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ONC: Dietary Supplements and Medical Food Supplements Containing Fish Oil (2013)

Citation:
 
Study Design:
Class:
- Click here for explanation of classification scheme.
Quality Rating:
Research Purpose:
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.
Inclusion Criteria:

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
Exclusion Criteria:
  • 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.
Description of Study Protocol:

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. 

 

Data Collection Summary:

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
Description of Actual Data Sample:

 

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

 

Summary of Results:

 

  • 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

    • Author Conclusion:
    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. 
    Funding Source:
    Reviewer Comments:

    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.

    Quality Criteria Checklist: Primary Research
    Relevance Questions
      1. Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies) Yes
      2. Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about? Yes
      3. Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice? Yes
      4. Is the intervention or procedure feasible? (NA for some epidemiological studies) Yes
     
    Validity Questions
    1. Was the research question clearly stated? Yes
      1.1. Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified? Yes
      1.2. Was (were) the outcome(s) [dependent variable(s)] clearly indicated? Yes
      1.3. Were the target population and setting specified? Yes
    2. Was the selection of study subjects/patients free from bias? Yes
      2.1. Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study? Yes
      2.2. Were criteria applied equally to all study groups? Yes
      2.3. Were health, demographics, and other characteristics of subjects described? Yes
      2.4. Were the subjects/patients a representative sample of the relevant population? Yes
    3. Were study groups comparable? Yes
      3.1. Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT) No
      3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? Yes
      3.3. Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.) Yes
      3.4. If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis? N/A
      3.5. If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.) N/A
      3.6. If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")? N/A
    4. Was method of handling withdrawals described? Yes
      4.1. Were follow-up methods described and the same for all groups? Yes
      4.2. Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.) Yes
      4.3. Were all enrolled subjects/patients (in the original sample) accounted for? Yes
      4.4. Were reasons for withdrawals similar across groups? Yes
      4.5. If diagnostic test, was decision to perform reference test not dependent on results of test under study? N/A
    5. Was blinding used to prevent introduction of bias? Yes
      5.1. In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate? Yes
      5.2. Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.) Yes
      5.3. In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded? N/A
      5.4. In case control study, was case definition explicit and case ascertainment not influenced by exposure status? N/A
      5.5. In diagnostic study, were test results blinded to patient history and other test results? N/A
    6. Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described? Yes
      6.1. In RCT or other intervention trial, were protocols described for all regimens studied? Yes
      6.2. In observational study, were interventions, study settings, and clinicians/provider described? N/A
      6.3. Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect? Yes
      6.4. Was the amount of exposure and, if relevant, subject/patient compliance measured? Yes
      6.5. Were co-interventions (e.g., ancillary treatments, other therapies) described? Yes
      6.6. Were extra or unplanned treatments described? N/A
      6.7. Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups? N/A
      6.8. In diagnostic study, were details of test administration and replication sufficient? Yes
    7. Were outcomes clearly defined and the measurements valid and reliable? Yes
      7.1. Were primary and secondary endpoints described and relevant to the question? Yes
      7.2. Were nutrition measures appropriate to question and outcomes of concern? Yes
      7.3. Was the period of follow-up long enough for important outcome(s) to occur? Yes
      7.4. Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures? Yes
      7.5. Was the measurement of effect at an appropriate level of precision? Yes
      7.6. Were other factors accounted for (measured) that could affect outcomes? ???
      7.7. Were the measurements conducted consistently across groups? Yes
    8. Was the statistical analysis appropriate for the study design and type of outcome indicators? Yes
      8.1. Were statistical analyses adequately described and the results reported appropriately? Yes
      8.2. Were correct statistical tests used and assumptions of test not violated? Yes
      8.3. Were statistics reported with levels of significance and/or confidence intervals? Yes
      8.4. Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)? Yes
      8.5. Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)? N/A
      8.6. Was clinical significance as well as statistical significance reported? Yes
      8.7. If negative findings, was a power calculation reported to address type 2 error? Yes
    9. Are conclusions supported by results with biases and limitations taken into consideration? Yes
      9.1. Is there a discussion of findings? Yes
      9.2. Are biases and study limitations identified and discussed? Yes
    10. Is bias due to study's funding or sponsorship unlikely? Yes
      10.1. Were sources of funding and investigators' affiliations described? Yes
      10.2. Was the study free from apparent conflict of interest? Yes