Omega 3 (Eicosapentaenoic Acid and Others)

Omega 3 (Eicosapentaenoic Acid and Others)

PEP Topic 
Anorexia
Description 

Eicosapentaenoic acid (EPA) is an essential omega-3 fatty acid, distinguished from other long-chain polyunsaturated fatty acids by its specific chemical configuration. Bluefish, swordfish, salmon, and mackerel are rich in EPA. EPA has been studied in anorexia, and omega 3 fatty acid supplementation has been evaluated for its effect in fatigue, peripheral neuropathy, and prevention of infection.

Effectiveness Not Established

Research Evidence Summaries

Bruera, E., Strasser, F., Palmer, J.L., 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, 129–134.

doi: 10.1200/JCO.2003.01.101
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Study Purpose:

To evaluate the efficacy of 1,000 mg fish oil capsules versus placebo of 1,000 mg olive oil capsules in a two-arm trial

Intervention Characteristics/Basic Study Process:

A daily dose of 18 capsules was given over a two-week period. Dosage decreased to a minimum of six capsules daily secondary to intolerance. Mean eicosapentaenoic acid (EPA) dose was 1.8 g/day. Docosahexaenoic acid dose was 1.2 g/day.

Sample Characteristics:

  • Eligibility requirements were presence of anorexia (> 3 on visual analog scale) plus weight loss (> 5% pre-illness weight), ability to maintain oral food intake over the course of study, normal cognition (using Mini-Mental State Score), written informed consent, and advanced cancer (locally recurrent or metastatic disease).
  • Sample size was 91 patients at outset, then randomized to 45 for study and 46 for placebo. After attrition, 30 patients for both groups completed the study.

Setting:

The two-site trial was conducted in the Acute Palliative Care Unit at Grey Nuns Hospital and the inpatient and outpatient areas at Cross Cancer Institute in Edmonton, Alberta, Canada.

Study Design:

A randomized, placebo-controlled, double-blinded trial design was used.

Measurement Instruments/Methods:

  • Visual analog scale (VAS) used to measure appetite, nausea, tiredness, and well-being
  • Anthropometric measures of height, weight, body composition, muscular circumference, and skinfolds done in the office on days 1 and 14
  • Functional level measured with Karnofsky Performance Status Scale and the Edmonton Functional Assessment Tool
  • Plasma phospholipids
  • Nutritional intake diary

Results:

Five patients in each group left the study secondary to gastrointestinal intolerance. There was no significant difference in any of the subjective or objective parameters between the two groups. Both groups showed an equal trend toward improved appetite, –9.8 for the fish oil and –9.0 for the olive oil placebo on the VAS.

Limitations:

  • Length of study was limited to two weeks. Period was based on previous megestrol acetate trial results and perceived need for short-term symptomatic amelioration.
  • Original study design was altered secondary to gastrointestinal intolerance: 18 capsules down to a minimum of 6 capsules per day. There was variance in actual amounts taken.
  • High attrition rate of 31% brings into question whether the original sample size was large enough and if the ultimate results were underpowered.
  • Whether the lack of significant findings was due to a reduced dose of fish oil or because of the short duration of study is questionable.

Jatoi, A., Rowland, K., Loprinzi, C.L., Sloan, J.A., Dakhil, S.R., MacDonald, N., . . . Christensen, B. (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. Journal of Clinical Oncology, 22, 2469–2476.

doi: http://dx.doi.org/10.1200/JCO.2004.06.024
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Study Purpose:

To evaluate the efficacy of ecosapentaenoic acid (EPA) supplement plus placebo versus megestrol acetate plus placebo supplement versus combination of both EPA supplement and megestrol

Intervention Characteristics/Basic Study Process:

The EPA dose was 1.09 g BID in supplement plus liquid placebo. The megesterol acetate dose was 600 mg/day plus placebo supplement BID. The combination dose was EPA 1.09 g supplement BID plus megesterol acetate 600 mg/day. Patients were stratified and randomized to one of three treatment arms. Median number of days on study was relatively equal for all three arms at slightly more than three months. Megesterol acetate served as the control arm secondary to its proven efficacy.

Sample Characteristics:

  • The study reported on 421 patients.
  • Inclusion was based on age 18 years or older with incurable malignancy other than brain, breast, ovarian, prostate, or endometrial cancer; life expectancy of three months or more; Eastern Cooperative Oncology Group performance status of 2 or better; and self-reported two-month weight loss of five or more pounds and/or physician-estimated daily intake of less than 20 calories/kg/day.
  • All patients had to perceive that weight loss was a problem, and the physicians had to view weight gain as a beneficial outcome.
  • Exclusion criteria other than previously listed tumor types were use of tube feedings or parenteral nutrition; edema or ascites; use of adrenal steroids (other than short-term dexamethasone with chemotherapy), androgens, progestational agents, or other appetite stimulants within the past month; brain metastases; insulin-requiring diabetes; pregnancy; lactation; poorly controlled hypertension or congestive heart failure; history of thromboembolism; and obstruction in alimentary tract, malabsorption, or intractable vomiting.

Setting:

The study was a collaborative effort of the North Central Cancer Treatment Group (NCCTG) and the National Cancer Institute of Canada, conducted at 26 primary treatment centers.

Study Design:

A double-blinded, randomized, three-armed trial design was used.

Measurement Instruments/Methods:

  • Weight measured at MD’s office at baseline and monthly
  • NCCTG questionnaire to measure appetite and weight loss at baseline, weekly, for four weeks, and then monthly 
  • Functional Assessment of Anorexia/Cachexia Therapy (FAACT) administered at same intervals as above
  • Single-item uniscale question to measure global quality of life administered at same intervals as above

Results:

The primary endpoint was weight gain of 10% or more (chosen because of previously proven efficacy of megesterol acetate). Among the three arms, 6% of patients achieved this in the EPA arm, 18% in the megesterol arm, and 11% in the combination arm. There was a p value of 0.01 showing greater efficacy with single-agent megesterol acetate. Appetite results using the NCCTG questionnaire were comparable for all three groups, showing varying degrees of favorable effects in all treatment arms. Appetite results using FAACT showed that the megesterol acetate and combination arms provided better appetite stimulation than EPA alone: 40 for EPA, 55 for megesterol acetate, and 55 for combination.

Conclusions:

There was no significant difference for survival times or quality of life between the three arms. Recommendation of authors is not to use EPA alone or in combination.

Sample size was very good, and statistical analysis was very thorough.

Limitations:

  • The study did not include a true placebo arm; therefore, the orexigenic effects of EPA cannot be determined but rather only suggested since there was an equivalent result on the NCCTG questionnaire when compared to megesterol acetate.
  • No definition of anorexia was provided.

Systematic Review/Meta-Analysis

Yavuzsen, T., Davis, M.P., Walsh, D., LeGrand, S., & Lagman, R. (2005). Systematic review of the treatment of cancer-associated anorexia and weight loss. Journal of Clinical Oncology, 23, 8500–8511.

doi: 10.1200/JCO.2005.01.8010
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Search Strategy:

Studies were included in the review if they reported on

  • Adult patients older than 18 years of age
  • Patients with nonhematologic malignancies
  • Patients with anorexia or symptoms of anorexia, such as lack of appetite, weight loss, poor performance status, and decreased quality of life.

Literature Evaluated:

The review involved only prospective, randomized controlled trials (RCTs; double- and single-blind or unblended and phase III trials). The quality of studies was assessed using the validated scale published by Jadad et al. (1996).

Sample Characteristics:

There were 55 studies reviewed that met the eligibility criteria.

Results:

Androgenic steroids
Androgenic steroids were studied in two studies involving 512 patients; no significant benefit was demonstrated.
 
Cannabinoids
Cannabinoids were studied in one RCT involving 469 patients; they did not confer an additional benefit.
 
Corticosteroids
Six studies investigated the use of corticosteroids in 647 patients. Some improvements in appetite were found; however, dosage and type of steroid varied such that optimal dose and duration of therapy could not be determined.
 
Cyproheptadine
Two studies investigated the use of cyproheptadine in 344 patients; these investigations had conflicting outcomes.
 
Eicosapentaenoic acid (EPA)
Three studies investigated the use of EPA in 689 patients; these reported conflicting results.
 
Erythropoietin (EPO)
EPO was investigated in two studies involving 417 patients. In one investigation, EPO was administered in combination with a COX-2 inhibitor with and without a specialized nutritional program. The intent-to-treat analysis was negative. No differences in food intake were noted.
 
Ghrelin
Ghrelin was investigated in one RCT involving seven patients; differences between groups were noted, but long-term safety data on the agent are not available.
 
Hydrazine sulfate
Five studies investigated the use of hydrazine sulfate in 796 patients. Multicenter RCTs in patients with lung and colon cancers did not demonstrate any benefit when compared to a placebo.
 
Interferon
Interferon was investigated in one study involving 57 patients; no differences were found.
 
Nonsteroidal anti-inflammatory drugs (NSAIDs)
NSAIDs were investigated in two trials involving 417 patients; these investigations failed to demonstrate a benefit in the NSAID arm.
 
Pentoxyfilline
One study investigated the use of pentoxyfilline in 70 patients and found no benefit. Melatonin was investigated in two studies involving 186 patients; these did not demonstrate any improvement in appetite or intake.
 
Progestins
Twenty-nine studies reviewed the safety and efficacy of progestins: 23 examined megesterol acetate (MA), and six investigated medroxyprogesterone acetate (MPA). Results favored progestins over placebo and found that side effects were tolerable. Ten studies assessed the influence of MA on quality of life; these demonstrated that the effect of MA on quality of life was minimal.
 
Prokinetics
Two studies investigated prokinetics for anorexia in a total of 55 patients. No improvement in caloric intake or appetite was noted.
 
Thalidomide
Thalidomide has not been investigated in prospective RCTs.

Conclusions:

Multiple RCTs have been conducted to investigate the safety and efficacy of pharmacologic agents to stimulate appetite. Only two therapeutic interventions for cancer-related anorexia demonstrated enough evidence to support their use in patients with cancer: corticosteroids and progestins. Other studies had mixed outcomes, positive results in only a single randomized trial, or were not placebo-controlled.

There is strong evidence supporting the use of progestins in patients with cancer, of which the most commonly reported drugs were MA and MPA. There was increased weight with both progestins; there was also evidence of a dose-response, but higher doses did not confer any additional benefit with regard to appetite. Metaclopromide is effective for nausea and early satiety but has not been shown to directly stimulate appetite.

The RCTs did not show sufficient evidence to justify the use of dronabinol, EPA, EPO, ghrelin, interferon, melatonin, nandrolone, NSAIDs, or pentoxyfilline in cancer-related anorexia. Cyproheptadine is a weak appetite stimulant, but side effects are limiting.

Nursing Implications:

The optimal dose, start time, and duration of treatment for many appetite stimulants are still unknown. A more systematic approach to research methodology is needed. In addition, uniform outcome measures to better assess the value of various appetite stimulants are needed. These should include subjective ratings of appetite and associated symptoms (e.g.,  early satiety) and objective measures (e.g., food consumed, weight gain, weight loss).


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