioration of nutritional status resulting from antineoplastic therapies by improving calorie and protein intake as well. Conclusions: Indeed, cancer-related sarcopenia/cachexia is a multifactorial syndrome characterized by inflammation, anorexia, weight loss, and muscle/adipose tissue loss mediated by proinflammatory cytokines, e.g. TNF-a and IL-6, resulting in increased chemotherapy toxicity, costs, morbidity and mortality. With this review we found that EPA can reduce inflammation and has the potential to modulate nutritional status/body composition. In view of the modest survival benefits of chemotherapy/radiotherapy in some cancers, important issues for physicians are to optimize well-being, Quality of Life via nutritional status and adequate body composition. Thus, improvement in nutritional status is a central outcome. Ó 2015 Elsevier Inc. All rights reserved.
Keywords: Cancer Nutrition Eicosapentanoic acid Muscle mass Body composition
Introduction Cancer: Nutritional deterioration, sarcopenia and cachexia Nutritional deterioration in cancer patients is a reality that continues untreated and is still a mystery for some clinicians. * Corresponding author. Tel.: þ351 217985141; fax: þ351 217985142. E-mail address: [email protected] (P. Ravasco). http://dx.doi.org/10.1016/j.nut.2014.12.002 0899-9007/Ó 2015 Elsevier Inc. All rights reserved.
Cancer cachexia is defined as a “multifactorial syndrome characterized by an ongoing loss of skeletal muscle mass (with or without loss of fat mass) that cannot be fully reversed by conventional nutritional support and leads to progressive functional impairment” [1]. The diagnosis of cachexia is made according to the following criteria: Weight loss greater than 5% in the last 6 mo or weight loss greater than 2% in individuals already showing nutritional depletion according to current body weight and height (body mass index [BMI] < 20 kg/m2) or reduced
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skeletal muscle mass (sarcopenia). Severity can be classified according to the degree of depletion of energy stores and of body protein, in combination with ongoing weight loss [1]. Patients who are cachectic may have anorexia, nausea, and other symptoms that may compromise food intake, reduce strength, impair functional capacity, and worsen their quality of life [2]. Although cancer treatments, such as chemotherapy or radiotherapy, may also cause weight loss and symptoms that may diminish nutritional status, the mechanisms associated with these clinical findings are totally different from those found in progressive tissue wasting [3–5]. Anorexia and increased energy expenditure may contribute to cancer cachexia; anorexia may be induced by proinflammatory cytokines (interleukin [IL]-1 a, IL-1 b, IL-6, and tumor necrosis factor [TNF]-a) released by both the tumor and the host’s immune system. Conversely, the hypermetabolic state may result from the production of acute phase proteins (C-reactive protein, fibrinogen, and a-1 antitrypsin) by the liver. Still, anorexia alone is not responsible for the wasting process and not all cancer patients are hypermetabolic [6]. Therefore, there have to be other mechanisms behind metabolic alterations associated with cancer cachexia, namely tumor and host factors that may activate lipogenic and proteolytic pathways [7]. All of these observations justify the research to find and/or optimize nutritional intervention that improves body composition, particularly muscle mass and muscle quality [7,8].
Body composition assessment Although patients’ weight loss is a highly relevant parameter to be assessed and registered in the clinical routine, it does not allow us to distinguish body compartments, namely lean body mass (LBM) or fat mass (FM), and therefore to identify muscle and/or fat loss [3,9]. Moreover, clinical reports show that nutritional status in cancer patients is highly diverse: Studies show a high prevalence of overweight and obesity, even in patients with low muscle mass. This body composition pattern, designated as sarcopenic obesity, has been established as a predictor of poor functional status, worse quality of life and reduced survival [4,5]. Body weight comprises two main compartments: fat free mass (FFM) and fat mass (FM); FFM includes mineral tissue and muscle mass, e.g., extracellular and intracellular water and metabolically active tissues: skeletal muscle and internal organs. According to the method used, different body composition compartments may be measured. Although simple and practical methods such as bioelectrical impedance analysis (BIA) do not distinguish skeletal muscle from other metabolically active tissues, image-based body composition methods like computed tomography (CT), allow a precise evaluation of the quantity and quality of skeletal muscle [10,11]. Recently, CT images at the level of the third lumbar vertebrae have been validated in oncology for body composition analysis, by comparison with the gold standard method: dual energy x-ray absorptiometry [11]. Studies have already used CT images to identify sarcopenic cancer patients and did find significant associations with disease prognosis and survival. Fearon et al [6]. found a prevalence of sarcopenia of 56% in pancreatic cancer patients by analyzing their CT images; sarcopenia was present in all BMI categories, including overweight/obese patients; these patients had the overall worst prognosis, even when compared with patients who were only sarcopenic and underweight [4, 9]. The fact is the presence of overweight/obesity may mask the presence of reduced muscle mass, and in the absence of
imaging body composition methods, sarcopenia may be underdiagnosed and undertreated [12]. Eicosapentaenoic acid Polyunsaturated fatty acids include two classes of fatty acids,
u-6 and u-3 fatty acids. The u-6 series includes linoleic acid (LA, 18:2 u-6), arachidonic acid (AA, 20:4 u-6), and gamma-linoleic acid (GLA, 18:3 u-6); all can be found in foods of animal origin, some vegetables, sunflower, soybeans, and grape seed oils. The u-3 series includes the alfa-linoleic acid (ALA, 18:3 u-3) present in green vegetables, in rapeseed and soybean oils; eicosapentaenoic acid (EPA, 20:5 u-3) and docosahexaenoic acid (DHA, 22:6 u-3) are ubiquitous in mammals, seafood, and marine products. u-3 polyunsaturated fatty acids are essential nutrients for humans, because humans lack the delta to 15 desaturase that converts u-6 fatty acids into u-3 fatty acids [5]. Although the use of vitamins, minerals, and other dietary supplements during cancer treatment remains controversial [11], it has been suggested that the supplementation with either fish oil or EPA alone in patients with advanced cancer and cachexia, may contribute to skeletal muscle preservation, improved appetite and weight gain [9]. EPA has different effects on LBM via two main mechanisms: reduced muscle degradation and increased muscle synthesis. EPA influences proteolysis by down regulating the acute phase response, by reducing serum concentration of C-reactive protein (CRP) and by suppressing IL-6 production [13]. On the other hand, EPA may decrease muscle wasting by down regulating the ubiquitin proteasome pathway that is the central pathway in muscle loss. Additionally, EPA reduces muscle apoptosis by reducing TNF-a [12,14]. EPA increases muscle insulin sensitivity, thus improving protein and calorie intake [13]. EPA also has indirect effects on nutritional status because it was demonstrated it reduces chemotherapy side effects and enhances tumor response to antineoplastic treatments [7]. Moreover, EPA may attenuate side effects from antineoplastic therapies, by improving calorie and protein intake [15]. It is worth mentioning that recent trials corroborate EPA’s potential benefits on muscle mass preservation [5,12,15–17]. EPA, weight and body composition The potential antiinflammatory effects of EPA and their influence on weight and body composition have already been shown in several studies (Table 1). Early reports did show positive and promising results: Maintenance or even improvement of weight and LBM. Wigmore et al. [14] reported that EPA supplementation had a positive effect on weight losing pancreatic cancer patients: 61% of patients experienced weight gain, whereas 17% became weight stable and 22% reduced the rate of weight loss. Even though no changes were found in anthropometric measures, after 1 mo of supplementation, a significant, although temporary, reduction in CRP concentration was found (P < 0.002), as well as a stabilization of resting energy expenditure. Similarly, in a study by Barber et al. [8] that enrolled weight losing pancreatic cancer patients, beneficial effects of EPA were described on weight and LBM. Daily energy intake was significantly increased (P ¼ 0.002), whereas both performance status and appetite significantly improved after 3 wk of supplementation (P < 0.005 and P < 0.01, respectively). Although EPA supplementation had positive effects on weight and LBM maintenance in the previously mentioned studies, these were uncontrolled, not-randomized, and enrolled a small
Table 1 Statistically and clinically positive intervention studies with EPA and/or DHA and outcomes Population and study design
Intervention
Outcomes
Results
Wigmore, et al [12]
18 patients Advanced pancreatic cancer Open-label, single-arm Phase II study 20 patients Pancreatic cancer Single-arm study
Fish oil capsules (1 g EPA 18%; DHA 12%) 2 g/d fish oil, increased at weekly intervals by 2 g, to maximum dose of 16 g/d.
Weight Anthropometry: MAMC and TSF
Increase in weight of 0.3 kg/month (P < 0.002). No significant change in MAMC and TSF values.
Fish oil-enriched oral nutritional supplement 2 cans/d (2.2 g EPA þ 0.96 g) Follow-up at 3 and 7 wk from baseline.
Weight Anthropometry: TSF þ MUAMC BIA: LBM and FM
Increase in weight at 3 and 7 wk of median 1 kg (P ¼ 0.028) and 2 kg (P ¼ 0.033), respectively. Increase in LBM at 3 and 7 wk of median 1.0 (P ¼ 0.0064) and 1.9 kg (P ¼ 0.0047), respectively. Decrease in median weight loss after 4 wk of EPA vs. pre study values (P < 0.005); reduction remained significant at 8 and 12 wk (P < 0.005). No significant change in MUAMC or TSF at 4, 8 or 12 wk of EPA vs. pre study values. Increase in weight and LBM (NS). Increase in LBM associated with better nutritional status (r ¼ 0.998, P ¼ 0.04). Increase in weight at end of week 3 (mean increase of 2.5 kg from baseline, P ¼ 0.03) and maintenance during chemotherapy. No significant change in LBM before and during chemotherapy.
Barber, et al [8]
Wigmore, et al [14]
26 patients Pancreatic cancer Single-arm study
Gelatin capsules high-purity EPA (500 mg) 1 g/d EPA on first week, 2 g/d for the second week, 4 g/d for the third week and 6 g/d thereafter Follow-up at 4, 8 and 12 wk
Weight Anthropometry: TSF and MUAMC
Bauer, et al [16]
7 patients Pancreatic and lung cancer Open-label, single-arm study 23 patients (15 patients at baseline) Advanced colorectal cancer Open-label, single-arm study
EPA enriched oral nutritional supplement At least 1 can/d (1.1 g EPA/d) Follow-up at 8 wk EPA enriched oral nutritional supplement 2 cans/d (1.18 g EPA þ 0.92 g DHA/day) Follow-up at 3 and 9 wk 4 cycles of chemotherapy regimen with FOLFIRI, commenced at end of week 3 and repeated every 2 wk. EPA enriched enteral feed (2.2 g EPA/d) during 5 d preoperatively, 2–10 d postoperatively and 11–21 d concomitantly with oral diet. Controls: Feeding regimen with an iso-caloric, iso-nitrogenous enteral feed. Fish-oil enriched oral nutritional supplement 2 cans/d (2.2 g EPAþ0.92 g) Supplement consumed from no later than 2 wk before surgery until discharge Mean SD time between trial entry and hospital admission: 23 2.5 d Mean SD time between hospital admission and discharge: 11 0.85 d Fish-oil enriched oral nutritional supplement (energy þ protein-dense) 2 cans/d (2 g EPAþ0.92 g DHA) Control group: Isocaloric oral nutritional supplement without EPA þ DHA. Follow-up at 3 and 5 wk
Weight LBM with staple isotope deuterium
Read, et al [7]
Ryan, et al [18]
53 patients Oesophageal cancer Double-blind, randomized, controlled trial
Weed, et al [19]
31 patients Head-neck cancer scheduled for surgery with curative intent Open-label, single-arm study
van der Meij, et al. [3]
40 patients Lung cancer Double-blind, randomized, controlled trial
Murphy RA, et al [20]
31 patients (24 controls vs. 16 intervention) Lung cancer Open-label, single arm study, contemporaneous control group
2 types of supplementation: 4 1 g gelatin capsules fish oil/d (2.2 g EPA) or 7.5 mL of liquid fish oil/d (2.2 g EPA). Control group: No intervention Follow-up after 2 cycles of chemotherapy (at least 6 wk)
Weight BIA: LBM (single frequency, tetrapolar device BIM-4, SEAC Pty Ltd)
Weight BIA: LBM and FM
Weight BIA: LBM and FM
Weight BIA: FFM MUAC
Weight CT images: Skeletal muscle, adipose tissue, muscle attenuation
EPA enriched feed regimen group: No significant difference in weight and FFM from preoperatively to day 21 postoperatively. Control group: Weight loss of 1.8 kg (P ¼ 0.03) and LBM loss of 1.9 kg (P ¼ 0.03). Increase/maintenance in weight in 57% patients until hospital discharge. Increase in LBM increase from trial entry to hospital discharge (þ3.2 kg, P < 0.001).
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Author (y)
EPA group: Weight maintenance (weight difference between intervention group and control group: 1.3 kg, P ¼ 0.02 at 3 wk and 1.7 kg, P ¼ 0.04 at 5 wk), less decrease in FFM (FFM difference between intervention (1.5 kg at 3 wk and 1.9 kg at 5 wk) and increased MUAMC, whereas the MUAMC in the control group decrease (difference between groups not significant at 3 and 5 wk). Fish oil group: 69% patients maintained or gained weight (mean weight change: 0.5 1.0 kg) and muscle (MM at baseline: 25.4 1.4 kg vs. MM at end of treatment: 25.4 1.5 kg, NS). Control group: 29% patients maintained or gained weight (mean weight change: 2.3 0.9 kg) and muscle (MM at baseline: 24.4 1.0 kg vs. MM at end of treatment: 23.5 1.0 kg, P < 0.002. 551
BIA, bioelectric impedance analysis; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; FM, fat mass; FFM, free fat mass; LBM, lean body mass; MM, muscle mass; MUAMC, midupper arm muscle circumference; MUAC, midupper arm circumference; NS, not significant; TSF, triceps skinfold thickness
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number of patients. Therefore, double-blind, randomized, and controlled clinical trials, including larger study populations were needed. Fearon et al. [6] conducted an international, multicenter, randomized, double-blind trial that enrolled at baseline 200 pancreatic cancer patients; this trial failed to show the potential advantage of an EPA-enriched supplement on nutritional parameters and quality of life, no difference between the experimental versus the control. The authors found two reasons for this lack of effect: low compliance to the oral nutritional supplement enriched with u-3 fatty acids. Indeed, in the pilot study of Barber et al. in 1999, a net gain of LBM was experienced with a dose of 2.1 g/d of EPA (equivalent to 1.9 cans/d); however, in the clinical trial by Fearon et al., the mean level of intake reached was 1.5 g of EPA (equivalent to 1.4 cans/d of nutritional supplement), which is insufficient to have a physiological effect, compared with an energy/protein dense control supplement. The other reason found by the authors was patients in the control group failed to declare the self-use of u-3 fatty acids supplements; both factors compromised any comparisons and differences between control and experimental group. Despite the lack of positive results, the EPA to enriched supplement was positively correlated with increased body weight and LBM (r ¼ 0.50, P < 0.001 and r ¼ 0.33, P < 0.036, respectively), as well as with a better quality of life (r ¼ 0.37, P ¼ 0.01). Plus, no statistically significant correlations were observed in the control group. To overcome the compliance issues, Fearon et al. [21] conducted a second large multicenter double-blind, randomized, placebo-controlled trial in gastrointestinal and lung cancer patients, to evaluate the effect of two doses (2 and 4 g/d) of EPA as soft gel capsules versus placebo for 8 wk. Besides weight and body composition, Karnofsky performance status, quality of life, CRP levels and appetite were also evaluated at 4-weekly intervals for 24 wk. A marginal statistically significance was found as well as an important clinical difference in increased weight in patients receiving 2 g of EPA daily, versus placebo; yet, no benefit was observed with a supplementation of 4 g/d of EPA, clarifying the lack of a dose response beyond 2 g/d. In what concerns the other outcomes, besides a modest improvement in physical function, no significant differences were observed. Based on these results, authors classified the potential benefits of u-3 fatty acids as marginal and even suggested further studies and comparisons with other agents or combination regimens with potential anticachectic effects. Similar results were obtained by Bruera et al. [2], which found no significant improvement in weight or body composition, as well as in physical function, appetite, or other symptoms after an intervention with fish oil capsules for 2 wk, equivalent to a mean daily dose of 1.8 g of EPA [5,11]. Recently, other clinical trials reported a positive effect of EPA on nutritional status, namely improved weight and LBM (Table 1). Ryan et al. conducted a double-blind, randomized controlled study in patients with esophageal cancer referred for surgery or neoadjuvant chemotherapy radiotherapy. The experimental group received 5 d of preoperative supplementation of an EPA-enriched formula, and the control group received a standard formula (without EPA) in both groups were maintained postoperatively by a jejunostomy for 21 d. LBM was preserved in the EPA group (55 kg preop versus 55.3 kg postop, P ¼ 0.08), whereas the control group had a significant loss of LBM (-1.9 3.7 kg, P ¼ 0.03). Moreover, postoperative inflammatory response was attenuated, with a lower expression of proinflammatory cytokines in the intervention group, conceivably because of EPA incorporation into cell membranes. Another recent study [19] was conducted in surgical cancer patients
treated perioperatively with an EPA-enriched nutritional supplement. Contrarily to the previous trial, this was an open-label, single-arm study in patients with head-neck cancer who received a protein þ energy-dense EPA-containing supplement in addition to oral intake or as part of their enteral feeding before surgery and throughout treatment until discharge. The authors found there was a significant increase in LBM versus baseline (P < 0.001). In a study of van der Meij et al. [3], the effect of an EPA containing nutritional supplement on nutritional status, body composition and inflammatory markers was also tested in patients with lung cancer; 33 patients with stage III non-small cell lung cancer referred for chemotherapy þ radiotherapy were included in a double-blind, randomized, controlled trial. Weight and LBM maintenance were achieved (P < 0.05) and there was a trend for increased midupper arm circumference (P ¼ 0.06) in the experimental group and not in the control group. Although no statistical difference was found on inflammatory markers between groups, patients in the EPA group presented higher EPA content in plasma phospholipids, that were negatively correlated with inflammatory markers, i.e., IL-6 and CRP (r ¼ 0.8, P < 0.04 and 0.8, P < 0.05, respectively). In the same study population and using the same study design, EPA effects in quality of life and functional status were assessed [10]. There was a significant improvement in quality-of-life dimensions, namely physical and cognitive functions (P ¼ 0.01), global health status (P ¼ 0.04), and social function (P ¼ 0.04) in the EPA intervention group and never in the control group. Also, patients in the intervention group had higher physical activity measured by accelerometer versus controls (P < 0.05). In an open-label trial with EPA supplements in non-small cell lung cancer patients during chemotherapy, CT scan images were used to assess body composition; weight and LBM were also evaluated [20]. CT showed the quantity and quality of muscle mass (skeletal muscle index and muscle attenuation); there was a reduction in muscle and fat tissue wasting, resulting in the maintenance of weight and muscle mass during chemotherapy. Muscle fat infiltration assessed with skeletal muscle attenuation showed that at the end of treatment, the control group had a significant reduction in muscle attenuation (30.1 1.7 HU versus 33.6 1.7 HU at baseline, P < 0.001), indicating an increase in muscle fat infiltration. A significant reduction in whole-body skeletal muscle (23.5 1.0 kg versus 24.4 1.0 kg at baseline, P ¼ 0.002) was also observed, whereas muscle attenuation and whole-body skeletal muscle were maintained during chemotherapy in the EPA intervention group [17,22]. All these positive results indicate EPA may be highly beneficial, but methodological issues in conducting intervention studies need to be clarified to have consistent data. Until now, we still have some inconsistent data surrounding the benefits of EPA, and we present the sum of negative intervention studies with EPA (Table 2). Clinical trials: Questions and challenges The high variability of study designs may be one of the major causes for the discrepant results found across studies using EPA supplementation we included in this review [23]. Subsequent studies adopted different and more accurate nutrition intervention methodologies with supplementation (randomized trials), to address limitations and problems identified in the first studies conducted with EPA supplementation, namely compliance and contamination between study arms [6,13]. In reality, Murphy et al. [7] tried to overcome these issues by conducting an open-label trial, in which patients could choose between two
Table 2 Statistically and clinically negative intervention studies with EPA and/or DHA and outcomes Population and study design
Intervention
Outcomes
Results
Fearon, et al [6]
200 pancreatic cancer pts Multicenter, double-blind, randomized, controlled trial
Fish-oil enriched oral nutritional supplement 2 cans/d (2.2 g EPAþ0.96 g) Control group: Identical oral nutritional supplement without EPA þ DHA. Follow-up at 8 wk from baseline
Weight BIA: LBM þ FM (multifrequency analyser Xitron Hydra)
Bruera, et al [2]
60 patients Advanced cancer (different location tumors) Double-blind, randomized, controlled trial
Anthropometry: MAC, TSF, and subscapular skinfold BIA: LBM and FM
Moses, et al [24]
19 patients (15 in intervention vs. 7 in control group) Pancreatic cancer Double-blind, randomized, controlled trial
Weight BIA: LBM (Xitron Hydra, Xitron Technologies)
No significant changes in weight or LBM in either group over 8 wk of supplementation vs. baseline values.
Jatoi, et al [23]
421 patients; different cancers excluding brain, prostate, gynecologic. Multicenter, double-blind, randomized trial
Weight
Fearon, et al [21]
518 patients Advanced gastrointestinal (n ¼ 287) and lung (n ¼ 231) cancer Multicenter, double-blind, randomized, controlled trial
Gelatin capsules of fish oil 3.24 EPAþ2.16 mg DHA/d Control group: Gelatin capsule with 1000 mg of olive oil Follow-up at 2 wk from baseline Fish-oil enriched oral nutritional supplement 2 cans/d (2.2 g EPAþ0.96 gDHA/d) Control group: Identical oral nutritional supplement without u-3 fatty acids. Follow-up at 8 wk from baseline Fish oil-enriched oral nutritional supplement: 2 cans/d (2.2 g EPAþ0.92 g DHA]. 3 groups: EPA supplement þ placebo; MA þ isocaloric, isonitrogenous placebo; EPA nutritional supplement þ megestrol acetate. Follow-up weekly for 4 wk and then monthly. Gelatin capsules of 95% EPA diester Two EPA doses tested: 2 g EPA/d and 4 g EPA/d Control group: Medium chain triacylglycerols Follow-up at 8 wk from baseline.
No statistical difference in weight or LBM between intervention and control. Significant attenuation of weight and LBM loss in both groups. Significant positive correlation between supplement intake and increased weight (r ¼ 0.5, P < 0.001) and LBM (r ¼ 0.33, P ¼ 0.036). No statistical difference for anthropometric measures and LBM between intervention and control group.
No significant change in weight with EPA alone or in combination with MA. 6% patients taking EPA supplement gained 10% baseline weight vs. 18% of patients taking MA (P ¼ 0.004). MA alone was more effective for weight gain: 1.3 kg vs. -1.0 kg in the EPA-treated arm, P ¼ 0.008 No statistical difference for weight and LBM between groups (P ¼ 0.066 and P ¼ 0.14, respectively). By comparison with control group, the group receiving 2 g EPA/d had a mean increase of 1.2 kg of weight and of 0.9 kg of LBM and group receiving 4 g EPA had a mean increase of 0.3 kg of weight and a mean decrease of 0.1 kg of LBM.
Weight BIA: LBM (Bodystat 1500 bioelectrical impedance analyzer)
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Author (y)
BIA, bioelectric impedance analysis; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; FM, fat mass; FFM, free fat mass; LBM, lean body mass; MM, muscle mass; MUAMC, midupper arm muscle circumference; MUAC, midupper arm circumference; NS, not significant; TSF, triceps skinfold thickness
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different types of supplementation: liquid fish oil or gelatin capsules. A compliance rate of >95% was achieved, allowing an EPA intake of 2.1 0.6 g/d, which is equivalent to the acknowledged therapeutic dose and may exert potential health benefits. This allowed for EPA intake to be similar to the recommended amount. The measurement of phospholipids’ EPA concentration may be a useful parameter to assess compliance and cross-arm contamination; notwithstanding, it may also be highly relevant to evaluate EPA incorporation in cell membranes and tissues. Despite the high compliance in the Murphy et al. [17] study, plasma EPA concentration in phospholipids was variable, as well as muscle mass change. Because EPA incorporation into cells and tissues is needed to have a physiological effect, it may explain why the results of EPA supplementation on body composition are conflicting. An association between muscle mass and physiological concentrations of EPA was already reported [4], with 55% of the variability in muscle change being explained by plasma EPA concentrations. The different methods used to assess body composition are another important limitation in EPA studies. Because body composition is the ultimate outcome analyzed in all studies, the chosen methodology to assess changes in body muscle and fat content has to be valid and concordant throughout studies. Most studies assessed body composition, especially LBM, with BIA; BIA is inexpensive, portable and safe, having a high potential to be implemented in clinical routine. However, it requires predictive and validated equations to estimate the quantity of lean tissues; moreover, hydration status (dehydration, edema) may alter BIA results. A recent study used CT scan images which, unlike BIA, provided a distinction among skeletal muscle mass and other lean tissues. Although the use of CT images for body composition assessment is a new area of research, it may become an accessible tool to be implemented in clinical practice as well, because CTs are routinely performed in cancer patients for diagnosis, staging and follow-up purposes. It requires specific software for image analysis and trained clinicians/researchers; yet, given the utmost added value of body composition analysis and its results and relevance for the overall prognosis and clinical management optimization, it is nowadays increasingly recognized as the gold standard for many cancer treatment centers. EPA and body composition in cancer: What the clinicians need to know This review aimed to convey the effect of oral nutritional supplementation enriched with EPA on important variables for patients: nutritional status, weight, and muscle mass, all of which are determinant for a better quality of life, and eventually disease progression and survival. Indeed, cancer-related sarcopenia/cachexia is a multifactorial syndrome characterized by inflammation, anorexia, weight loss, loss of muscle, and adipose tissue, mediated by proinflammatory cytokines, e.g., TNF-a and IL-6. All of the previously mentioned alterations may result in increased chemotherapy toxicity, costs, morbidity, and mortality. What needs be clarified is if EPA can reduce proinflammatory production and acute phase protein synthesis and if this is the potential way by which it modulates nutritional status. In detail, it is strongly advocated that the addition of EPA has a synergic effect with several chemotherapy agents. The mechanisms for these effects are not clear but may be associated with increased lipid peroxidation, tumor cell susceptibility to apoptosis, drug uptake, or even enhanced drug activation and diminished angiogenesis and metastasis. If all these clinical outcomes
improve, body composition improves, as well as phase angle indicating improved cellularity. In view of the modest survival benefits of cytotoxic chemotherapy/radiotherapy in some cancers, important issues for physicians are to optimize well-being, overall quality of life via nutritional status and adequate body composition. Thus, improvement in nutritional status is a central outcome. Future research Randomized controlled trials are needed to address the limitations and problems identified by authors in previous studies and to more accurately evaluate the potential benefits of EPA on outcomes as suggested in this review. Furthermore, studies need to be conducted in homogeneous groups of patients (same type of tumor, stage, treatment, dose/fractions) to clarify if patients supplemented with EPA do have a better response to chemotherapy/radiotherapy, in what doses is EPA supplementation effective, and comparisons with placebo arm is important to be blinded. The administration of EPA seems effective in improving nutritional status, weight, and muscle mass. In oncology, body composition has emerged as an important prognostic factor, and is associated with poor performance status, greater treatments’ toxicity and worse quality of life. Depletion of lean body mass and skeletal muscle (sarcopenia) in cancer patients has been well documented. Our review does show EPA supplementation may have a sustained positive effect in incrementing lean body mass (P ¼ 0.05) versus standard supplements. Another area to explore is u-3 fatty acids may help in the management of chronic inflammation; clinical trials have shown a diminution in CRP, IL-6, and TNF-a with EPA supplementation, whereas other studies have not shown significant differences. Of note, a reduced proinflammatory status could prevent cachexia. References [1] Fearon K, Strasser F, Anker SD, Bosaeus I, Bruera E, Fainsinger RL, et al. Definition and classification of cancer cachexia: An international consensus. Lancet Oncol 2011;12:423–4. [2] Bruera E, Strasser F, Palmer JL, Willey J, Calder P, Amyotte G, et al. Effect of fish oil on appetite and other symptoms in patients with advanced cancer and anorexia/cachexia: A double-blind, placebo-controlled study. J Clin Oncol 2003;21:129–34. [3] van der Meij BS, Langius JAE, Smit EF, Spreeuwenberg MD, Von Blomberg BME, Heijboer AC, et al. Oral nutritional supplements containing (u-3) polyunsaturated fatty acids affect the nutritional status of patients with stage III non-small cell lung cancer during multimodality treatment. J Nutr 2010;140:1774–80. [4] Murphy RA, Mourtzakis M, Chu QS, Reiman T, Mazurak VC. Skeletal muscle depletion is associated with reduced plasma (u-3) fatty acids in non-small cell lung cancer patients. J Nutr 2010;140:1602–6. [5] Mostofsky DI, Yehuda S, Salem N. Fatty acids-physiological and behavioral functions. Humana Press; 2001. [6] Fearon K, Von Meyenfeldt MF, Moses AGW, Van Geenen R, Roy A, Gouma DJ, et al. Effect of a protein and energy dense u-3 fatty acid enriched oral supplement on loss of weight and lean tissue in cancer cachexia: A randomised double blind trial. Gut 2003;52:1479–86. [7] Read JA, Beale PJ, Volker DH, Smith N, Childs A, Clarke SJ. Nutrition intervention using an eicosapentaenoic acid (EPA)-containing supplement in patient with advanced colorectal cancer. Effects on nutritional and inflammatory status: A phase II trial. Support Care Cancer 2007;15:301–7. [8] Barber MD, Ross JA, Voss AC, Tisdale MJ, Fearon K. The effect of an oral nutritional supplement enriched with fish oil on weight-loss in patients with pancreatic cancer. Br J Cancer 1999;81:80–6. [9] Murphy RA, Yeung E, Mazurak VC, Mourtzakis M. Influence of eicosapentaenoic acid supplementation on lean body mass in cancer cachexia. Br J Cancer 2011;105:1469–73. [10] van der Meij BS, Langius JAE, Spreeuwenberg MD, Slootmaker SM, Paul MA, Smit EF, et al. Oral nutritional supplements containing u-3 polyunsaturated fatty acids affect quality of life and functional status in lung cancer patients during multimodality treatment: An RCT. Eur J Clin Nutr 2012;66:399–404.
G. Pappalardo et al. / Nutrition 31 (2015) 549–555 [11] Rock CL, Doyle C, Demark-Wahnefried W, Meyerhardt J, Courneya KS, Schwartz AL, et al. Nutrition and physical activity guidelines for cancer survivors. CA Cancer J Clin 2012;62:242–74. [12] Wigmore SJ, Ross JA, Falconer S, Plester CE, Tisdale MJ, Carter DC, et al. The effect of polyunsaturated fatty acids on the progress of cachexia in patients with pancreatic cancer. Nutrition 1996;12:S27–30. [13] Dewey A, Baughan C, Dean T, Higgins B, Johnson I. Eicosapentaenoic acid(EPA), an omega to 3 to fatty acid from fish oils) for the treatment of cancercachexia. Cochrane Database Syst Rev 2007;24:CD004597. [14] Wigmore SJ, Barber MD, Ross JA, Tisdale MJ, Fearon K. Effect of oral eicosapentaenoic acid on weight loss in patients with pancreatic cancer. Nutr Cancer 2000;36:177–84. [15] Barber MD, Fearon K. Tolerance and incorporation of high-dose eicosapentaenoic acid diester emulsion by patients with pancreatic cancer cachexia. Lipids 2001;36:347–51. [16] Bauer JD, Capra S. Nutrition intervention improves outcomes in patients with cancer cachexia receiving chemotherapy- a pilot study. Support Care Cancer 2005;13:270–4. [17] Murphy RA, Mourtzakis M, Chu QSC, Baracos VE, Reiman T, Mazurak VC. Supplementation with fish oil increases first-line chemotherapy efficacy in patients with advanced non-small cell lung cancer. Cancer 2011; 117:3774–80. [18] Ryan AM, Reynolds JV, Healy L, Byrne M, Moore J, Brannelly N, et al. Enteral nutrition enriched with eicosapentaenoic acid (EPA) preserves lean body mass following esophageal cancer surgery: Results of a double-blinded randomized controlled trial. Ann Surg 2009;249:355–63.
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[19] Weed HG, Ferguson ML, Gaff RL, Hustead DS, Nelson JL, Voss AC. Lean body mass gain in patients with head and neck squamous cell cancer treated perioperatively with protein-and energy-dense nutritional supplement containing eicosapentaenoic acid. Head Neck 2011;33: 1027–33. [20] Murphy RA, Mourtzakis M, Chu QSC, Baracos VE, Reiman T, Mazurak VC. Nutritional intervention with fish oil provides a benefit over standard of care for weight and skeletal muscle mass in patients with non-small cell lung cancer receiving chemotherapy. Cancer 2011;117:1775–82. [21] Fearon K, Barber MD, Moses AG, Ahmedzai SH, Taylor GS, Tisdale MJ, et al. Double-blind, placebo-controlled, randomized study of eicosapentaenoic acid diester in patients with cancer cachexia. J Clin Oncol 2006;24:3401–7. [22] Bougnoux P, Hajjaji N, Maheo K, Couet C, Chevalier S. Fatty acids and breast cancer: Sensitization to treatment and prevention of metastatic regrowth. Prog Lipid Res 2010;49:76–86. [23] Jatoi A, Rowland K, Loprinzi CL, Sloan JA, Dakhil SR, MacDonald N, et al. An eicosapentaenoic acid supplement versus megestrol acetate versus both for patients with cancer-associated wasting: A north central cancer treatment group and national institute of Canada collaborative effort. J Clin Oncol 2004;22:2469–76. [24] Moses AWG, Slater C, Preston T, Barber MD, Fearon K. Reduced total energy expenditure and physical activity in cachectic patients with pancreatic cancer can be modulated by an energy and protein dense oral supplement enriched with u-3 fatty acids. Br J Cancer 2004;90: 996–1002.
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Applied nutritional investigation
Eicosapentaenoic acid in cancer improves body composition and modulates metabolism Giulia Pappalardo R.D., Ana Almeida R.D., Paula Ravasco M.D., Ph.D., M.Sc., R.D. * ~o da Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal rio de Nutric¸a Laborato
a r t i c l e i n f o
a b s t r a c t
Article history: Received 8 August 2014 Accepted 2 December 2014
Objectives: The objective of this review article is to present the most recent intervention studies with EPA on nutritional outcomes in cancer patients, e.g. nutritional status, weight & lean body mass. Methods: For this purpose a PubMedÒ and MedLineÒ search of the published literature up to and including January 2014 that contained the keywords: cancer, sarcopenia, EPA, u-3 fatty acids, weight, intervention trial, muscle mass was conducted. The collected data was summarized and written in text format and in tables that contained: study design, patient’ population, sample size, statistical significance and results of the intervention. The paper will cover malignancy, body composition, intervention with EPA, physiological mechanisms of action of EPA, effect of EPA on weight and body composition, future research. Results: In cancer patients deterioration of muscle mass can be present regardless of body weight or Body Mass Index (BMI). Thus, sarcopenia in cancer patients with excessive fat mass (FM), entitled sarcopenic obesity, has gained greater relevance in clinical practice; it can negatively influence patients’ functional status, tolerance to treatments & disease prognosis. The search for an effective nutritional intervention that improves body composition (preservation of muscle mass and muscle quality) is of utmost importance for clinicians and patients. The improvement of muscle quality is an even more recent area of interest because it has probable implications in patients’ prognosis. Eicosapentaenoic acid (EPA) has been identified as a promising nutrient with the wide clinical benefits. Several mechanisms have been proposed to explain EPA potential benefits on body composition: inhibition of catabolic stimuli by modulating pro-inflammatory cytokines production and enhancing insulin sensitivity that induces protein synthesis; also, EPA may attenuate deterioration of nutritional status resulting from antineoplastic therapies by improving calorie and protein intake as well. Conclusions: Indeed, cancer-related sarcopenia/cachexia is a multifactorial syndrome characterized by inflammation, anorexia, weight loss, and muscle/adipose tissue loss mediated by proinflammatory cytokines, e.g. TNF-a and IL-6, resulting in increased chemotherapy toxicity, costs, morbidity and mortality. With this review we found that EPA can reduce inflammation and has the potential to modulate nutritional status/body composition. In view of the modest survival benefits of chemotherapy/radiotherapy in some cancers, important issues for physicians are to optimize well-being, Quality of Life via nutritional status and adequate body composition. Thus, improvement in nutritional status is a central outcome. Ó 2015 Elsevier Inc. All rights reserved.
Keywords: Cancer Nutrition Eicosapentanoic acid Muscle mass Body composition
Introduction Cancer: Nutritional deterioration, sarcopenia and cachexia Nutritional deterioration in cancer patients is a reality that continues untreated and is still a mystery for some clinicians. * Corresponding author. Tel.: þ351 217985141; fax: þ351 217985142. E-mail address: [email protected] (P. Ravasco). http://dx.doi.org/10.1016/j.nut.2014.12.002 0899-9007/Ó 2015 Elsevier Inc. All rights reserved.
Cancer cachexia is defined as a “multifactorial syndrome characterized by an ongoing loss of skeletal muscle mass (with or without loss of fat mass) that cannot be fully reversed by conventional nutritional support and leads to progressive functional impairment” [1]. The diagnosis of cachexia is made according to the following criteria: Weight loss greater than 5% in the last 6 mo or weight loss greater than 2% in individuals already showing nutritional depletion according to current body weight and height (body mass index [BMI] < 20 kg/m2) or reduced
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skeletal muscle mass (sarcopenia). Severity can be classified according to the degree of depletion of energy stores and of body protein, in combination with ongoing weight loss [1]. Patients who are cachectic may have anorexia, nausea, and other symptoms that may compromise food intake, reduce strength, impair functional capacity, and worsen their quality of life [2]. Although cancer treatments, such as chemotherapy or radiotherapy, may also cause weight loss and symptoms that may diminish nutritional status, the mechanisms associated with these clinical findings are totally different from those found in progressive tissue wasting [3–5]. Anorexia and increased energy expenditure may contribute to cancer cachexia; anorexia may be induced by proinflammatory cytokines (interleukin [IL]-1 a, IL-1 b, IL-6, and tumor necrosis factor [TNF]-a) released by both the tumor and the host’s immune system. Conversely, the hypermetabolic state may result from the production of acute phase proteins (C-reactive protein, fibrinogen, and a-1 antitrypsin) by the liver. Still, anorexia alone is not responsible for the wasting process and not all cancer patients are hypermetabolic [6]. Therefore, there have to be other mechanisms behind metabolic alterations associated with cancer cachexia, namely tumor and host factors that may activate lipogenic and proteolytic pathways [7]. All of these observations justify the research to find and/or optimize nutritional intervention that improves body composition, particularly muscle mass and muscle quality [7,8].
Body composition assessment Although patients’ weight loss is a highly relevant parameter to be assessed and registered in the clinical routine, it does not allow us to distinguish body compartments, namely lean body mass (LBM) or fat mass (FM), and therefore to identify muscle and/or fat loss [3,9]. Moreover, clinical reports show that nutritional status in cancer patients is highly diverse: Studies show a high prevalence of overweight and obesity, even in patients with low muscle mass. This body composition pattern, designated as sarcopenic obesity, has been established as a predictor of poor functional status, worse quality of life and reduced survival [4,5]. Body weight comprises two main compartments: fat free mass (FFM) and fat mass (FM); FFM includes mineral tissue and muscle mass, e.g., extracellular and intracellular water and metabolically active tissues: skeletal muscle and internal organs. According to the method used, different body composition compartments may be measured. Although simple and practical methods such as bioelectrical impedance analysis (BIA) do not distinguish skeletal muscle from other metabolically active tissues, image-based body composition methods like computed tomography (CT), allow a precise evaluation of the quantity and quality of skeletal muscle [10,11]. Recently, CT images at the level of the third lumbar vertebrae have been validated in oncology for body composition analysis, by comparison with the gold standard method: dual energy x-ray absorptiometry [11]. Studies have already used CT images to identify sarcopenic cancer patients and did find significant associations with disease prognosis and survival. Fearon et al [6]. found a prevalence of sarcopenia of 56% in pancreatic cancer patients by analyzing their CT images; sarcopenia was present in all BMI categories, including overweight/obese patients; these patients had the overall worst prognosis, even when compared with patients who were only sarcopenic and underweight [4, 9]. The fact is the presence of overweight/obesity may mask the presence of reduced muscle mass, and in the absence of
imaging body composition methods, sarcopenia may be underdiagnosed and undertreated [12]. Eicosapentaenoic acid Polyunsaturated fatty acids include two classes of fatty acids,
u-6 and u-3 fatty acids. The u-6 series includes linoleic acid (LA, 18:2 u-6), arachidonic acid (AA, 20:4 u-6), and gamma-linoleic acid (GLA, 18:3 u-6); all can be found in foods of animal origin, some vegetables, sunflower, soybeans, and grape seed oils. The u-3 series includes the alfa-linoleic acid (ALA, 18:3 u-3) present in green vegetables, in rapeseed and soybean oils; eicosapentaenoic acid (EPA, 20:5 u-3) and docosahexaenoic acid (DHA, 22:6 u-3) are ubiquitous in mammals, seafood, and marine products. u-3 polyunsaturated fatty acids are essential nutrients for humans, because humans lack the delta to 15 desaturase that converts u-6 fatty acids into u-3 fatty acids [5]. Although the use of vitamins, minerals, and other dietary supplements during cancer treatment remains controversial [11], it has been suggested that the supplementation with either fish oil or EPA alone in patients with advanced cancer and cachexia, may contribute to skeletal muscle preservation, improved appetite and weight gain [9]. EPA has different effects on LBM via two main mechanisms: reduced muscle degradation and increased muscle synthesis. EPA influences proteolysis by down regulating the acute phase response, by reducing serum concentration of C-reactive protein (CRP) and by suppressing IL-6 production [13]. On the other hand, EPA may decrease muscle wasting by down regulating the ubiquitin proteasome pathway that is the central pathway in muscle loss. Additionally, EPA reduces muscle apoptosis by reducing TNF-a [12,14]. EPA increases muscle insulin sensitivity, thus improving protein and calorie intake [13]. EPA also has indirect effects on nutritional status because it was demonstrated it reduces chemotherapy side effects and enhances tumor response to antineoplastic treatments [7]. Moreover, EPA may attenuate side effects from antineoplastic therapies, by improving calorie and protein intake [15]. It is worth mentioning that recent trials corroborate EPA’s potential benefits on muscle mass preservation [5,12,15–17]. EPA, weight and body composition The potential antiinflammatory effects of EPA and their influence on weight and body composition have already been shown in several studies (Table 1). Early reports did show positive and promising results: Maintenance or even improvement of weight and LBM. Wigmore et al. [14] reported that EPA supplementation had a positive effect on weight losing pancreatic cancer patients: 61% of patients experienced weight gain, whereas 17% became weight stable and 22% reduced the rate of weight loss. Even though no changes were found in anthropometric measures, after 1 mo of supplementation, a significant, although temporary, reduction in CRP concentration was found (P < 0.002), as well as a stabilization of resting energy expenditure. Similarly, in a study by Barber et al. [8] that enrolled weight losing pancreatic cancer patients, beneficial effects of EPA were described on weight and LBM. Daily energy intake was significantly increased (P ¼ 0.002), whereas both performance status and appetite significantly improved after 3 wk of supplementation (P < 0.005 and P < 0.01, respectively). Although EPA supplementation had positive effects on weight and LBM maintenance in the previously mentioned studies, these were uncontrolled, not-randomized, and enrolled a small
Table 1 Statistically and clinically positive intervention studies with EPA and/or DHA and outcomes Population and study design
Intervention
Outcomes
Results
Wigmore, et al [12]
18 patients Advanced pancreatic cancer Open-label, single-arm Phase II study 20 patients Pancreatic cancer Single-arm study
Fish oil capsules (1 g EPA 18%; DHA 12%) 2 g/d fish oil, increased at weekly intervals by 2 g, to maximum dose of 16 g/d.
Weight Anthropometry: MAMC and TSF
Increase in weight of 0.3 kg/month (P < 0.002). No significant change in MAMC and TSF values.
Fish oil-enriched oral nutritional supplement 2 cans/d (2.2 g EPA þ 0.96 g) Follow-up at 3 and 7 wk from baseline.
Weight Anthropometry: TSF þ MUAMC BIA: LBM and FM
Increase in weight at 3 and 7 wk of median 1 kg (P ¼ 0.028) and 2 kg (P ¼ 0.033), respectively. Increase in LBM at 3 and 7 wk of median 1.0 (P ¼ 0.0064) and 1.9 kg (P ¼ 0.0047), respectively. Decrease in median weight loss after 4 wk of EPA vs. pre study values (P < 0.005); reduction remained significant at 8 and 12 wk (P < 0.005). No significant change in MUAMC or TSF at 4, 8 or 12 wk of EPA vs. pre study values. Increase in weight and LBM (NS). Increase in LBM associated with better nutritional status (r ¼ 0.998, P ¼ 0.04). Increase in weight at end of week 3 (mean increase of 2.5 kg from baseline, P ¼ 0.03) and maintenance during chemotherapy. No significant change in LBM before and during chemotherapy.
Barber, et al [8]
Wigmore, et al [14]
26 patients Pancreatic cancer Single-arm study
Gelatin capsules high-purity EPA (500 mg) 1 g/d EPA on first week, 2 g/d for the second week, 4 g/d for the third week and 6 g/d thereafter Follow-up at 4, 8 and 12 wk
Weight Anthropometry: TSF and MUAMC
Bauer, et al [16]
7 patients Pancreatic and lung cancer Open-label, single-arm study 23 patients (15 patients at baseline) Advanced colorectal cancer Open-label, single-arm study
EPA enriched oral nutritional supplement At least 1 can/d (1.1 g EPA/d) Follow-up at 8 wk EPA enriched oral nutritional supplement 2 cans/d (1.18 g EPA þ 0.92 g DHA/day) Follow-up at 3 and 9 wk 4 cycles of chemotherapy regimen with FOLFIRI, commenced at end of week 3 and repeated every 2 wk. EPA enriched enteral feed (2.2 g EPA/d) during 5 d preoperatively, 2–10 d postoperatively and 11–21 d concomitantly with oral diet. Controls: Feeding regimen with an iso-caloric, iso-nitrogenous enteral feed. Fish-oil enriched oral nutritional supplement 2 cans/d (2.2 g EPAþ0.92 g) Supplement consumed from no later than 2 wk before surgery until discharge Mean SD time between trial entry and hospital admission: 23 2.5 d Mean SD time between hospital admission and discharge: 11 0.85 d Fish-oil enriched oral nutritional supplement (energy þ protein-dense) 2 cans/d (2 g EPAþ0.92 g DHA) Control group: Isocaloric oral nutritional supplement without EPA þ DHA. Follow-up at 3 and 5 wk
Weight LBM with staple isotope deuterium
Read, et al [7]
Ryan, et al [18]
53 patients Oesophageal cancer Double-blind, randomized, controlled trial
Weed, et al [19]
31 patients Head-neck cancer scheduled for surgery with curative intent Open-label, single-arm study
van der Meij, et al. [3]
40 patients Lung cancer Double-blind, randomized, controlled trial
Murphy RA, et al [20]
31 patients (24 controls vs. 16 intervention) Lung cancer Open-label, single arm study, contemporaneous control group
2 types of supplementation: 4 1 g gelatin capsules fish oil/d (2.2 g EPA) or 7.5 mL of liquid fish oil/d (2.2 g EPA). Control group: No intervention Follow-up after 2 cycles of chemotherapy (at least 6 wk)
Weight BIA: LBM (single frequency, tetrapolar device BIM-4, SEAC Pty Ltd)
Weight BIA: LBM and FM
Weight BIA: LBM and FM
Weight BIA: FFM MUAC
Weight CT images: Skeletal muscle, adipose tissue, muscle attenuation
EPA enriched feed regimen group: No significant difference in weight and FFM from preoperatively to day 21 postoperatively. Control group: Weight loss of 1.8 kg (P ¼ 0.03) and LBM loss of 1.9 kg (P ¼ 0.03). Increase/maintenance in weight in 57% patients until hospital discharge. Increase in LBM increase from trial entry to hospital discharge (þ3.2 kg, P < 0.001).
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Author (y)
EPA group: Weight maintenance (weight difference between intervention group and control group: 1.3 kg, P ¼ 0.02 at 3 wk and 1.7 kg, P ¼ 0.04 at 5 wk), less decrease in FFM (FFM difference between intervention (1.5 kg at 3 wk and 1.9 kg at 5 wk) and increased MUAMC, whereas the MUAMC in the control group decrease (difference between groups not significant at 3 and 5 wk). Fish oil group: 69% patients maintained or gained weight (mean weight change: 0.5 1.0 kg) and muscle (MM at baseline: 25.4 1.4 kg vs. MM at end of treatment: 25.4 1.5 kg, NS). Control group: 29% patients maintained or gained weight (mean weight change: 2.3 0.9 kg) and muscle (MM at baseline: 24.4 1.0 kg vs. MM at end of treatment: 23.5 1.0 kg, P < 0.002. 551
BIA, bioelectric impedance analysis; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; FM, fat mass; FFM, free fat mass; LBM, lean body mass; MM, muscle mass; MUAMC, midupper arm muscle circumference; MUAC, midupper arm circumference; NS, not significant; TSF, triceps skinfold thickness
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number of patients. Therefore, double-blind, randomized, and controlled clinical trials, including larger study populations were needed. Fearon et al. [6] conducted an international, multicenter, randomized, double-blind trial that enrolled at baseline 200 pancreatic cancer patients; this trial failed to show the potential advantage of an EPA-enriched supplement on nutritional parameters and quality of life, no difference between the experimental versus the control. The authors found two reasons for this lack of effect: low compliance to the oral nutritional supplement enriched with u-3 fatty acids. Indeed, in the pilot study of Barber et al. in 1999, a net gain of LBM was experienced with a dose of 2.1 g/d of EPA (equivalent to 1.9 cans/d); however, in the clinical trial by Fearon et al., the mean level of intake reached was 1.5 g of EPA (equivalent to 1.4 cans/d of nutritional supplement), which is insufficient to have a physiological effect, compared with an energy/protein dense control supplement. The other reason found by the authors was patients in the control group failed to declare the self-use of u-3 fatty acids supplements; both factors compromised any comparisons and differences between control and experimental group. Despite the lack of positive results, the EPA to enriched supplement was positively correlated with increased body weight and LBM (r ¼ 0.50, P < 0.001 and r ¼ 0.33, P < 0.036, respectively), as well as with a better quality of life (r ¼ 0.37, P ¼ 0.01). Plus, no statistically significant correlations were observed in the control group. To overcome the compliance issues, Fearon et al. [21] conducted a second large multicenter double-blind, randomized, placebo-controlled trial in gastrointestinal and lung cancer patients, to evaluate the effect of two doses (2 and 4 g/d) of EPA as soft gel capsules versus placebo for 8 wk. Besides weight and body composition, Karnofsky performance status, quality of life, CRP levels and appetite were also evaluated at 4-weekly intervals for 24 wk. A marginal statistically significance was found as well as an important clinical difference in increased weight in patients receiving 2 g of EPA daily, versus placebo; yet, no benefit was observed with a supplementation of 4 g/d of EPA, clarifying the lack of a dose response beyond 2 g/d. In what concerns the other outcomes, besides a modest improvement in physical function, no significant differences were observed. Based on these results, authors classified the potential benefits of u-3 fatty acids as marginal and even suggested further studies and comparisons with other agents or combination regimens with potential anticachectic effects. Similar results were obtained by Bruera et al. [2], which found no significant improvement in weight or body composition, as well as in physical function, appetite, or other symptoms after an intervention with fish oil capsules for 2 wk, equivalent to a mean daily dose of 1.8 g of EPA [5,11]. Recently, other clinical trials reported a positive effect of EPA on nutritional status, namely improved weight and LBM (Table 1). Ryan et al. conducted a double-blind, randomized controlled study in patients with esophageal cancer referred for surgery or neoadjuvant chemotherapy radiotherapy. The experimental group received 5 d of preoperative supplementation of an EPA-enriched formula, and the control group received a standard formula (without EPA) in both groups were maintained postoperatively by a jejunostomy for 21 d. LBM was preserved in the EPA group (55 kg preop versus 55.3 kg postop, P ¼ 0.08), whereas the control group had a significant loss of LBM (-1.9 3.7 kg, P ¼ 0.03). Moreover, postoperative inflammatory response was attenuated, with a lower expression of proinflammatory cytokines in the intervention group, conceivably because of EPA incorporation into cell membranes. Another recent study [19] was conducted in surgical cancer patients
treated perioperatively with an EPA-enriched nutritional supplement. Contrarily to the previous trial, this was an open-label, single-arm study in patients with head-neck cancer who received a protein þ energy-dense EPA-containing supplement in addition to oral intake or as part of their enteral feeding before surgery and throughout treatment until discharge. The authors found there was a significant increase in LBM versus baseline (P < 0.001). In a study of van der Meij et al. [3], the effect of an EPA containing nutritional supplement on nutritional status, body composition and inflammatory markers was also tested in patients with lung cancer; 33 patients with stage III non-small cell lung cancer referred for chemotherapy þ radiotherapy were included in a double-blind, randomized, controlled trial. Weight and LBM maintenance were achieved (P < 0.05) and there was a trend for increased midupper arm circumference (P ¼ 0.06) in the experimental group and not in the control group. Although no statistical difference was found on inflammatory markers between groups, patients in the EPA group presented higher EPA content in plasma phospholipids, that were negatively correlated with inflammatory markers, i.e., IL-6 and CRP (r ¼ 0.8, P < 0.04 and 0.8, P < 0.05, respectively). In the same study population and using the same study design, EPA effects in quality of life and functional status were assessed [10]. There was a significant improvement in quality-of-life dimensions, namely physical and cognitive functions (P ¼ 0.01), global health status (P ¼ 0.04), and social function (P ¼ 0.04) in the EPA intervention group and never in the control group. Also, patients in the intervention group had higher physical activity measured by accelerometer versus controls (P < 0.05). In an open-label trial with EPA supplements in non-small cell lung cancer patients during chemotherapy, CT scan images were used to assess body composition; weight and LBM were also evaluated [20]. CT showed the quantity and quality of muscle mass (skeletal muscle index and muscle attenuation); there was a reduction in muscle and fat tissue wasting, resulting in the maintenance of weight and muscle mass during chemotherapy. Muscle fat infiltration assessed with skeletal muscle attenuation showed that at the end of treatment, the control group had a significant reduction in muscle attenuation (30.1 1.7 HU versus 33.6 1.7 HU at baseline, P < 0.001), indicating an increase in muscle fat infiltration. A significant reduction in whole-body skeletal muscle (23.5 1.0 kg versus 24.4 1.0 kg at baseline, P ¼ 0.002) was also observed, whereas muscle attenuation and whole-body skeletal muscle were maintained during chemotherapy in the EPA intervention group [17,22]. All these positive results indicate EPA may be highly beneficial, but methodological issues in conducting intervention studies need to be clarified to have consistent data. Until now, we still have some inconsistent data surrounding the benefits of EPA, and we present the sum of negative intervention studies with EPA (Table 2). Clinical trials: Questions and challenges The high variability of study designs may be one of the major causes for the discrepant results found across studies using EPA supplementation we included in this review [23]. Subsequent studies adopted different and more accurate nutrition intervention methodologies with supplementation (randomized trials), to address limitations and problems identified in the first studies conducted with EPA supplementation, namely compliance and contamination between study arms [6,13]. In reality, Murphy et al. [7] tried to overcome these issues by conducting an open-label trial, in which patients could choose between two
Table 2 Statistically and clinically negative intervention studies with EPA and/or DHA and outcomes Population and study design
Intervention
Outcomes
Results
Fearon, et al [6]
200 pancreatic cancer pts Multicenter, double-blind, randomized, controlled trial
Fish-oil enriched oral nutritional supplement 2 cans/d (2.2 g EPAþ0.96 g) Control group: Identical oral nutritional supplement without EPA þ DHA. Follow-up at 8 wk from baseline
Weight BIA: LBM þ FM (multifrequency analyser Xitron Hydra)
Bruera, et al [2]
60 patients Advanced cancer (different location tumors) Double-blind, randomized, controlled trial
Anthropometry: MAC, TSF, and subscapular skinfold BIA: LBM and FM
Moses, et al [24]
19 patients (15 in intervention vs. 7 in control group) Pancreatic cancer Double-blind, randomized, controlled trial
Weight BIA: LBM (Xitron Hydra, Xitron Technologies)
No significant changes in weight or LBM in either group over 8 wk of supplementation vs. baseline values.
Jatoi, et al [23]
421 patients; different cancers excluding brain, prostate, gynecologic. Multicenter, double-blind, randomized trial
Weight
Fearon, et al [21]
518 patients Advanced gastrointestinal (n ¼ 287) and lung (n ¼ 231) cancer Multicenter, double-blind, randomized, controlled trial
Gelatin capsules of fish oil 3.24 EPAþ2.16 mg DHA/d Control group: Gelatin capsule with 1000 mg of olive oil Follow-up at 2 wk from baseline Fish-oil enriched oral nutritional supplement 2 cans/d (2.2 g EPAþ0.96 gDHA/d) Control group: Identical oral nutritional supplement without u-3 fatty acids. Follow-up at 8 wk from baseline Fish oil-enriched oral nutritional supplement: 2 cans/d (2.2 g EPAþ0.92 g DHA]. 3 groups: EPA supplement þ placebo; MA þ isocaloric, isonitrogenous placebo; EPA nutritional supplement þ megestrol acetate. Follow-up weekly for 4 wk and then monthly. Gelatin capsules of 95% EPA diester Two EPA doses tested: 2 g EPA/d and 4 g EPA/d Control group: Medium chain triacylglycerols Follow-up at 8 wk from baseline.
No statistical difference in weight or LBM between intervention and control. Significant attenuation of weight and LBM loss in both groups. Significant positive correlation between supplement intake and increased weight (r ¼ 0.5, P < 0.001) and LBM (r ¼ 0.33, P ¼ 0.036). No statistical difference for anthropometric measures and LBM between intervention and control group.
No significant change in weight with EPA alone or in combination with MA. 6% patients taking EPA supplement gained 10% baseline weight vs. 18% of patients taking MA (P ¼ 0.004). MA alone was more effective for weight gain: 1.3 kg vs. -1.0 kg in the EPA-treated arm, P ¼ 0.008 No statistical difference for weight and LBM between groups (P ¼ 0.066 and P ¼ 0.14, respectively). By comparison with control group, the group receiving 2 g EPA/d had a mean increase of 1.2 kg of weight and of 0.9 kg of LBM and group receiving 4 g EPA had a mean increase of 0.3 kg of weight and a mean decrease of 0.1 kg of LBM.
Weight BIA: LBM (Bodystat 1500 bioelectrical impedance analyzer)
G. Pappalardo et al. / Nutrition 31 (2015) 549–555
Author (y)
BIA, bioelectric impedance analysis; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; FM, fat mass; FFM, free fat mass; LBM, lean body mass; MM, muscle mass; MUAMC, midupper arm muscle circumference; MUAC, midupper arm circumference; NS, not significant; TSF, triceps skinfold thickness
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different types of supplementation: liquid fish oil or gelatin capsules. A compliance rate of >95% was achieved, allowing an EPA intake of 2.1 0.6 g/d, which is equivalent to the acknowledged therapeutic dose and may exert potential health benefits. This allowed for EPA intake to be similar to the recommended amount. The measurement of phospholipids’ EPA concentration may be a useful parameter to assess compliance and cross-arm contamination; notwithstanding, it may also be highly relevant to evaluate EPA incorporation in cell membranes and tissues. Despite the high compliance in the Murphy et al. [17] study, plasma EPA concentration in phospholipids was variable, as well as muscle mass change. Because EPA incorporation into cells and tissues is needed to have a physiological effect, it may explain why the results of EPA supplementation on body composition are conflicting. An association between muscle mass and physiological concentrations of EPA was already reported [4], with 55% of the variability in muscle change being explained by plasma EPA concentrations. The different methods used to assess body composition are another important limitation in EPA studies. Because body composition is the ultimate outcome analyzed in all studies, the chosen methodology to assess changes in body muscle and fat content has to be valid and concordant throughout studies. Most studies assessed body composition, especially LBM, with BIA; BIA is inexpensive, portable and safe, having a high potential to be implemented in clinical routine. However, it requires predictive and validated equations to estimate the quantity of lean tissues; moreover, hydration status (dehydration, edema) may alter BIA results. A recent study used CT scan images which, unlike BIA, provided a distinction among skeletal muscle mass and other lean tissues. Although the use of CT images for body composition assessment is a new area of research, it may become an accessible tool to be implemented in clinical practice as well, because CTs are routinely performed in cancer patients for diagnosis, staging and follow-up purposes. It requires specific software for image analysis and trained clinicians/researchers; yet, given the utmost added value of body composition analysis and its results and relevance for the overall prognosis and clinical management optimization, it is nowadays increasingly recognized as the gold standard for many cancer treatment centers. EPA and body composition in cancer: What the clinicians need to know This review aimed to convey the effect of oral nutritional supplementation enriched with EPA on important variables for patients: nutritional status, weight, and muscle mass, all of which are determinant for a better quality of life, and eventually disease progression and survival. Indeed, cancer-related sarcopenia/cachexia is a multifactorial syndrome characterized by inflammation, anorexia, weight loss, loss of muscle, and adipose tissue, mediated by proinflammatory cytokines, e.g., TNF-a and IL-6. All of the previously mentioned alterations may result in increased chemotherapy toxicity, costs, morbidity, and mortality. What needs be clarified is if EPA can reduce proinflammatory production and acute phase protein synthesis and if this is the potential way by which it modulates nutritional status. In detail, it is strongly advocated that the addition of EPA has a synergic effect with several chemotherapy agents. The mechanisms for these effects are not clear but may be associated with increased lipid peroxidation, tumor cell susceptibility to apoptosis, drug uptake, or even enhanced drug activation and diminished angiogenesis and metastasis. If all these clinical outcomes
improve, body composition improves, as well as phase angle indicating improved cellularity. In view of the modest survival benefits of cytotoxic chemotherapy/radiotherapy in some cancers, important issues for physicians are to optimize well-being, overall quality of life via nutritional status and adequate body composition. Thus, improvement in nutritional status is a central outcome. Future research Randomized controlled trials are needed to address the limitations and problems identified by authors in previous studies and to more accurately evaluate the potential benefits of EPA on outcomes as suggested in this review. Furthermore, studies need to be conducted in homogeneous groups of patients (same type of tumor, stage, treatment, dose/fractions) to clarify if patients supplemented with EPA do have a better response to chemotherapy/radiotherapy, in what doses is EPA supplementation effective, and comparisons with placebo arm is important to be blinded. The administration of EPA seems effective in improving nutritional status, weight, and muscle mass. In oncology, body composition has emerged as an important prognostic factor, and is associated with poor performance status, greater treatments’ toxicity and worse quality of life. Depletion of lean body mass and skeletal muscle (sarcopenia) in cancer patients has been well documented. Our review does show EPA supplementation may have a sustained positive effect in incrementing lean body mass (P ¼ 0.05) versus standard supplements. Another area to explore is u-3 fatty acids may help in the management of chronic inflammation; clinical trials have shown a diminution in CRP, IL-6, and TNF-a with EPA supplementation, whereas other studies have not shown significant differences. Of note, a reduced proinflammatory status could prevent cachexia. References [1] Fearon K, Strasser F, Anker SD, Bosaeus I, Bruera E, Fainsinger RL, et al. Definition and classification of cancer cachexia: An international consensus. Lancet Oncol 2011;12:423–4. [2] Bruera E, Strasser F, Palmer JL, Willey J, Calder P, Amyotte G, et al. Effect of fish oil on appetite and other symptoms in patients with advanced cancer and anorexia/cachexia: A double-blind, placebo-controlled study. J Clin Oncol 2003;21:129–34. [3] van der Meij BS, Langius JAE, Smit EF, Spreeuwenberg MD, Von Blomberg BME, Heijboer AC, et al. Oral nutritional supplements containing (u-3) polyunsaturated fatty acids affect the nutritional status of patients with stage III non-small cell lung cancer during multimodality treatment. J Nutr 2010;140:1774–80. [4] Murphy RA, Mourtzakis M, Chu QS, Reiman T, Mazurak VC. Skeletal muscle depletion is associated with reduced plasma (u-3) fatty acids in non-small cell lung cancer patients. J Nutr 2010;140:1602–6. [5] Mostofsky DI, Yehuda S, Salem N. Fatty acids-physiological and behavioral functions. Humana Press; 2001. [6] Fearon K, Von Meyenfeldt MF, Moses AGW, Van Geenen R, Roy A, Gouma DJ, et al. Effect of a protein and energy dense u-3 fatty acid enriched oral supplement on loss of weight and lean tissue in cancer cachexia: A randomised double blind trial. Gut 2003;52:1479–86. [7] Read JA, Beale PJ, Volker DH, Smith N, Childs A, Clarke SJ. Nutrition intervention using an eicosapentaenoic acid (EPA)-containing supplement in patient with advanced colorectal cancer. Effects on nutritional and inflammatory status: A phase II trial. Support Care Cancer 2007;15:301–7. [8] Barber MD, Ross JA, Voss AC, Tisdale MJ, Fearon K. The effect of an oral nutritional supplement enriched with fish oil on weight-loss in patients with pancreatic cancer. Br J Cancer 1999;81:80–6. [9] Murphy RA, Yeung E, Mazurak VC, Mourtzakis M. Influence of eicosapentaenoic acid supplementation on lean body mass in cancer cachexia. Br J Cancer 2011;105:1469–73. [10] van der Meij BS, Langius JAE, Spreeuwenberg MD, Slootmaker SM, Paul MA, Smit EF, et al. Oral nutritional supplements containing u-3 polyunsaturated fatty acids affect quality of life and functional status in lung cancer patients during multimodality treatment: An RCT. Eur J Clin Nutr 2012;66:399–404.
G. Pappalardo et al. / Nutrition 31 (2015) 549–555 [11] Rock CL, Doyle C, Demark-Wahnefried W, Meyerhardt J, Courneya KS, Schwartz AL, et al. Nutrition and physical activity guidelines for cancer survivors. CA Cancer J Clin 2012;62:242–74. [12] Wigmore SJ, Ross JA, Falconer S, Plester CE, Tisdale MJ, Carter DC, et al. The effect of polyunsaturated fatty acids on the progress of cachexia in patients with pancreatic cancer. Nutrition 1996;12:S27–30. [13] Dewey A, Baughan C, Dean T, Higgins B, Johnson I. Eicosapentaenoic acid(EPA), an omega to 3 to fatty acid from fish oils) for the treatment of cancercachexia. Cochrane Database Syst Rev 2007;24:CD004597. [14] Wigmore SJ, Barber MD, Ross JA, Tisdale MJ, Fearon K. Effect of oral eicosapentaenoic acid on weight loss in patients with pancreatic cancer. Nutr Cancer 2000;36:177–84. [15] Barber MD, Fearon K. Tolerance and incorporation of high-dose eicosapentaenoic acid diester emulsion by patients with pancreatic cancer cachexia. Lipids 2001;36:347–51. [16] Bauer JD, Capra S. Nutrition intervention improves outcomes in patients with cancer cachexia receiving chemotherapy- a pilot study. Support Care Cancer 2005;13:270–4. [17] Murphy RA, Mourtzakis M, Chu QSC, Baracos VE, Reiman T, Mazurak VC. Supplementation with fish oil increases first-line chemotherapy efficacy in patients with advanced non-small cell lung cancer. Cancer 2011; 117:3774–80. [18] Ryan AM, Reynolds JV, Healy L, Byrne M, Moore J, Brannelly N, et al. Enteral nutrition enriched with eicosapentaenoic acid (EPA) preserves lean body mass following esophageal cancer surgery: Results of a double-blinded randomized controlled trial. Ann Surg 2009;249:355–63.
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[19] Weed HG, Ferguson ML, Gaff RL, Hustead DS, Nelson JL, Voss AC. Lean body mass gain in patients with head and neck squamous cell cancer treated perioperatively with protein-and energy-dense nutritional supplement containing eicosapentaenoic acid. Head Neck 2011;33: 1027–33. [20] Murphy RA, Mourtzakis M, Chu QSC, Baracos VE, Reiman T, Mazurak VC. Nutritional intervention with fish oil provides a benefit over standard of care for weight and skeletal muscle mass in patients with non-small cell lung cancer receiving chemotherapy. Cancer 2011;117:1775–82. [21] Fearon K, Barber MD, Moses AG, Ahmedzai SH, Taylor GS, Tisdale MJ, et al. Double-blind, placebo-controlled, randomized study of eicosapentaenoic acid diester in patients with cancer cachexia. J Clin Oncol 2006;24:3401–7. [22] Bougnoux P, Hajjaji N, Maheo K, Couet C, Chevalier S. Fatty acids and breast cancer: Sensitization to treatment and prevention of metastatic regrowth. Prog Lipid Res 2010;49:76–86. [23] Jatoi A, Rowland K, Loprinzi CL, Sloan JA, Dakhil SR, MacDonald N, et al. An eicosapentaenoic acid supplement versus megestrol acetate versus both for patients with cancer-associated wasting: A north central cancer treatment group and national institute of Canada collaborative effort. J Clin Oncol 2004;22:2469–76. [24] Moses AWG, Slater C, Preston T, Barber MD, Fearon K. Reduced total energy expenditure and physical activity in cachectic patients with pancreatic cancer can be modulated by an energy and protein dense oral supplement enriched with u-3 fatty acids. Br J Cancer 2004;90: 996–1002.
