EAL

Omega 3 Fatty Acid and Oncology

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

This study was designed to test efficacy & safety of an integrated treatment consisted of a nutrition component (polyphenols, antioxidants, essential fatty acids, vitamins, and calories) and a pharmacologic component (medroxiprogesterone acetate and COX-2 inhibitor)approach for addressing cancer anorexia and oxidative stress in advanced cancer patients.

Inclusion Criteria:

18 to 80 years old
Histologically confirmed tumor of any site at advanced stage, especially cancers inducing early cachexia (head & neck and gastrointestinal cancers)
Have lost at least 5% of their ideal (or pre-illness) body weight in the last 3 months and/or have abnormal values of proinflammatory cytokines, reactive oxygen species (ROS), and antioxidant enzymes predictive of onset of clinical cachexia
Be currently under treatment with antineoplastic therapy with curative or palliative intent (chemotherapy or hormone therapy) or supportive care
Have a life expectancy of > 4 months from time of enrollment
Informed consent

Exclusion Criteria:

Subjects Cannot:

Be pregnant
Have significant comorbidities
Have impaired food intake due to mechanical obstruction
Be receiving medical treatments that induce significant changes of metabolism or body weight such as enteral or parenteral nutrition, corticosteroids, insulin, or any other drug potentially capable of influencing body weight

Description of Study Protocol:

Recruitment

Total of 40 patients planned for recruitment
As of January 2004 (cut point for inclusion in analysis for this publication) 28 subjects enrolled from July 2002 to December 2003
25 subjects were evaluable
14 subjects have completed full 16 weeks (4 months) of planned treatment
20 subjects have completed 8 weeks (2 months), or one-half, of planned treatment

Design

Phase II, non-randomized, intervention trial (Timeseries)

Blinding used (if applicable)

N/A

Intervention (if applicable)

Nutrition Components

Diet containing > 400 mg polyphenols obtained from diet (onions, apples, oranges, red wine, or green tea) or supplemented p.o. by tablets if dietary intake not acheivable.
p.o. intake of 2 cans/d Prosure (Abbott Laboratories) (620 kcal; 2.2 g eicosapentaenoic acid (EPA); 0.92 g decosahexaenoic acid (DHA))
p.o. 300 mg/d alpha-lipoic acid (Tiobec, Laborest, Nerviano)
p.o. 2.7 g/d carbocysteine lysine salt (Fluifort, Dompe)
p.o. 400 mg/d vitamin E; 30,000 IU/day vitamin A; 500 mg/d vitamin C

Pharmacologic Components

p.o. 500 mg/d medroxiprogesterone acetate (Pharmacia-Pfizer)
p.o. 200 mg/d COX-2 Inhibitor (Celecoxib; Pharmacia-Pfizer)

Statistical Analysis

Paired Student's t test or Wilcoxon signed rank test (baseline vs. post-treatment values)
Significance determined at 5%, 1%, and 0.1% levels for two-sided test

Data Collection Summary:

Timing of Measurements

Baseline, 1 month, 2 months, 4 months

Dependent Variables

Clinical Variables

Complete Response, Partial Response, Stable Disease, or Progressive Disease were measured before and after treatment and are defined as outlined in:
- Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000;92(3):205-16.
Performance Status per ECOG (Eastern Cooperative Oncology Group) Scale before & after treatment (measured by same clinician to minimize bias)

Nutritional/Functional Variables

Weight
Lean Body Mass (LBM) by bioimpedentiometry
Appetite evaluated by Visual Analogue Scale (0-10
Resting Energy Expenditure (REE; kcal/d) by indirect calorimetry (calculated in a subset of patients0
Grip Strength by dynamometer

Laboratory Values

Serum levels of proinflammatory cytokine (IL-6 & TNF-alpha)
Serum leptin levels
Blood levels of reactive oxygen species (ROS) by Free Oxygen Radicals Test (FORT)
Antioxidant enzyme activity (evaluation by photometer of erythrocyte levels of antioxidant enzyme glutathione peroxidase (GPx)

Quality of Life

European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 version 3
Euro QL EQ-5D_index (generic health status measure encompassing 5 dimensions: mobility, self-care, usual activity, pain/discomfort, anxiety/depression) with scale ranging from 1 = "full health" to 9 = "death" and the QL EQ-5D_VAS (overall health state on a 10 cm Visual Analogue Scale (VAS)) with scale ranging from 0 to 100
Multidimensional Fatigue Symptom Inventory-Short Form (30 item questionnaire on principal manifestations of fatigue) and the Vigor Sub-scale

Independent Variables

Integrated treatment approach consisting of a nutrition component (polyphenols, antioxidants, essential fatty acids, vitamins, and calories) and a pharmacologic component (medroxiprogesterone acetate and COX-2 inhibitor). Compliance was verified by count of tablets/cans returned by patients.

Description of Actual Data Sample:

Initial N:

28 subjects enrolled as of January 2004 (cut point for inclusion in analysis for this publication)
Total of 40 patients planned for recruitment

Attrition (final N):

25 subjects evaluated
2 patients withdrawn from study due to noncompliance
1 patient died of "progressive disease"

Age (yrs) & Gender:

Mean + SD = 58.2 + 9.0
Range = 36 to 76
12 Males & 16 Females

Ethnicity:

Italian

Tumor Site (n (% of sample)):

Head & Neck: 14 (50)
Breast: 4 (14.3)
Lung: 3 (10.7)
Stomach: 2 (7.1)
Ovary: 2 (7.1)
Uterine Sarcoma: 1 (3.6)
Colon: 1 (3.6)
Pancreas: 1 (3.6)

Disease Stage (n (% of sample)):

II: 1 (3.6)
IIIA: 1 (3.6)
IV: 26 (92.8)

ECOG Performance Status (n (% of sample)):

0: 1 (3.6)
1: 16 (57.1)
2: 11 (39.3)

Anthropometrics (e.g., were groups same or different on important measures):

Weight (kg):

Mean + SD = 51.4 + 11.0
Range = 36-76

Height (m):

Mean + SD = 1.59 + 0.07
Range = 1.45-1.75

Body Mass Index (kg/m²):

Mean + SD = 20.5 + 4.7
Range = 14.4-31.6
< 18.5 = 13 subjects (46.4% of sample)
18.5-25 = 12 subjects (42.9% of sample)
> 25 = 3 subjects (10.7% of sample)

Timing of Intervention:

5 patients started intervention at same time as starting chemotherapy
18 patients received treatment beginning during chemotherapy
2 patients received treatment immediately post-chemotherapy

Location: University of Cagliari, Department of Medical Oncology, Cagliari, Italy

Summary of Results:

Variables: Clinical	Improvement: "progressive disease" to "stable disease"	Improvement: "stable disease" to "partial response"	Unchanged: "stable disease"	Worsened: "stable disease" to "progressive disease"
Response*	n = 3	n = 2	n = 3	n = 6

Variables: Clinical	ECOG Performance Status Unchanged	ECOG Performance Status Improved
Performance Status*	n = 11	n = 3

*Objective response & Performance Status evaluated in 14 patients who completed full 4 months of treatment intervention

Variables: Nutritional & Functional

Baseline
n=25

1 Month (p-value vs baseline (n=25))

2 Months (p-value vs baseline (n=20))

4 Months (p-value vs baseline (n=14))

Weight (kg)

51.3+10.1

52.7+11.1 (p=0.009)

55.3+10.6 (p=0.013)

58+12.4 (p=0.019)

LBM (kg)

35.1+8.6

35.9+8.8 (p=0.067)

37.6+8.2 (p=0.045)

40.5+9.1 (p=0.023)

Appetite

4.79+2.7

6.71+2.1 (p=0.004)

7.2+1.8 (p=0.050)

8.0+2.0 (p=0.074)

Grip Strength
24.9+8.9

24.7+7.5 (p=0.723)

27.8+6.1 (p=0.831)

30.5+9.0 (p=0.977)

ROS (FORT units)
496.2+91.9

442.3+96.2 (p=0.029)

425.9+89.4 (p=0.037)

434.6+108.1 (p=0.108)

GPx (units/L)
8,837.2+3176

7,857.5+2,563 (p=0.131)

8,047.7+3,069.6 (p=0.137)

8,944.1+4,035.1 (p=0.606)

IL-6 (pg/mL)
14.9+7.5

10.7+7.7 (p=0.030)

8.5+6.9 (p=0.020)

7.0+4.9 (p=0.004)

TNF-alpha (pg/mL)
32.5+21.8

21.8+18.8 (p=0.018)

19.4+16.6 (p=0.084)

14.5+9.0 (p=0.002)

Leptin (ng/mL)

3.9+4.3

5.6+7.2 (p=0.211)

7.3+7.8 (p=0.306)

18.7+19.5 (p=0.027)

Variables: Quality of Life	Baseline n=25	1 Month (p-value vs baseline (n=25))	2 Months (p-value vs baseline (n=20))	4 Months (p-value vs baseline (n=14))
EORTC QLQ-30*	56.1+16.7	65.9+17.6 (p=0.003)	70.2+13.5 (p=0.019)	62.0+14.1 (p=0.459)
EQ-5D_index*	0.33+0.4	0.45+0.3 (p=0.128)	0.59+0.3 (p=0.144)	0.54+0.3 (p=0.029)
EQ-5D_VAS*	44.1+2.2	55.8+2.2 (p=0.022)	62.1+2.0 (p=0.038)	61.9+1.9 (p=0.089)
MFSI-SF (fatigue)**	37.0+19.7	21.4+18.1 (p=0.019)	20.1+14.9 (p=0.006)	25.0+16.0 (p=0.179)
MFSI-SF (subscale "vigor")**	4.57+3.0	7.0+5.1 (p=0.054)	7.0+3.0 (p=0.077)	8.5+6.4 (p=0.195)

*Increasing score corresponds to improvement of QOL
**Decreasing score corresponds to amelioration of fatigue

Other Findings

Safety:

Treatment was well-tolerated with no withdrawals from study due to toxicity.
One patient interrupted medroxiprogesterone acetate after 2 months due to leg deep vein thrombosis (DVT).
One patient interrupted treatment after 2 months due to supervening pancreatitis

Author Conclusion:

Results are encouraging.
Results should be interpreted with caution because this is an uncontrolled study reported at an interim phase.
Ultimate goal should be to translate the results obtained in advanced cancer patients into a prevention trial of individuals at risk of developing cancer cachexia and oxidative stress.

Funding Source:

Government:

Regione Autonoma Sardegna (Italy)

Reviewer Comments:

This study provides encouraging results, but interpretation is difficult because:

Small sample size.
Not blinded.
No control group.
No placebo.
Reported at interim point; study requires completion and further reporting of final results.
There were so many components of the intervention that it is difficult to know which component accounted for which change in clinical, laboratory, and QOL measures.
This intervention requires further study before widespread recommendation of this approach.

The above mentioned shortcomings make results of this study difficult to apply to clinical practice.

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?		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.)	No
	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?	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?	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?	No
	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?	???
	7.6.	Were other factors accounted for (measured) that could affect outcomes?	No
	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)?	N/A
	8.5.	Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)?	No
	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

Variables: Nutritional & Functional	Baseline n=25	1 Month (p-value vs baseline (n=25))	2 Months (p-value vs baseline (n=20))	4 Months (p-value vs baseline (n=14))
Weight (kg)	51.3+10.1	52.7+11.1 (p=0.009)	55.3+10.6 (p=0.013)	58+12.4 (p=0.019)
LBM (kg)	35.1+8.6	35.9+8.8 (p=0.067)	37.6+8.2 (p=0.045)	40.5+9.1 (p=0.023)
Appetite	4.79+2.7	6.71+2.1 (p=0.004)	7.2+1.8 (p=0.050)	8.0+2.0 (p=0.074)
Grip Strength	24.9+8.9	24.7+7.5 (p=0.723)	27.8+6.1 (p=0.831)	30.5+9.0 (p=0.977)
ROS (FORT units)	496.2+91.9	442.3+96.2 (p=0.029)	425.9+89.4 (p=0.037)	434.6+108.1 (p=0.108)
GPx (units/L)	8,837.2+3176	7,857.5+2,563 (p=0.131)	8,047.7+3,069.6 (p=0.137)	8,944.1+4,035.1 (p=0.606)
IL-6 (pg/mL)	14.9+7.5	10.7+7.7 (p=0.030)	8.5+6.9 (p=0.020)	7.0+4.9 (p=0.004)
TNF-alpha (pg/mL)	32.5+21.8	21.8+18.8 (p=0.018)	19.4+16.6 (p=0.084)	14.5+9.0 (p=0.002)
Leptin (ng/mL)	3.9+4.3	5.6+7.2 (p=0.211)	7.3+7.8 (p=0.306)	18.7+19.5 (p=0.027)