Oncology

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Citation:

Burns CP, Halabi S, Clamon G, et al:  Phase II study of high-dose fish oil capsules for patients with cancer-related cachexia.  A Cancer and Leukemia Group B study.  Cancer 2004;101:370-378.

 
Study Design:
Before-After Study
Class:
D - Click here for explanation of classification scheme.
Quality Rating:
Positive POSITIVE: See Quality Criteria Checklist below.
Research Purpose:

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.

Inclusion Criteria:
  • > 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.
Exclusion Criteria:
  • 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
Description of Study Protocol:

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.

 

Data Collection Summary:

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
Description of Actual Data Sample:

 

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.

 

Summary of Results:
  • 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.

 

Variables

Treatment Group

Measures (confidence interval)

Statistical Significance

Body weight

  • Gained Weight (>5% or reached UBW)

 

  • Stabilized Weight (<5% gain or<5% loss)

 

  • Lost Weight (loss >5% weight )

 

  • Unevaluable

 

6 patients (17%; 95% CI 0.06-0.33)

 

 

24 patients (66%)

 

 

6 patients (17%; Range 3.4-6.2 kg)

 

6 patients were unevaluable

p-values not presented

QOL change from baseline  (FAACT)      

  • Non-Weight Gainers

 

  • Weight Gainers                 

 

 

-0.2 [n=13; -27.6-19.4]

 

7.6 [n=6; 2.3-18.2]

 

Total 3.3 [n=19; -14.0-18.2]                                 

p-values not presented

Patients who gained weight had higher FAACT scores than those who didn't gain weight                                     

QOL change from baseline  (FACT-G)      

  • Non-Weight Gainers

 

  • Weight Gainers                 
 

 

-2.0 [n=13; -10.4 -13.5]

 

 

3.2 [n=6; 1.9-5.5]

 

Total 1.9 [n=19; -7.8-13.5]

 p-values not presented

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.

Patients were intended to continue taking the capsules for at least 2 months (nonresponders) or 3 months (responders).  10 (23%) subjects completed the protocol.  Reasons for early terminations were
  • 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%)
Author Conclusion:

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.

Funding Source:
Government: National Cancer Institute
Reviewer Comments:

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.

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? ???
2. Was the selection of study subjects/patients free from bias? ???
  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? ???
3. Were study groups comparable? N/A
  3.1. Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT) N/A
  3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? N/A
  3.3. Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.) N/A
  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%.) N/A
  4.3. Were all enrolled subjects/patients (in the original sample) accounted for? Yes
  4.4. Were reasons for withdrawals similar across groups? N/A
  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? No
  5.1. In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate? No
  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.) No
  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? N/A
  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? N/A
  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? N/A
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? No
  7.7. Were the measurements conducted consistently across groups? N/A
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)? ???
  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? N/A
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