Skip to main content Accessibility help
×
Home

Information:

  • Access
  • Cited by 125

Figures:

Actions:

      • Send article to Kindle

        To send this article to your Kindle, first ensure no-reply@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle. Find out more about sending to your Kindle.

        Note you can select to send to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

        Find out more about the Kindle Personal Document Service.

        n-3 Fatty acids, cancer and cachexia: a systematic review of the literature
        Available formats
        ×

        Send article to Dropbox

        To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Dropbox.

        n-3 Fatty acids, cancer and cachexia: a systematic review of the literature
        Available formats
        ×

        Send article to Google Drive

        To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Google Drive.

        n-3 Fatty acids, cancer and cachexia: a systematic review of the literature
        Available formats
        ×
Export citation

Abstract

Use of n-3 fatty acids (FA) has been reported to be beneficial for cancer patients. We performed a systematic review of the literature in order to issue recommendations on the clinical use of n-3 FA in the cancer setting. A systematic search was performed in MEDLINE, EMBASE, Cochrane and Healthstar databases. We selected clinical trials or prospective observational studies including patients with cancer and life expectancy >2 months, in which enteral supplements with n-3 FA were administered. Parameters evaluated individually were clinical (nutritional status, tolerance, survival and hospital stays), biochemical (inflammatory mediators), and functional (functional status, appetite and quality of life (QoL)). Seventeen studies met the inclusion criteria; eight were of high quality. The panel of experts established the following evidence: (1) oral supplements with n-3 FA benefit patients with advanced cancer and weight loss, and are indicated in tumours of the upper digestive tract and pancreas; (2) the advantages observed were: increased weight and appetite, improved QoL, and reduced post-surgical morbidity; (3) there is no defined pattern for combining different n-3 FA, and it is recommended to administer >1·5 g/day; and (4) better tolerance is obtained administering low-fat formulas for a period of at least 8 weeks. All the evidences were grade B but for ‘length of treatment’ and ‘advantage of survival’ it was grade C. Our findings suggest that administration of n-3 FA (EPA and DHA) in doses of at least 1·5 g/day for a prolonged period of time to patients with advanced cancer is associated with an improvement in clinical, biological and QoL parameters.

n-3 and n-6 PUFA are named according to the position of the first double bond from the methyl terminus of the hydrocarbon chain of the molecule. Most of the n-6 and n-3 PUFA are metabolised from precursors, linoleic acid (18 : 2n-6) and α-linolenic acid (18 : 3n-3), respectively, by a series of elongation and desaturation reactions to yield longer, more unsaturated fatty acids (FA) (Karmali, 1996).

n-3 and n-6 PUFA have a number of vital functions in the human body as structural phospholipids of the cell membrane; they modulate membrane fluidity, cellular signalling and cellular interaction (Kelley, 2001; Vancassel et al. 2001).

While n-6 FA have potent inflammatory effects, n-3 FA have lesser pro-inflammatory effects, and these two classes of FA compete in the production of inflammatory lipid mediators. These potent immunoregulatory metabolites are synthesised from 20-C PUFA precursors. EPA or arachidonic acid are mobilised from the cell membrane by the action of phospholipase enzymes, especially phospholipase A2 and phospholipase C, and subsequently metabolised by cycloxygenase or lipoxygenase enzymes into PG, thromboxanes and leukotrienes. EPA gives rise to 3-series PG and thromboxanes and 5-series leukotrienes, the difference being the presence of an additional double bond in the structure. Because cell membrane phospholipids normally contain much higher levels of arachidonic acid than of the other 20-C PUFA, arachidonic acid is the most common eicosanoid precursor and gives rise to 2-series PG and thromboxanes and 4-series leukotrienes.

n-3 FA (e.g. EPA and DHA) reduce production of inflammatory cytokines associated with several chronic diseases, anorexia associated with these diseases and anorexia associated with immunotherapy with these cytokines (Meydani, 1996).

Many factors influence tumour induction and cancer growth, including a range of cytokines and growth factors, and genotoxic and oxidative stress. During cancer progression, cell turnover, differentiation and apoptosis are impaired. n-3 PUFA have emerged as anti-carcinogenic nutrients of potential benefit in cancer, through regulation of either enzyme expression and/or activity and end-product concentrations, or by modulating the levels of available precursors for biosynthetic pathways. They work through several actions to protect against the initiation and early stages of cancer, including decreasing tumour cell proliferation, enhancing tumour cell apoptosis, promoting cell differentiation, and limiting angiogenesis (Roynette et al. 2004).

During the past 20 years, several dozen studies have investigated the effects of n-3 PUFA on human immune and inflammatory responses. Most of these studies involved supplementing diets with marine oils containing EPA and DHA or purified EPA and DHA. These promising results prompted us to conduct this systematic review, which was first discussed by a panel of experts and finally presented in this document.

Materials and methods

The systemised review has been designed according to the Quorum statement (Moher et al. 1999). We located and subsequently analysed the scientific literature available from 1996 to 2006 in several of the most widely used databases, including MEDLINE, EMBASE, The Cochrane Library databases on clinical trials and the online version of the Healthstar database. The search terms used for the review were: fish oil, fatty acid, epa, eicosapentaenoic, docosahexaenoic, omega 3, tumour, neoplasm, cancer, carcinoma, appetite, cachexia, economics, cost analysis, cost benefit and quality of life (QoL). Bibliographies were checked, and experts in the field were contacted for additional studies. The realisation of a quantitative analysis of the selected papers was not considered, due to the small sample of the studied populations and also because the heterogeneousness of the papers would not assure the reliability of the results. The inclusion criteria for studies selected for analysis were those including patients of both sexes aged >18 years with malignant neoplasms associated with cachectic syndrome, a life expectancy >2 months, and not undergoing chemotherapy or radiotherapy at the time of the study. Studies on patients treated with surgery for potentially cachectising gastrointestinal malignancies were also included.

Studies on patients with potentially cachectising concomitant diseases such as renal or heart failure and autoimmune diseases, or patients with potentially hormone-sensitive or emetogenic brain, breast, ovarian, prostrate or endometrial cancer that would prevent proper oral intake were excluded.

The selected studies were analysed by two independent reviewers who coded the results separately and resolved any discrepancies by discussion and consensus between them. When there was no consensus, a third reviewer resolved the differences found. The results were presented to a panel of experts selected from among the different medical specialties related to the subject of the study (oncology, endocrinology, general surgery and intensive medicine), all of whom were opinion leaders in the nutritional implications in their field.

Studies existing in the medical literature with a higher level of scientific evidence were selected, including meta-analyses of clinical trials, clinical trials and prospective observational studies with large samples (on those issues where clinical trials were not located), economic evaluations of health technologies and qualitative studies. The study design aspects assessed to consider a study of high scientific quality were: randomised assignment of control and experimental groups, existence of a concurrent control group, prospective design, use of blinding, and sample size sufficient to detect significant differences. Studies conducted in animals or in languages other than English, French or Spanish were not considered.

The studies collected could analyse biochemical, clinical and functional parameters following nutritional support with supplements enriched with n-3 FA EPA and DHA over a variable period up to 3 months. The following clinical outcomes were noted: nutritional status, tolerance and gastrointestinal complications, incidence of post-surgical infection, length of hospital stay and survival. The functional parameters collected were: appetite, disease-specific and overall QoL (Karnofsky scale and ECOG performance status scale). Laboratory parameters analysed included plasma FA composition, pro-inflammatory response mediators: TNF, IL-1, IL-6, PG, and C-reactive protein as a marker of inflammatory response.

Two independent reviewers selected and analysed the information collected. Studies were classified according to the level of evidence based on the table prepared by the Agència d'Avaluació de Tecnologia Mèdica (Jovell & Navarro Rubio, 1995) (Table 1). Based on the analysis and evaluation of the evidence collected, recommendations were subsequently formulated on the suitability of the conditions for adoption of a health technology or intervention according to the recommendation grades established by the Canadian Task Force (http://www.ctfphc.org) (Table 2). Finally, the quality of the clinical trials collected was assessed using the scale proposed by Jadad et al. (1996) which is illustrated in Fig. 1.

Table 1 Level of evidence for study classification according to the Agència d'Avaluació de Tecnología Mèdica (Jovell & Navarro Rubio, 1995)

Table 2 Recommendation grades for specific clinical preventive actions according to the Canadian Task Force (CTF)

Fig. 1 Grading of clinical trial quality (after Jadad et al. 1996).

Results and evidence recommendations

Fifty clinical trials and prospective studies were reviewed and analysed. Of these, only seventeen met the selection criteria. The studies that were selected for evaluation are summarised in Table 3. Relevant aspects regarding the design, results and conclusions of each study are shown in the table. In the level of evidence column, the quality grade assigned to each of the clinical trials is indicated. The final assessment and evidence grade were agreed by consensus by the panel of experts. A summary of the quality of the studies by the different parameters analysed is shown in Table 4.

Table 3 Summary of the selected studies

‘Level of evidence’ refers to study characteristics according to type of design, as described in Table; CT, clinical trial; E group, experimental group; C group, control group; NA, not applicable; M, megestrol acetate; WN, well nourished; MN, malnourished; PBMC, peripheral blood mononuclear cells.

* Quality grade agreed by expert panel.

Table 4 Results by parameters analysed

* As described in Table 1.

Is the provision of supplements containing n-3 fatty acids beneficial in cancer patients?

Yes, in patients with advanced cancer and weight loss.

Recommendation grade: B

In which type of tumours?

Pancreas and upper digestive tract cancer

There are currently no studies on other types of neoplasms, although a recent study (Jatoi et al. 2004) showed good results in terms of weight maintenance or gain in various solid tumours.

Recommendation grade: B

Is there an appropriate fatty acid pattern?

The higher quality studies (Kenler et al. 1996; Fearon et al. 2003; Burns et al. 2004; Jatoi et al. 2004) used combinations of EPA and DHA in a 2 : 1 ratio. Some studies (Wigmore et al. 1996; Gogos et al. 1998; Zuijdgeest-Van Leeuwen et al. 2000) with positive results used EPA only.

Recommendation grade: B

What is the recommended dose?

Available data recommend the administration of 1·5 to 2 g EPA/day. Although Fearon et al. (2003) and Wigmore et al. (1996) found no advantages in exceeding 2 g/day, Burns administered much higher doses with good results (4·7 g EPA/day).

Recommendation grade: B

What is their tolerance and safety?

The incidence of adverse effects at the recommended doses is low. Although there is no direct recommendation, better tolerance has been reported when EPA was administered as part of a low-fat nutritional formula (Fearon et al. 2003) than as concentrated capsules (Burns et al. 2004, Bruera et al. 2003).

Recommendation grade: B

How long should they be given?

One higher quality study in patients with advanced pancreatic cancer (Fearon et al. 2003) recommends at least 8 weeks. Positive clinical effects have been observed in post-surgical patients from 1 week of treatment. Some biological markers have shown improvement after 1 week of nutritional treatment.

Given the low incidence of adverse effects at the recommended doses, treatment can be maintained for as long as there are objective benefits.

Recommendation grade: C

Are there markers of efficacy and effectiveness?

It is recommended to assess efficacy using anthropometric measures (weight, BMI), bioimpedance (lean mass), functional parameters and QoL scales.

Recommendation grade: B

Are there any advantages in terms of survival?

The study by Gogos et al. (1998) showed statistically significant advantages in survival (P < 0·025). These differences increased (P < 0·001) when well-nourished patients fed supplement were compared to malnourished patients fed placebo. The Fearon et al. (2003) study did not find differences in survival as well as the study by Jatoi et al. (2004) when compared with megestrol acetate, anyhow it was not placebo controlled.

Recommendation grade: C

Discussion

The anti-inflammatory effects of n-3 PUFA and their beneficial effects for cardiovascular health have prompted a number of studies on the management of autoimmune and inflammatory diseases. Fish-oil supplementation has reduced the symptoms of several diseases such as Ig-A nephropathy, asthma, and Crohn's inflammatory-bowel disease. Other conditions that were improved with n-3 FA supplementation include: arthritis, ulcerative colitis, lupus, psoriasis, cystic fibrosis, re-stenosis after angioplasty, and renal functions after liver or kidney transplantation. It also decreased circulating levels of IL-1, IL-2, IL-4, IL-6, TNF, and γ-interferon in patients with advanced colorectal cancer, improved survival of patients with cancers of different organs, and reduced weight loss in patients with pancreatic cancer (Wigmore et al. 1996). The intake of fish oils in those studies ranged from 4 to 20 g/d for 6 weeks to 60 months (Kelley, 2001; Roynette et al. 2004).

According to our systematic review, in neoplastic diseases the provision of diets supplemented with n-3 FA showed measurable benefits in the different biochemical, clinical and functional parameters considered. The majority of the studies support with varying grades of recommendations supplementation with diets rich in n-3 FA in this type of patients. Elia et al. (2006) reached similar conclusions in their systematic review for enterally fed patients as well as those taking oral supplements with a decrease in the complications, especially the infectious ones, as well as a decrease in hospital stays and an improvement in the inflammatory markers.

The most appropriate proportion of n-6 and n-3 FA is a controversial subject. Because of their respective anti-inflammatory and pro-inflammatory natures, the n-6 : n-3 FA ratio should be kept as low as possible (Xia et al. 2005) One of the possible ways to achieve this is to keep the proportion of lipids low, which additionally has the positive effect of achieving a reduced satiating effect. In the studies considered, the n-6 : n-3 FA ratio was approximately 1 : 3.

Dose of EPA is an issue of great concern. Although some of the best trials have not achieved a dose greater than 1·5 g/d other studies have found increased benefit with higher doses (between 1·5 and 4 g/d). This probably means that under 1·5 g/d there is hardly any effect and that superior doses may obtain improved results.

The negative results obtained in the study by Bruera et al. (2003) should be noted, and, in our opinion, were due to the use of a patient group with tumours of very diverse origin (we found clear efficacy in cancer of the pancreas and upper digestive tract) who were treated nutritionally for a short period of 2 weeks, although they later received unmasked treatment for a longer period (treatment time was 7 weeks in the study by Barber et al. (1999a) and 8 weeks in the study by Fearon et al. (2003).

Jatoi et al. (2004) showed increased weight and appetite in their study of patients treated with EPA. Both patients with gastrointestinal and lung tumours showed lower percentages of weight gain and appetite than those previously reported by other authors and lower than those observed in their study of megestrol, another drug with proven efficacy as an anti-anorexigenic agent. However, no differences were found versus megestrol with respect to appetite, QoL or overall survival.

Finally, it should be noted that most of the studies analysed reported better tolerance when EPA was administered as part of a low-fat nutritional formula instead of in the form of concentrated capsules. On the other hand the role of DHA separated from EPA has not been clearly ascertained in human subjects as most trials deal with both products in combination.

Conclusions

In cancer patients, supplementation with FA (EPA and/or DHA) in the diet or in the form of concentrated capsules seems to be associated with an improvement in various clinical, biochemical and QoL parameters. Regarding duration of supplementation evidence is conflicting but data suggest that good results can be obtained with prolonged nutrition (8 weeks).

It is recommended that prospective studies be carried out to relate the efficacy of nutritional support with EPA in terms of both clinical parameters (body mass, survival and QoL) and biochemical parameters (plasma levels of EPA, C-reactive protein and PG).

We can conclude that, although prognosis has traditionally been defined in terms of morbidity and mortality, we should currently incorporate multidimensional concepts that include measures of functional status, QoL, patient satisfaction and economic evaluation. This is extremely important in situations where the patients, as in this systematic review, are cancer patients with associated cachexia, since application of any support in such patients must be shown to be effective (Resolution ResAP (2003)3).

We were unable to evaluate economic outcomes or cost-effectiveness/utility in this systematic review due to the lack of this information in the studies used (Voss & Gallagher-Allred, 1996).

Acknowledgements

This study was conducted with an educational grant from Abbott Laboratories, Madrid, Spain.

References

Barber, MD, Ross, JA, Voss, AC, Tisdale, MJ & Fearon, KC (1999 a) The effect of an oral nutritional supplement enriched with fish oil on weight-loss in patients with pancreatic cancer. British Journal of Cancer 81(1), 8086.
Barber, MD, Ross, JA, Preston, T, Shenkin, A & Fearon, KC (1999 b) Fish oil-enriched nutritional supplement attenuates progression of the acute-phase response in weight-losing patients with advanced pancreatic cancer. Journal of Nutrition 129(6), 11201125.
Barber, MD, McMillan, DC, Preston, T, Ross, JA & Fearon, KC (2000) Metabolic response to feeding in weight-losing pancreatic cancer patients and its modulation by fish-oil-enriched nutritional supplement. Clinical Science 98, 389399.
Barber, MD, Fearon, KC, Tisdale, MJ, McMillan, DC & Ross, JA (2001 a) Effect of a fish oil-enriched nutritional supplement on metabolic mediators in patients with pancreatic cancer cachexia. Nutrition & Cancer 40(2), 118124.
Barber, MD & Fearon, KC (2001 b) Tolerance and incorporation of a high-dose eicosapentaenoic acid diester emulsion by patients with pancreatic cancer cachexia. Lipids 36(4), 347351.
Bruera, E, Strasser, F, Palmer, JL, Willey, J, Calder, K, Amyotte, G & Baracos, V (2003) 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 21(1), 129134.
Burns, CP, Halabi, S, Clamon, GH, Hars, V, et al. (1999) Phase I clinical study of fish oil fatty acid capsules for patients with cancer cachexia: cancer and leukaemia group B. Clinical Cancer Research 5, 39423947.
Burns, P, Halabi, S, Clamon, G, Kaplan, E, et al. (2004) Phase II study of high-dose fish oil capsules for patients with cancer-related cachexia. A Cancer and Leukemia Group B study. Cancer 101, 370378.
Elia, M, Van Bokhorst-de van der Schueren, MA, Garvey, J, Goedhart, A, Lundholm, K, Nitenberg, G & Stratton, RJ (2006) Enteral (oral or tube administration) nutritional support and eicosapentaenoic acid in patients with cancer: a systematic review. International Journal of Oncology 28(1), 523.
Fearon, KC, Von Meyenfeldt, MF, Moses, AG, et al. (2003) 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 randomized double blind trial. Gut 52(10), 14791486.
Gogos, CA, Ginopoulos, P, Salsa, B, Apostolidou, E, Zoumbos, NC & Kalfarentzos, F (1998) Dietary omega-3 polyunsaturated fatty acids plus vitamin E restore immunodeficiency and prolong survival for severely ill patients with generalized malignancy: a randomized control trial. Cancer 82(2), 395402.
Jadad, AR, Moore, RA, Carroll, D, Jenkinson, C, Renolds, JM, Gavaghan, DJ & McQuay, HJ (1996) Assessing the quality of reports on randomized clinical trials: Is blinding necessary? Controlled Clin Trials 17, 112.
Jatoi, A, Rowland, K, Loprinzi, CL, Sloan, JA, et al. (2004) 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. J Clin Oncol 22, 24692476.
Jovell, JA & Navarro Rubio, MD (1995) Evaluación de la evidencia científica. Med Clin 105, 2629.
Karmali, R (1996) Historical perspective and potential use of n-3 fatty acids in therapy of cancer cachexia. Nutrition 12, S2S4.
Kelley, DS (2001) Modulating of human immune and inflammatory responses by dietary fatty acids. Nutrition 17, 669673.
Kenler, AS, Swails, WS, Driscoll, DF, et al. (1996) Early enteral feeding in postsurgical cancer patients. Fish oil structured lipid-based polymeric formula versus a standard polymeric formula. Annals of Surgery 223(3), 316333.
Meydani, S (1996) Effects of (n-3) polyunsaturated fatty acids on cytokine production and their biological function. Nutrition 12, S8S14.
Moher, D, Cook, DJ, Eastwood, S, Olkin, I, Rennie, D & Stroup, DF (1999) Improving the quality of randomised controlled trials meta-analyses reports: the QUOROM statement. Quality of reporting Meta-analyses. Lancet 354(9193), 18961900.
Moses, AWG, Slater, C, Preston, T, Barber, MD & Fearon, KC (2004) 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. British Journal of Cancer 90, 9961002.
Resolution ResAP (2003)3 on food and nutritional care in hospitals..
Roynette, CE, Calder, P, Dupertuis, YM & Pichard, C (2004) N-3 polyunsaturated fatty acids and colon cancer prevention. Clin Nutr 23, 139151.
Swails, WS, Kenler, AS, Driscoll, DF, et al. (1997) Effect of a fish oil structured lipid-based diet on prostaglandin release from mononuclear cells in cancer patients after surgery. Journal of Parenteral & Enteral Nutrition 21(5), 266274.
Vancassel, S, Barthelemy, C, Lejeune, B, Martineau, J, Guilloteau, D, Andres, C & Chalon, S (2001) Plasma fatty acid levels in autistic children. Prostaglandins Leukotrienes and Essential Fatty Acids 65(1), 17.
Voss, AC & Gallagher-Allred, C (1996) The importance of outcomes research in documenting the benefit of nutrition intervention. Nutrition 12, 5960.
Wigmore, SJ, Ross, JA, Falconer, JS, et al. (1996) The effect of polyunsaturated fatty acids on the progress of cachexia in patients with pancreatic cancer. Nutrition 12(Suppl. 1), S27S30.
Wigmore, SJ, Barber, MD, Ross, JA, Tisdale, MJ & Fearon, KC (2000) Effect of oral eicosapentaenoic acid on weight loss in patients with pancreatic cancer. Nutrition & Cancer 36(2), 177184.
Xia, S-H, Wang, J & Kang, JX (2005) Decreased n-6/n-3 fatty acid ratio reduces the invasive potential of human lung cancer cells by down regulation of cell adhesion/invasion-related genes. Carcinogenesis 26, 779784.
Zuijdgeest-Van Leeuwen, SD, Dagnelie, PC, Wattimena, JL, et al. (2000) Eicosapentaenoic acid ethyl ester supplementation in cachectic cancer patients and healthy subjects: effects on lipolysis and lipid oxidation. Clinical Nutrition 19(6), 417423.