Examine the potential of high dose oral fish oil fatty acid supplements to slow weight loss and improve quality of life in patients with malignancy-related cachexia.

• > 18 years of age
• histologic diagnosis of malignancy not amenable to curative treatment
• weight loss >2% of body weight within the 1-month period before enrollment
• adequate renal, liver, and bone marrow function
• normal free or total thyroxine levels
• concurrent chemotherapy and radiotherapy allowed (abdominal/pelvic radiation must have been completed at least 3 weeks prior to study initiation).  Investigational drugs were not allowed.

• life expectancy < 2 months
• major surgery within 3 weeks of the study
• ingestion of certain medications (e.g. steroids, dronabinol, megestrol acetate, diuretics)
• one or more of the folllowing medical conditions: Edema, GI obstruction, pregnancy, ascites, congestive heart failure, metabolic disorders, uncontrolled infection, primary or metastatic brain tumors
• Eastern Cooperative Oncology Group performance status of 3 or 4
• ingestion of omega-3 fatty acid supplements within 4 weeks of study initiation

Recruitment: Not described.

Design:  Patients received high dose omega-3 fatty acids from fish oil capsulesdaily for a study period of > 1 month.  Use of supportive care drugs, antidiarrhea medications, antiemetics and analgesics were allowed only if clinically necessary.  Diuretics were avoided if possible.

Blinding used (if applicable): Not blinded.

Intervention (if applicable):  Patients were asked to take a dose of 0.15 g/Kg of omega-3 fatty acids from fish oil capsules/day in 2 divided doses (1 dose with breakfast, 1 dose with lunch). The number of fish oil capsules differed according to weight (i.e 70Kg patient dose = 11 one gram capsules). Compliance with drug dose was monitored via patient questioning.  Treatment plan was to cotinue supplements for a minimum of 2 months, even in patients who continued to lose weight, to conduct an adequate trial.

Note: The initial dose of the supplement to be provided was 0.30g/kg. This dose was provide to the 1st 13 patients, which was the maximum tolerated dose established in the Phase I study.  Dose reduction was insitututed for the remainder of the study to 0.15 g/kg/day because patients were unwilling or unable to take the number of required fish oil capsules.

Statistical Analysis:  Primary endpoint was weight change from time at last treatment follow-up compared with baseline or reaching the pre-cachexia baseline weight. An indicator variable was used to define weight change as a gain of > 5%.  This design had a power of 96% and a type I error rate of 0.08. 

Response rates and 95% confidence intervales based on the binomial distribution were calculated for measured weights.

Three patients not included in analysis due to drop-out.

Timing of Measurements: At baseline and at last treatment follow-up.

Dependent Variables

• Body weight: Method of measurement was not defined.  Operational defiinition of weight change was a gain of > 5%.
• Quality of life:  Data were collected during the 53-item version of the Functional Assessment of Anorexia/Cachexia Therapy (FAACT [Version 3] scales)

Independent Variable

• Dosage of omega-3 fatty acids

Initial N: 43 entered. 3 did not take the capsules because of disease progression and were not included in the response analysis.  4 were not included in the weight analysis (3 due to edema requiring diuretics; 1 had no weight data recorded)

Sex:  29 men, 14 women

Age: Median age 67 years (range 42-84 years)

Ethnicity: Not reported

Other relevant demographics:

• Median weight at entry 64 kg (range 40-89)
• median weight loss over 1 month 2.7 (4% overall)
• median BMI 21.1 (range 14.6-33.7)
• median serum prealbumin level 16 mg/dL (range 5-58) (reference range 18-45)
• median serum albumin level 3.5 mg/dL (range 0.9-4.5) (reference range 3.5-5)
• median creatinine height index for 23 patients in whom it was measured was 62 (range 30-107).

Location: Multiple study sites associated with the Cancer and Leukemia Group B Cooperative Group.

• Median treatment time was 1.2 months (range 0.5 days to 3.1 months). 
• Patients typically received the assigned dose except one patient recruited early who was assigned 0.3 g/kg  but required dose reduction to 0.15 g/kg for the last 4 days of a 31 day tratment period due to side effects. 
• Another patient who was assigned to 0.15 g/kg, experienced dose increase to 0.2 g/kg for last 20 days of a 77 day treatment period because of failure to gain weight. 
• Two more patients assigned to .15 g/kg erroneuously received doses of 0.2 g/kg and 0.1 g/kg respectively.

Other Findings:Reported side effects from the 40 patients who took at least 1 capsule:

• nausea (n=11; 28%)
• abnormal taste in mouth (n=10; 26%)
• abnormal taste of food (n=9; 23%)
• excessive belching (n=9; 23%)
• excessive flatulence (n=9; 23%)
• emesis (n=8; 20%)
• diarrhea (n=7; 18)
• abnormal body smell (n=4; 10%)
• dyspepsia (n=2; 5%)

No significant change in serum prealbumin concentration from baseline.

• Progressive cancer    4 (9%)
• Adverse medical event/new problem    5 (12%)
• Death    2 (5%)
• Withdrawal of consent (16 withdrew due to side effects or refusal of further therapy; 3 did not state reason for withdrawal)    19 (44%)
• Failure to begin treatment    3 (7%)

Using previously established criteria, equal numbers of patients gained wieght and continumed to lose weight.  Weight stabilization was associated with taking the omega-3 capsules.  Many patients who did not responde were unable to tlerate the capsules. 

The entire group exhibited median weight loss of 0.8 kg. This statistic includes patients who took only a few capsules and patients who had a tuncated treatment course.  Predicted weight loss for these patients would be at least a further 4.6%.  The entire group however experienced actual weight loss of 1.2%.

Patients who gained weight had a better QOL score at 30 days posttreatment.  These results should be intrepreted with caution Only a small number of patients completed the posttreatment assessments.  A correlation does not prove a cause-and-effect relationship;  thus we cannot be certain that the weight gain was directly responsible for the improved QOL.

Although there was not an increase in median weight for the entrie study group, an appreciable fraction of patients with advanced cancer cachexia who could tolerate the supplement experienced a reversal of their weight loss or a gain as a result of taking daily concentrated capsules of omega-3 fatty acids for > 1 month.

These patients were malnourished as reflected by their degree of underweight and low serum prealbumin levels at entry.  It may have been that their poor nutritional status was so extreme that expectation for weight gain as defined in operational definition was too aggressive.  Nonetheless, the response by a subset of patients is promising

This study did not have a placebo control, which weakens study design.

Patient compliance to fish oil capsule consumption was ascertained by questioning only.  This may have affected the quality of information about compliance to intervention.

On re-analysis to determine if this study helps elucidate if EPA helps to reduce the catabolic effects of cancer, the same comments hold.