- Click here for explanation of classification scheme.

To determine if an eicosapentaenoic acid-containing nutritional supplement, alone or in combination with megestrol acetate (MA), improves weight, appetite, quality of life, and survival in advanced cancer patients who are suffering from cancer-associated wasting, compared with MA alone.

Patients > 18 years with incurable malignancies and

• estimated life expectancy > 3 months
• Eastern Cooperative Oncology Group (ECOG) performance score > 2
• self-reported 2 month weight loss of at least 5 lb (2.3 kg) and/or physician-estimated caloric intake of < 20 Cal/kg body weight/d
• self-perceived weight loss and/or appetite as a problem and physician viewed weight gain as beneficial
• chemotherapy or radiation was permitted

• Malignancies of the brain, breast, ovaries, prostate, or endrometrial cancer
• ongoing tube-feeding or parenteral nutrition
• use of adrenal steroids (except short-term dexamethasone with chemotherapy), androgens, progestational agents, or other appetite stimulants in the past month
• brain metastases
• pregnant or unwillingness to use contraceptives if of child-bearing capacity; nursing
• Any of the following conditions: edema or ascites, insulin-requiring diabetes; poorly controlled hypertension; congestive heart failure; history of thromboembolism; obstruction of the alimentary tract; malabsorption;intractable vomiting.

Recruitment:  Patients with incurable malignances recruited from a total of 26 primary treatment sites between Feb 2000 and Aug 2002.

Design: Prior to randomization, patients were stratified based on cancer type; GI vs thoracic, vs other; severity of weight loss < 10 lb (4.6 kg) vs > 10 lb in the preceding 2 months; planned concurrent chemotherapy, yes vs no; age , <50 vs > 50 years; and Good, Bad, Unsure index (a validated stratification factor)  

After stratification, patients were randomized to one of 3 arms:

• EPA supplement, 2 cans/day (providing 1.09 G EPA, 0.46 DHA/can)plus placebo liquid suspension appearing identical to MA
• MA liquid suspension 600 mg/d orally plus isocaloric, isonitrogenous (300 Cal, 16 g protein plus unspecified amounts of vitamins A,D,E,K, folic acid, beta-carotene) placebo cans of control supplement
• EPA supplement, 2 cans/day plus MA liquid susupension 600 mg/d orally

 

Measurements of the dependent variables were made at study entry, weekly, then monthly.

Patients continued treatment as long as both the patient and treating oncologist considered it beneficial or until concerning or intolerable side effects occurred.

Blinding used: Double-blinding was used.

Statistical Analysis: 

• The EPA only and EPA plus MA were compared to the MA plus standard supplement using 2, two-sided tests using a 2%-5% type 1 error rate.
• Primary endpoint was gain of at least 10% nonfluid weight
• Differences between groups in appetite-related categoric variables were analyzed with Fisher's exact test
• Continuous variables such as QOL ratings, ordinal baseline variables, and toxicity data, were compared among groups with Wilcoxon rank sum tests or independent sample t test
• Patients who dropped out before a weight assessment were considered to have experienced treatment failure in an intent-to-treat fashion
• All analyses were carried out with two-sided tests and 2.5% type I error rates when using the reference arm approach. 

 

Timing of Measurements:  At study entry and monthly:

• history and physical exam, including weight measurement in oncologist's office
• toxicity assessment

At baseline, weekly for 4 weeks, then monthly:

• North Central Cancer Treatment Group (NCCTG) questionnaire for appetite and weight
• single-item Uniscale question measured QOL
• Functional Assessment of Anorexia/Cachexia (FAACT) questionnaire

Dependent Variables

• Body weight  (self-reported by patients)
• Toxicity assessed by treating oncologist
• Appetite 
• QOL 

Independent Variables

• EPA
• MA
• EPA + MA

 

Initial N: 429 recruited.  421 deemed assessable. 

• 6 excluded from analysis because of withdrawal before starting intervention
• 2 failed to meet eligibility requirements after randomization. 

After stratification, 141 were randomized to the EPA group, 140 to the MA group, and 140 to the MA plus EPA group.  The groups were comparable at baseline. 

Patients stayed in the study for slightly more than 3 months for the group as a whole. 

Over the study period, patients in the EPA, MA, and MA + EPA withdrew because they:

• declined further treatment and/or experienced toxicity (48-54%)
• died (16-19%)
• chose alternative treatment (1-4%)
• developed other medical problems (8-12%)
• other reasons (e.g. failure to keep clinic appts) (16-24%)

Age: 65, 66+/-11 years

Ethnicity: not reported

Malignancy Type:

• lung: 39-40%
• GI: 32-36%
• other: 22-29%

Planned concurrent chemotherapy: 68-70%

Anthropometrics:

• Pounds weight lost in 2 months prior to study initiation
  • < 10 lbs: 37-39%
  • > 10 lbs: 61-63%

Location: North Central Cancer Treatment Group in collaboration with the National Cancer Institute of Canada

 

 

Variables	EPA Group Measures	MA Group Measures	MA + EPA Group Measures	Statistical Significance of Group Difference
Body Weight Physician reported gain over baseline   0% Gain     1-4% gain   5-9% Gain   >10%	63%   22%   9%   6%	61%   11%   10%   18%	55%   20%   14%   11%	Pimary endpoint:10% weight gain above baseline MA group had significantly more patients achieiving this endpoint (P=.01) Findings from patient reported gain was similar (P=.08)
Absolute weight change	-1.0	1.3	0.1	P=.008 for EPA vs MA P=.03 across all arms AUC indicated no difference across arms
Appetite NCCTG questionaire (% improvement baseline food intake)	64%	68%	66%	P=.69
FAACT questionaire 4 week score for "I have a good appetite"	40	55	55	MA and MA + EPA p=.004
QOL (uniscale score)	56	55	56	P=.93

This study demonstrates that an EPA supplement does not result in notable improvement in weight, survival, or QOL compared with MA.  Combination therapy (EPA + MA) provides no benefit over and above MA alone.  Additional study is needed to develop and test new agents and approaches for the treatment of cancer-associated wasting.  Appetite improvement as assessed by the NCCTG questionnaire was roughtly comparable across all arms, although the FACCT seemed to suggest that the MA-treated arms gained greater appetitie stimulation over time.  It should be noted that this progestational agent is nonetheless limited in its ability to trreat cancer-associated wasting. 

The study is well designed, has a large N, was carefully stratified and randomized.  Some shortcomings should be noted.  There is no true control group, limiting interpretation of findings.  A variety of cancers are included.  This limits generalizability but others might say that this reflects clinical reality.  In severely ill patients, a 10% weight gain may be an impossible goal.  Other studies have focused on high doses EPA (see Burns, et al in this data base).  It is possible that the amount of omega-3 fatty acids used in the study was too small to make an effect.  Finally, it is not possible to verify that patients actually consumed treatments as plasma EPA levels were not measured.  Further, weight was self-reported. 

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