By Alana Grinnell
As part of my assessment in my final year of my Master of Nutrition & Dietetics I undertook a critical literature review investigating the impacts of eicosapentaenoic acid (EPA), alone or in conjunction with oral nutritional supplementation (ONS), on improving outcomes in cancer cachexia. This article provides a brief overview of the findings of my review. If you are interested in reading the full version please email me at [email protected] and I will forward you a copy.
Cancer cachexia is a wasting syndrome that has long been recognised as one of the most adverse effects of cancer . It has recently been defined by a panel of experts as a:
Multifactorial syndrome characterised 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. The pathophysiology is characterised by a negative protein and energy balance driven by a variable combination of reduced food intake and abnormal metabolism [1, p. 490].
It is prevalent in more than 50% of cancer patients with this number increasing to approximately 80% in advanced stage cancers [2-5]. As many dietitians working in oncology will know, cancer cachexia can be extremely debilitating and very difficult to treat. It differs to malnutrition and starvation, thus traditional nutritional therapies, such as high energy high protein diets and ONS, have failed to demonstrate improved outcomes . Unfortunately the exact causes of cancer cachexia remain largely unknown, although it is well recognised to involve a number of complex inflammatory interactions between the host and the tumour [6-11].
Over the past decade a large amount of research has been done to investigate nutritional interventions to reverse the progression of cancer cachexia with mixed results [1,6,10-22]. These studies have mainly focused on high calorie oral nutritional supplements and EPA supplementation, due to EPA’s anti-inflammatory properties.
This critical literature review included 15 studies, most of which were randomised controlled trials. Other studies used included open label, non-randomised experimental studies, phase II trials, post hoc analyses and descriptive studies. The studies were categorised into two categories: EPA capsule supplementation and EPA enriched ONS. All studies focused on the efficacy of EPA as a means of modulating the inflammatory processes involved in cancer cachexia to improve outcomes of weight, body composition, lean body mass (LBM), fatty acid profiles, and quality of life (QOL).
Omega-3/EPA Capsule Supplementation and Cancer Cachexia
EPA has been investigated as a means of treating cancer cachexia because of its ability to down-regulate the production of proinflammatory cytokines and the acute phase protein response pathway. Additionally in vitro studies have indicated that EPA has anti-tumour and anti-cachectic effects [12,23]. Six studies in the review focused on using only fish oil or EPA containing capsules to determine if EPA alone has a beneficial impact on cancer cachexia [4,9,12,15,19,24].
Three non-blinded experimental studies [4,12,24] provided support for the efficacy of EPA only supplementation. These studies had level III-2 evidence as the lack of blinding and randomisation exposed them to observer and responder bias . All three studies found that EPA supplementation was associated with changes in fatty acid profiles and stabilisation of weight [4,12,24]. In contrast, two other studies investigating EPA supplementation found no statistically significant effects of fish oil or EPA on cancer cachexia outcomes [9,19]. There were, however, some trends identified toward improvements which could be attributed, at least in part, to the use of EPA [9,19]. Burns et al found that a pre-treatment downward trend in weight was reversed for some, but not all, patients. Additionally, 66% of study participants experienced stabilisation of weight after supplementation with EPA . Fearon et al undertook a level II evidence study which included a large sample size, matched control group and double blinding and were still unable to demonstrate statistically significant improvements in the investigated outcomes. Fearon et al did, however, demonstrate some improvements in weight and LBM with 2g EPA supplementation but this was not statistically significant.
These studies seem to suggest that EPA supplementation has the potential to improve weight and LBM but further research is required to determine the exact effect of EPA in cancer cachexia. Additionally the optimal dose, formulation and administrative route for EPA supplementation needs to be determined. It is possible that the effect of EPA alone is minimal and that further investigation needs to focus on the combination of EPA with other agents.
Oral Nutritional Support Incorporating EPA and Cancer Cachexia
In light of this, the majority of studies identified in the literature have investigated the effects of ONS enriched with EPA on cancer cachexia outcomes [2,7,26-30].
One of the most notable of these studies was undertaken by Fearon et al in a randomised, double blind placebo controlled trial. Fearon et al investigated the effects of an EPA enriched ONS compared with an isocaloric isonitrogenous ONS on weight, LBM, and QOL in patients with advanced unresectable pancreatic cancer. This study provides level II evidence that administration of both the control and the intervention ONS (whether EPA enriched or not) was associated with a significant stabilisation of weight and LBM. A significant positive correlation was found in the intervention group between daily ONS intake and increases in weight and LBM. Additionally weight gain was associated with improved QOL in the intervention group only (P
Further to the work of Fearon and colleagues, two other studies conducted post hoc analyses on the data collected by Fearon et al’s study [2,26,]. Combined the findings of these two studies might suggest that nutrition intervention with or without EPA enrichment is able to improve dietary intake, QOL and stabilise weight and LBM. However the limitations of post hoc analyses should be taken into account and these results need to be interpreted with care [2,31,32]. Additional support for the efficacy of EPA enriched ONS comes from studies providing level III-3 to level II evidence [2,29,30]. These three studies all investigated the impacts of an EPA enriched ONS on various cancer cachexia outcome measures. Bauer & Capra found that a nutrition intervention with counselling by a dietitian and prescription of an EPA enriched ONS resulted in significant improvements in protein and energy intakes, nutritional status, functional capacity, and QOL. In a more recent study, Weed et al investigated weight loss and found that the EPA enriched ONS was associated with improvements in weight in patients who were able to consume at least 75% of the two cans prescribed/day. Van der Meij et al identified similar improvements in nutritional status and inflammatory markers in their double blind, placebo controlled RCT.
In contrast with the above studies, two studies clearly demonstrated no benefits from administration of an EPA enriched ONS in cancer cachexia in comparison with other treatment arms [27,28]. In a study of five different treatment arms, Mantovani et al compared an EPA enriched ONS with four other treatment arms and demonstrated no improvements in LBM, resting energy expenditure or fatigue symptoms. Similarly, Jatoi et al undertook a level II evidence study comparing three treatment arms with concurrent placebo controls. The study compared the appetite stimulant Megestrol Acetate (MA) with an EPA enriched ONS and maintained blinding by providing those in the control groups with a placebo MA or ONS. This meant that all study participants received nutritional support which may or may not have included EPA enrichment. Jatoi et al concluded that the single-agent MA was more effective at improving weight gain than either of the other two treatment groups. What the study failed to include was the impact of the isocaloric, isonitrogenous ONS provided with the MA as an ONS control. This may have caused confounding to occur.
The vast majority of these studies have demonstrated trends for improved outcomes in cancer cachexia but are unable to establish statistical significance. Furthermore, most studies have demonstrated varying degrees of improvement in weight, LBM, survival and/or QOL measures with administration of ONS. This suggests that nutrition support does play a role in improving cancer cachexia outcomes but the efficacy of EPA enrichment remains to be proven.
Currently there is insufficient evidence to draw conclusions concerning the efficacy of EPA supplementation either alone or in conjunction with ONS. A number of these studies do, however, indicate the efficacy of ONS in supporting weight stabilisation or gain in patients experiencing varying degrees of cancer cachexia. Few large, well-designed studies are available in this area due to the common limitations of high drop-out rates, short intervention times, the lack of a universal definition for cancer cachexia, and the effect of different cancer types, stages and locations. As the prevalence of cancer and cancer cachexia increases, these limitations will need to be addressed to develop long-term, large, level II evidence studies to investigate effective cancer cachexia treatment methods.
1.Fearon K, Strasser F, Anker SD, Bosaeus I, Bruera E, Fainsinger RL, et al. Definition and classification of cancer cachexia: an international consensus. The Lancet Oncology. 2011 5//;12(5):489-95.
2.Bauer J, Capra S, Battistutta D, Davidson W, Ash S. Compliance with nutrition prescription improves outcomes in patients with unresectable pancreatic cancer. Clinical Nutrition. 2005 12//;24(6):998-1004.
3.Dewey A, Baughan C, Dean T, Higgins B, Johnson I. Eicosapentaenoic acid (EPA, an omega-3 fatty acid from fish oils) for the treatment of cancer cachexia. Cochrane Database of Systematic Reviews. 2007 //(1).
4.Taylor LA, Pletschen L, Arends J, Unger C, Massing U. Marine phospholipids–a promising new dietary approach to tumor-associated weight loss. Support Care Cancer. 2010;18(2):159-70. PubMed PMID: 869497985; 19404684. English.
5.Granda-Cameron C, DeMille D, Lynch MPCMSNA, Huntzinger C, Alcorn T, Levicoff J, et al. An Interdisciplinary Approach to Manage Cancer Cachexia. Clinical Journal of Oncology Nursing. 2010;14(1):72-80. PubMed PMID: 222754329; 20118029. English.
6.Kumar NB, Kazi A, Smith T, Crocker T, Yu D, Reich RR, et al. Cancer cachexia: traditional therapies and novel molecular mechanism-based approaches to treatment. Current treatment options in oncology. 2010 Dec;11(3-4):107-17. PubMed PMID: 21128029. Pubmed Central PMCID: PMC3016925. Epub 2010/12/04. eng.
7.Fearon KCH, von Meyenfeldt MF, Moses AGW, van Geenen R, Roy A, Gouma DJ, et al. Effect of a protein and energy dense n-3 fatty acid enriched oral supplement on loss of weight and lean tissue in cancer cachexia: a randomised double blind trial. Gut. 2003 October 1, 2003;52(10):1479-86.
8.Grimble RF. Nutritional therapy for cancer cachexia. Gut. 2003 October 1, 2003;52(10):1391-2.
9.Fearon KCH, 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. Journal of Clinical Oncology. 2006 //;24(21):3401-7.
10.Skipworth RJE, Stewart GD, Dejong CHC, Preston T, Fearon KCH. Pathophysiology of cancer cachexia: Much more than host–tumour interaction? Clinical Nutrition. 2007 12//;26(6):667-76.
11.Donohoe CL, Ryan AM, Reynolds JV. Cancer Cachexia: Mechanisms and Clinical Implications. Gastroenterology Research and Practice. 2011;2011:13.
12.Wigmore SJ, Barber MD, Ross JA, Tisdale MJ, Fearon KCH. Effect of Oral Eicosapentaenoic Acid on Weight Loss in Patients With Pancreatic Cancer. Nutrition and cancer. 2000 2000/03/01;36(2):177-84.
13.Capra S, Bauer J, Davidson W, Ash S. Nutritional Therapy for Cancer-Induced Weight Loss. Nutrition in Clinical Practice. 2002 August 1, 2002;17(4):210-3.
14.Persson CR, Johansson BBK, Sjoden P-O, Glimelius BLG. A Randomized Study of Nutritional Support in Patients With Colorectal and Gastric Cancer. Nutrition and cancer. 2002 2002/01/01;42(1):48-58.
15.Bruera E, Strasser F, Palmer JL, Willey J, Calder K, 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. Journal of Clinical Oncology. 2003 January 1, 2003;21(1):129-34.
16.Ravasco P, Monteiro-Grillo I, Camilo ME. Does nutrition influence quality of life in cancer patients undergoing radiotherapy? Radiotherapy and Oncology. 2003 5//;67(2):213-20.
17.Ravasco P, Monteiro-Grillo I, Vidal PM, Camilo ME. Nutritional Deterioration in Cancer: The Role of Disease and Diet. Clinical Oncology. 2003 12//;15(8):443-50.
18.Baracos VE, Mazurak VC, Ma DWL. n-3 Polyunsaturated fatty acids throughout the cancer trajectory: influence on disease incidence, progression, response to therapy and cancer-associated cachexia. Nutrition Research Reviews. 2004;17(2):177-92. PubMed PMID: 221246510; 19079925. English.
19.Burns CP, Halabi S, Clamon G, Kaplan E, Hohl RJ, Atkins JN, et al. Phase II study of high-dose fish oil capsules for patients with cancer-related cachexia: A cancer and leukemia group B study. Cancer. 2004 //;101(2):370-8.
20.Baldwin C, Spiro A, Ahern R, Emery PW. Oral nutritional interventions in malnourished patients with cancer: A systematic review and meta-analysis. Journal of the National Cancer Institute. 2012 //;104(5):371-85.
21.Das UN. Can cancer cachexia be prevented/treated? Nutrition. 2012 9//;28(9):844-8.
22.Fearon KCH. The 2011 ESPEN Arvid Wretlind lecture: Cancer cachexia: The potential impact of translational research on patient-focused outcomes. Clinical Nutrition. 2012 10//;31(5):577-82.
23.Bauer JD, Capra S. Nutrition intervention improves outcomes in patients with cancer cachexia receiving chemotherapy–a pilot study. Support Care Cancer. 2005;13(4):270-4. PubMed PMID: 884098186; 15583950. English.
24.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 nonsmall cell lung cancer receiving chemotherapy. Cancer. 2011;117(8):1775-82.
25.NHMRC: How to use the evidence: assessment and application of scientific evidence. Canberra: National Health and Medical Research Council; 2000.
26.Davidson W, Ash S, Capra S, Bauer J. Weight stabilisation is associated with improved survival duration and quality of life in unresectable pancreatic cancer. Clinical Nutrition. 2004 4//;23(2):239-47.
27.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 Cancer Institute of Canada Collaborative Effort. Journal of Clinical Oncology. 2004 June 15, 2004;22(12):2469-76.
28.Mantovani G, Macciò A, Madeddu C, Gramignano G, Serpe R, Massa E, et al. Randomized phase III clinical trial of five different arms of treatment for patients with cancer cachexia: interim results. Nutrition. 2008 4//;24(4):305-13.
29.van der Meij BS, Langius JAE, Smit EF, Spreeuwenberg MD, von Blomberg BME, Heijboer AC, et al. Oral Nutritional Supplements Containing (n-3) Polyunsaturated Fatty Acids Affect the Nutritional Status of Patients with Stage III Non-Small Cell Lung Cancer during Multimodality Treatment1-3. The Journal of Nutrition. 2010 Oct 2010;140(10):1774-80. PubMed PMID: prod.academic_MSTAR_756319223; 20739445. English.
30.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 a protein- and energy-dense nutritional supplement containing eicosapentaenoic acid. Head & Neck. 2011;33(7):1027-33.
31.Elliott HL. Post hoc analysis: use and dangers in perspective. Journal of hypertension Supplement : official journal of the International Society of Hypertension. 1996 Sep;14(2):S21-4; discussion S4-5. PubMed PMID: 8934374. Epub 1996/09/01. eng.
32.Moses AWG, Slater C, Preston T, Barber MD, Fearon KCH. 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 n-3 fatty acids. Br J Cancer. 2004 //print;90(5):996-1002.