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© 2003 American Society for Clinical Oncology Effect of Fish Oil on Appetite and Other Symptoms in Patients With Advanced Cancer and Anorexia/Cachexia: A Double-Blind, Placebo-Controlled Study
From the Department of Palliative Care and Rehabilitation Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, TX; Palliative Care Program, Grey Nuns Community Hospital and Health Center, Cross Cancer Institute, and University of Alberta, Department of Agricultural, Food and Nutritional Sciences, and Department of Oncology, Edmonton, Alberta, Canada. Address reprint requests to Eduardo Bruera, MD, Department of Palliative Care and Rehabilitation Medicine (Box 0008), The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030-0049; email: ebruera{at}mail.mdanderson.org.
Purpose: To determine whether high doses of fish oil, administered over 2 weeks, improve symptoms in patients with advanced cancer and decreased weight and appetite. Patients and Methods: Sixty patients were randomly assigned to fish oil capsules or placebo. Appetite, tiredness, nausea, well-being, caloric intake, nutritional status, and function were prospectively assessed at days 1 and 14. Results: The baseline weight loss was 16 ± 11 and 16 ± 8 kg in the fish oil (n = 30) and placebo (n = 30) group respectively, whereas the baseline appetite (0 mm = best and 10 mm = worst) was 58 ± 24 mm and 67 ± 19 mm, respectively (P = not significant). The mean daily dose was 10 ± 4 (fish oil group) and 9 ± 3 (placebo group) capsules, which provided 1.8 g of eicosapentaenoic acid and 1.2 g of docosahexaenoic acid in the fish oil group. No significant differences in symptomatic or nutritional parameters were found (P < .05), and there was no correlation between changes in different variables between days 1 and 14 and the fish oil doses. Finally, the majority of the patients were not able to swallow more than 10 fish oil capsules per day, mainly because of burping and aftertaste. Conclusion: Fish oil did not significantly influence appetite, tiredness, nausea, well-being, caloric intake, nutritional status, or function after 2 weeks compared with placebo in patients with advanced cancer and loss of both weight and appetite.
CACHEXIA OCCURS in more than 80% of patients who have advanced cancer.1 These patients present with loss of appetite, chronic nausea, fatigue, and objective changes in body weight, lean body mass, and total body fat.2 N-3 fatty acids, which are present in fish oil, have been widely studied in animal models.3–5 These acids have been shown to lower the level of proinflammatory cytokines in healthy volunteers6,7 as well as in patients having advanced pancreatic cancer8,9 or AIDS.10 N-3 fatty acids, particularly eicosapentaenoic acid (EPA), also have been associated with a decrease in urinary elimination of a tumor-derived factor that induces muscle protein degradation.11 Both cytokines and other factors that induce proteolysis in skeletal muscle have been associated with the syndrome of cancer anorexia/cachexia.12 Uncontrolled studies have found that both fish oil administered alone13,14 or as part of nutritional supplements15 EPA administered alone16 are capable of stabilizing weight loss in some patients who have pancreatic cancer. Furthermore, a placebo-controlled study of 60 patients having generalized solid tumors who underwent fish oil treatment until death reported a survival advantage and increased performance status, and no changes in body weight or albumin level were observed; however, symptom distress was not assessed.17 Fish oil capsules are widely available as a form of complementary or alternative medicine and are frequently used as such by cancer patients.18 Because of an absence of controlled trials examining the symptomatic and nutritional effects of fish oil, we conducted a prospective randomized, placebo-controlled trial in patients with advanced cancer and loss of weight and appetite. Because short-term symptomatic effects are important for these patients and because prior studies with megestrol acetate observed nutritional effects within 2 weeks,19 we selected a 2-week course of fish oil capsules.
Patients having advanced cancer (defined as locally recurrent or metastatic cancer) were recruited from the Acute Palliative Care Unit at Grey Nuns Hospital and the inpatient and outpatient areas at the Cross Cancer Institute in Edmonton, Alberta, Canada, from April 1999 until September 2000.20
Eligibility Criteria and Randomization
Treatment
The pharmacist did not disclose the type of medication given to the investigators or patients until the termination of the study unless clinically required to do so. The patients were allowed to receive other drugs, including opioids and adjuvant analgesics. Specifically, 30 patients received opioid analgesics, 17 received adjuvant analgesics, 20 received prokinetic antiemetics, eight received corticosteroids, 11 received antidepressants, and three received methylphenidate; none of them received progestins. In addition, five patients received chemotherapy, and four received antineoplastic hormonal therapy. The patients were allowed to continue on their medication regime during the study; however, no changes were made during the 14-day study period except for administering analgesics or taking other major symptom control measures.
Assessment Anthropometric measurements were performed on days 1 and 14. Specifically, on day 1, each patient’s height and preillness stable weight were documented. A study nurse measured weight using a standardized balance with the patients barefooted and wearing light clothes. Also, multiple-frequency bioimpedance analysis (BIA-101A. B1527D body composition analyzer; RJL Systems, Clinton Township, MI) was used to estimate the patients’ total body fat, lean mass, and water.25 In addition, the study nurse measured the patients’ arm muscular circumference, nondominant arm triceps skinfold (average of three measurements), and subscapular skinfold (average of three measurements). The patients’ function level was measured using the Karnofsky performance scale and Edmonton Functional Assessment Test.26 Compliance with and tolerability of the capsule regimen were assessed during the first 14 days. The patients documented the number of capsules taken daily. On day 14, their difficulty in tolerating the regimen was measured on a scale of 1 to 4 (1 = no difficulty, 4 = extremely difficult). Patients were also asked whether they experienced any new symptoms. Because no established toxicity scales for dose-limiting fish oil–related side effects are available,14 we used the question of tolerability and new symptoms to assess toxicity. Plasma phospholipids (PLs) were measured following standard procedures. Whole blood (3 mL) was layered on top of Ficoll Hypaque gradients and centrifuged. Serum was collected from the top and stored immediately at -70°C for plasma lipid analysis. Plasma (100 µL) fatty acids were extracted using chloroform/methanol (2:1 by vol), and plasma PLs were isolated on G-plates. The PL band was visualized with 8-anilino-1-naphthalene-sulfonic acid and identified under ultraviolet light using appropriate standards. The band was scraped and the C17:0 standard was added to the scraped plasma PL (10 µg of C17:0), followed by direct methylation. Fatty acid methyl esters were prepared by methylation using 14% (w/v) BF3/methanol reagent and separated by automated gas liquid chromatography (Vista 6010; Varian Instruments, Georgetown, ON) on a fused silica BP20 capillary column (25 m x 0.25 mm internal diameter; Varian Instruments), as previously described. Peaks of fatty acid methyl esters were identified by comparisons with standards purchased from Supelco Canada, Montreal, Canada, and Sigma Chemical, Montreal, Canada, companies. Fatty acid content of plasma was calculated using the area peak of the internal standard.27
Data Analysis and Sample Size Calculations
Descriptive statistics were used to summarize the patient characteristics, results of baseline assessment, and tolerability of the capsule regimen. The average baseline scores for age, weight, appetite, and tiredness in the two groups were compared using the t test. Also, the patients’ baseline sex distribution was compared using the
Ninety-one patients were considered to be eligible for and agreed to participate in the study and were randomly assigned to fish oil or placebo. The patient flow is illustrated in Fig 1  . Three patients randomly assigned to fish oil and one to placebo did not receive the allocated treatment because of delayed start, change of mind, or death. Twenty-seven patients (27 of 87; 31%) dropped out during the double-blind phase. Four patients died (two in the fish oil group and two in the placebo group), and seven patients experienced disease progression (five patients receiving fish oil and two receiving placebo) with esophageal perforation, difficulty swallowing, disease-related sepsis, or general deterioration. Five patients in each group discontinued treatment because of gastrointestinal symptoms. Of those receiving fish oil, two patients experienced fish belching, two experienced nausea, and one experienced vomiting and constipation. Of those receiving placebo, one patient each had vomiting, nausea, hematemesis, diarrhea, and abdominal pain. In all cases, side effects subsided rapidly on discontinuation of capsules. In all, 60 patients (60 of 91; 66%) completed the double-blind phase.
The patients’ characteristics are listed in Table 2 . For patients assigned to fish oil, the lean body mass was 24.0 ± 7 kg, triceps skinfold was 14.2 ± 8 cm, and arm circumference was 26.0 ± 4 cm; for patients assigned to placebo, the corresponding values were 23.7 ± 4 kg, 11.4 ± 8 cm, and 25.1 ± 4 cm, respectively. None of these characteristics was found to differ significantly between the two groups.
Patients in the fish oil group took a mean of 9.8 ± 4 capsules per day, whereas those in the placebo group took a mean of 9.2 ± 3 capsules (P = not significant). Of the assessable patients, one tolerated 18 capsules (placebo) and six tolerated 15 or more capsules (five on fish oil and one on placebo). During the double-blinded treatment phase, there were no significant differences in any of the subjective or objective parameters between the two groups (Table 3 ). There was a strong trend for improved appetite in both groups (-9.8 ± 20 mm and -9.0 ± 27 mm in the fish oil and placebo group, respectively) (Fig 2). Furthermore, in the fish oil group, no significant associations between the mean number of capsules taken and appetite, weight loss, or caloric intake were found, but there was a trend for tiredness (Table 3). The treatment with 14 days of fish oil or placebo did not significantly modify lean body mass (difference between day 14 and baseline for fish oil was 0.49 ± 6.2 kg; for placebo, it was -0.55 ± 3.9 kg), triceps skinfold (fish oil, -0.34 ± 3 cm; placebo, -0.02 ± 2 cm), and arm circumference (fish oil, -0.19 ± 1 cm; placebo, -0.31 ± 1 cm). One patient receiving placebo in the subset studied for fatty acid composition showed unusually high levels of EPA and DHA in plasma phospholipid analysis and was likely to have been self-supplementing with fish oil products.
Blood levels of phospholipids were obtained in 13 patients receiving fish oil and 10 patients receiving placebo. The levels of C20:5 (3) (EPA) are reported for both groups at baseline and at day 15 as percentage of total fatty acids and as absolute amount. At baseline, patients receiving fish oil had 1.8 ± 0.3 mcg/mL EPA (0.7% ± 0.1% of total fatty acids), and those receiving placebo had 1.1 ± 0.2 mcg/mL EPA (0.5% ± 0.1% of total fatty acids). After 14 days of supplementation, patients receiving fish oil had 14.0 ± 4.5 mcg/mL EPA (4.4% ± 0.7% of total fatty acids), and those receiving placebo had 0.9 ± 0.2 mcg/mL EPA (0.6% ± 0.1% of total fatty acids). The observed levels for patients receiving fish oil reflect those reported by other groups.13,15,16
The tolerability of the capsule regimen was rated "not difficult at all" in 20 and 19 patients in the fish oil and placebo groups, respectively; "slightly difficult" in eight and eight patients, respectively; "moderately difficult" in two and three patients, respectively; and "extremely difficult" in no patients. More patients in the fish oil group than in the placebo group experienced new symptoms (Table 3 The patients used the following concomitant medications: 30 patients received opioid analgesics, 17 received adjuvant analgesics, 20 received prokinetic antiemetics, 11 received antidepressants, eight received corticosteroids, and three received methylphenidate. No patient received progestational agents. Five patients received chemotherapy, and four received antineoplastic hormonal therapy.
We did not find significant improvement in appetite, other symptoms, nutritional status, or physical function after the administration of fish oil for 2 weeks using a mean daily dose of 1.8 g of EPA and 1.2 g of DHA as compared with that of the placebo in patients having advanced cancer. We also observed no correlation between most subjective and objective outcomes and dose in the fish oil group (Table 3  ). The absence of significant benefits regarding symptoms or nutritional status cannot be considered proof that such benefits do not exist. However, the findings for appetite using our well-powered sample size indicate that fish oil administered at a high dose had no clinically relevant effects over the 2-week observation period. Our power calculations were based on the detection of a difference in appetite as a primary end point. Research on other drugs for cachexia, such as megestrol acetate,24,27 thalidomide,29 and corticosteroids,30 have found that appetite is an earlier and more sensitive variable than nutritional indices or weight gain. Therefore, it is unlikely that improvement in nutritional indices or weight gain would have occurred in the complete absence of appetite improvement. The administration of fish oil, providing a mean EPA dose of 1.8 g per day, was suggested to be effective in influencing weight loss and inflammatory parameters in prior studies.8,15–17 Our study showed that fish oil, even in this highly coached population, could only be taken at a mean dose of 10 capsules per day. It is unknown whether higher doses are more effective at influencing appetite, but they are unlikely to be tolerated in cancer patients. In addition, although a longer observation would be desirable, it may be associated with further dropouts because of complications or death. Also, it can be argued that effects not observed for more than 2 weeks are unlikely to be clinically useful in patients having advanced cancer and loss of weight and appetite. Because of the nature of the patients studied, the emphasis of the present study is on rapid improvement of quality of life. Whether an intervention preventing further weight loss without symptomatic benefit after 2 weeks might yield improved symptom control after a longer period of supplementation remains to be proven in the patient population studied. Selected patient populations with expected long-term survival and severe cachexia might potentially benefit from therapies that have a long latency period for symptomatic improvement. In this study, the median survival for the overall group was 14.2 ± 1.9 weeks, reflecting a very ill patient population. Survival analysis of the different treatment groups in this heterogeneous population is not appropriate because of the various primary tumors and tumor stages.
The number of dropouts in this study was consistent with that in previous studies, by our group19,22 and by others,31 of patients having advanced cancer and loss of weight and appetite. The reason for withdrawal for 10 (37%) of the 27 patients who dropped out was the development of gastrointestinal symptoms. Some of these symptoms were likely to be related to the oil supplements, and they occurred at a similar frequency in both the fish oil and olive oil (placebo) groups. Among the patients who completed the study, there were also a number of minor side effects, including belching and fish oil after taste (Table 4
Our findings indicate that the currently available fish oil capsule preparations are not well tolerated. These findings of a narrow therapeutic window for fish oil are supported by the two other studies investigating fish oil capsules in cancer patients.13–14 A phase I study14 of 22 patients with incurable neoplastic disease found a maximum-tolerated dose of 0.3 g of fish oil per day (the composition of the fish oil was different than that in this study), with gastrointestinal dose-limiting toxicities (oily diarrhea, "unable to tolerate in esophagus or stomach"). In a dose-escalation study13 of 18 patients with unresectable pancreatic cancer, a median maximum dose of 12 g of fish oil per day (same capsule composition as this study) was tolerated. Therefore, long-term compliance with fish oil preparations is difficult. Because, in our study, placebo capsules were not well tolerated either, the consumption of high doses of oily capsules might be inherently problematic. At present, it is not known whether the tolerability of oral supplementation with n-3 fatty acids can be improved by using preparations containing EPA instead of fish oil. In one study, 26 patients with unresectable pancreatic cancer and a median weight loss per month of 2 kg tolerated doses of 6 g/d of high-purity (95%) EPA over several months.16 A new high-purity preparation of EPA as a 20% oil and water diester emulsion was studied in a phase I study of five cancer patients.32 They tolerated the preparation at a mean dose of approximately 18 g per day (range, 9 to 27 g per day). This or other high-concentration preparations may be required if higher EPA doses are demonstrated to be more effective for objective or subjective variables. At the present time, though, information is lacking. In one recent study, 33 researchers observed an improvement in lean body mass in patients who received a similar dose of EPA (2.2 g per day) for cancer cachexia. Specifically, the investigators observed a positive correlation between the quantity of nutritional supplements enriched with n-3 fatty acids and lean body mass and weight. In our study, we did not observe a trend of improved weight or lean body mass. Although we used similar outcomes such as bioelectrical impedance and anthropometrics, our patients received treatment for 2 weeks, compared with 8 weeks in the comparative study. Our results regarding nutritional status should be regarded with caution because of the much shorter duration of our study. Further research is required to demonstrate whether higher doses of n-3 fatty acids given over longer periods of time are capable of improving lean body mass. The mechanism of action of n-3 fatty acids involves immune modulation with modifications in the arachidonic acid metabolism, eicosanoid-pathway intermediates, induction of apoptosis, and proinflammatory cytokines, as well as the attenuation of increased protein catabolism in muscle.34 It is possible that, in future research, patient populations can be characterized with distinct anorexia/cachexia syndromes, possibly those with more pronounced inflammatory alterations, that may respond better to n-3 fatty acids than did our patients with a variety of advanced malignancies. It may be argued that oleic acid, the placebo used, was not inert because metabolic interactions between the fatty acids are reported that may impede some of their effects. We analyzed the fatty acid composition in a subgroup of patients (38%) and found no change in any of the fractions studied after 2 weeks of supplementation. Neither the study performed by Fearon et al33 nor this one showed any changes in subjective variables. In previous studies of other agents, such as progestins, improvement in appetite and symptoms, including early satiety, preceded a change in anthropometric and nutritional variables.27,35 Therefore, it is possible that n-3 fatty acids affect lean body mass without producing any major subjective benefits. This will require testing in future research. However, a lack of symptom improvement would be one of the limitations of this treatment in patients having incurable progressive malignancy. Our findings indicate that fish oil used as alternative or complementary medicine at the study dose or even at much higher doses is not useful in improving subjective and objective manifestations of cancer anorexia/cachexia. One potential concern would be the purchase and use of fish oil capsules of patients out of the context of the study (A. Voss, personal communication, 2002); this could result in a number of placebo patients actually receiving fish oil without the knowledge of the investigator. In fact, the blood levels of EPA and DHA in one of our patients indicated that he was taking fish oil. However, because of the low frequency of this event in our sample, it is unlikely that use of over-the-counter fish oil had any effect on the results of our study. Future research should attempt to improve the patients’ ability to digest, absorb, and incorporate n-3 fatty acids into tissues. Patients having clear evidence of metabolic cachexia, particularly loss of lean body mass, may be better candidates for these studies than those who do not. Adequate energy and protein supplementation should be maintained during such studies, as EPA alone does not seem to significantly affect appetite and caloric intake. For example, in our study, ad libitum food intake did not increase significantly after 2 weeks of fish oil administration. Both dietary counseling and the use of food supplements and appetite stimulants should be considered in future research.
Project supported in part by the Tobacco Settlement Foundation, Houston, TX. F.S. is supported by BIL grant no. KFS 950-09-1999 from Swiss Cancer Research Inselspital, Bern, Switzerland.
1. Dunlop R: Clinical epidemiology of cancer cachexia, in Bruera E, Higginson I (eds): Cachexia-Anorexia in Cancer Patients. Oxford, United Kingdom, Oxford University Press, 1996, pp 76–82 2. Bruera E, Fainsinger R: Clinical management of cachexia and anorexia, in Doyle D, Hanks GWC, MacDonald N (eds): Oxford Textbook of Palliative Medicine (ed 2). Oxford, United Kingdom, Oxford University Press, 1998, pp 548–556
3. Beck SA, Smith KL, Tisdale MJ: Anticachectic and antitumor effect of eicosapentaenoic acid and its effect on protein turnover. Cancer Res 51:6089–6093, 1991 4. Tisdale MJ: Inhibition of lipolysis and muscle protein degradation by EPA in cancer cachexia. Nutrition 12:S31–S33, 1996[Medline]
5. Whitehouse AS, Smith HJ, Drake JL, et al: Mechanism of attenuation of skeletal muscle protein catabolism in cancer cachexia by eicosapentaenoic acid. Cancer Res 61:3604–3609, 2001 6. Endres S, Ghorbani R, Kelley VE, et al: The effect of dietary supplementation with n-3 polyunsaturated fatty acids on the synthesis of interleukin-1 and tumor necrosis factor by mononuclear cells. N Engl J Med 320:265–271, 1989[Abstract] 7. Meydani SN, Lichtenstein AH, Cornwall S, et al: Immunologic effects of national cholesterol education panel step-2 diets with and without fish-derived N-3 fatty acid enrichment. J Clin Investig 92:105–113, 1993[Medline] 8. Wigmore SJ, Fearon KC, Maingay JP, et al: Down-regulation of the acute-phase response in patients with pancreatic cancer cachexia receiving oral eicosapentaenoic acid is mediated via suppression of interleukin-6. Clin Sci (Colch) 92:215–221, 1997[Medline] 9. Wigmore SJ, Fearon KC, Ross JA: Modulation of human hepatocyte acute phase protein production in vitro by n-3 and n-6 polyunsaturated fatty acids. Ann Surg 225:103–111, 1997[CrossRef][Medline] 10. Hellerstein MK, Wu K, McGrath M, et al: Effects of dietary n-3 fatty acid supplementation in men with weight loss associated with the acquired immune deficiency syndrome: Relation to indices of cytokine production. J AIDS Hum Retrovirol 11:258–270, 1996[Medline] 11. Wigmore SJ, Todorov PT, Barber MD, et al: Characteristics of patients with pancreatic cancer expressing a novel cancer cachectic factor. Br J Surg 87:53–58, 2000[Medline] 12. Tisdale MJ: Metabolic abnormalities in cachexia and anorexia. Nutrition 16:1013–1014, 2000[CrossRef][Medline] 13. Wigmore SJ, Ross JA, Falconer JS, et al: The effect of polyunsaturated fatty acids on the progress of cachexia in patients with pancreatic cancer. Nutrition 12:S27–S30, 1996[Medline]
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29. Bruera E, Neumann CM, Pituskin E, et al: Thalidomide in patients with cachexia due to terminal cancer: Preliminary report. Ann Oncol 10:857–859, 1999 30. Bruera E, Roca E, Cedaro L, et al: Action of oral methylprednisolone in terminal cancer patients: A prospective randomized double-blind study. Cancer Treat Rep 69: 751–754, 1985[Medline]
31. Maltoni M, Nanni O, Scarpi E, et al: High-dose progestins for the treatment of cancer anorexia-cachexia syndrome: A systematic review of randomised clinical trials. Ann Oncol 12:289–300, 2001 32. Barber MD, Fearon KC: Tolerance and incorporation of a high-dose eicosapentaenoic acid diester emulsion by patients with pancreatic cancer cachexia. Lipids 36:347–351, 2001[Medline] 33. Fearon KCH, von Meyenfeldt MF, Moses AGW, et al, on behalf of the Cancer Cachexia Study Group: An energy and protein dense, high n-3 fatty acid oral supplement promotes weight gain in cancer cachexia. Eur J Cancer 37:27, 2001 (abstr)
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test, and differences in the distribution of tumor types between the groups were compared using the Fisher’s exact test because of small frequencies in some categories. Comparisons of the differences between days 1 and 14 between the groups were also made using the t test. Use of the Wilcoxon two-sample test resulted in findings similar to those of the corresponding t-test analyses. Finally, Pearson’s correlation coefficient was calculated for the average number of capsules taken and variables such as appetite and tiredness in the fish oil group only. The SAS software program (version 8; SAS Institute, Cary, NC) and SPSS Base (version 10.0; SPSS, Chicago, IL) were used for the analyses. 
