EAL

ONC: EPA/Omega 3 Fatty Acids (2006)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

To identify prognostic indicators in patients with brain metastasis receiving stereotactic radiotherapy and to assess the prognostic importance of supplementation with omega 3 fatty acids (n-3 FA) on survival.

Inclusion Criteria:

Brain metastasis from differing primary tumors
Treated with stereotactic radiotherapy (SRT) at the National Cancer Institute in Milan

For intervention patients, additional stratification included:

Only patients with high risk received this therapy. This included metastases localized to important neurological areas such as Rolandic area, Para-Rolandic area, brain stem, and chiasma and patients treated previously with radiation.

Exclusion Criteria:

Not described

Description of Study Protocol:

Recruitment Not described, retrospective study

Design Retrospective review of patients receiving SRT for brain metastases of different origins at the NCI of Milan between August 1, 1991 and December 31, 1997. Subjects received a mean dosage of 37.8 Gy (range 10-60 Gy) of SRT as follows:

Single Shot Approach: 40 minutes for the 1st or single lesion, 25 minutes at each further lesion

Fractionated Approach: 10-20 minutes intial session, 10 minutes subsequent session; Total of 4 sessions (mean) and 65 minutes of treatment per isocenter; Median fractionation dose 1.8 Gy (range 2-4 Gy)

Patients also received 14 days of dexamethasone with an initial dose of 16 mg/day with progressive reduction for a standard median dose of 4-16 mg/day dexamethasone and anti-convulsants when necessary. Presence of radiation necrosis was assessed with MRI or CT scan plus PET scan, with confirmation of some with biopsy or surgery. If radiation necrosis occurred patients were provided with an osmotic forced agent (250 cc, 18% Mannitol 3 times per week) and dexamethasone for at least 10 months.

143 patients received n-3FA supplementation with 3 capsules Esapent and bioflavonoid supplementation with 0.2g silymarin (flavonoid found in milk thistle) daily commencing 2 weeks post completion of SRT and continuing for up to 20 weeks.

Patients completed a daily symptom diary for up to 20 weeks post treatment which included daily documentation of headache, nausea, vomiting, dizziness, seizures, motor sensory impairment, and epilepsy. ECOG performance status was recorded for all patients. Patients were also followed-up post treatment with a CT, MRI, or PET scan at 45 day intervals.

Blinding used Not applicable

Intervention Two weeks following the completion of SRT, 143 patients considered high risk received daily supplementation with 2.45 g of n-3FA in a ratio of eicosapentanoic acid (EPA) to docohexanoic (DHA) of 0.9-1.5 (3 cups/day of Esapent). These patients also received 0.2g silymarin, a flavonoid found in milk thistle. Supplementation was continued for up to 20 weeks.

Subjects were followed up at a mean of 65 days (range 40-90 days). However, those still undergoing chemotherapy or radiation therapy were not seen for follow-up.

Statistical Analysis

Kaplan-Meyer survival curves (using the 1st day of SRT)
Log-rank test and the k-test (comparison of survival curves)
Cox proportional hazards model
Significance was set at p<0.05

Data Collection Summary:

Timing of Measurements

Symptom diary (nausea, vomiting, dizziness, seizures, motor sensory impairment, and epilepsy) - daily
ECOG Performance Status - timing not specified
CT, MRI, or PET scan - 45 day intervals
Treatment Group Follow-up - 65 days (range 40-90 days), not all included

Dependent Variables

Survival - measured in weeks
Number of radionecroses - assessed by MRI or CT scan with PET scan

Independent Variables Presence or absence of 2.45g n-3FA and 0.2g sylimarin flavonoid supplementation.

Description of Actual Data Sample:

Initial N: 405 [Treatment: 143 (50 males, 93 females), Control: 262 (116 males, 146 females)]

Attrition (final N): Not described

Age: All Subjects: median 55.6 years (range not specified)

Treatment: mean 53.7±13.21 years

Ethnicity: Not described

Other relevant demographics:

Demographics of Treatment Groups

Variable Control   (n=262) Treatment (n=143)

Site of Primary Tumor

    Lung 116 69

    Breast 79 55

    Melanoma 25 8

    Other 42 11

ECOG Performance Status

    0 69 52

    1 116 57

    2 65 31

    3 8 3

    4 4 0

Previous Surgical Treatment

    Yes 42 32

    No 220 111

Dose Fractionation

    Yes 126 73

    No 136 70

Diameter of Lesions

    >35mm 71 47

    <35mm 191 96

Anthropometrics

Location: National Cancer Institute, Milan

Not described

Demographics of Treatment Groups
Variable	Control (n=262)	Treatment (n=143)
Site of Primary Tumor
Lung	116	69
Breast	79	55
Melanoma	25	8
Other	42	11
ECOG Performance Status
0	69	52
1	116	57
2	65	31
3	8	3
4	4	0
Previous Surgical Treatment
Yes	42	32
No	220	111
Dose Fractionation
Yes	126	73
No	136	70
Diameter of Lesions
>35mm	71	47
<35mm	191	96

Summary of Results:

Variables

Control Group

Treatment group

Statistical Significance of Group Difference

Median Survival (weeks)

54.1

88.8

p=0.001

Number of Radionecroses

37 (14.1%)

5 (3.49%)

p=0.001

Other Findings

Analysis of Impact of Variables on Outcome
Variable	Univariate Analysis log rank test	Risk Ratio Cox Analysis
Gender	NS (p=0.30901)	-
Site of Primary Tumor	p= 0.00016 (k-test)	-
ECOG Performance Status	NS (p=0.20010, k-test)	1.01 (0.92, 1.31)
Previous Surgical Treatment	p=0.00212	3.25 (1.99, 5.34)
Supplementation of n-3FA and flavinoid	p=0.0123	1.63 (1.17, 2.21)
Dose Fractionation	p=0.034	1.20 (0.85, 1.68)
Diameter of Lesions	NS (p=0.29387)	1.42 (0.95, 2.1)
Number of Lesions	p=0.00189	1.60 (1.19, 2.18)

Results of Univariate Analysis:

Site of Primary
- Best Outcome: Other Sites
- Worst Outcome: Melanoma
Dose Fractionation
- Significant by univariate analysis, but non-significant by Cox analysis
No Impact
- Gender
- ECOG Performance Status
- Size of Metastases

Author Conclusion:

Three prognostic factors important to the use of SRT in brain metastases:

Previous surgical treatment
Number of lesions treated
Use of n-3FA and flavonoid supplementation

The use of supplementation in patients with re-irradiation or lesions in "delicate areas" of the brain increased survival by more than 50%. The reasons for this are unknown and further studies are warranted.

Funding Source:

Industry:

Novartis Nutrition Corporation

Pharmaceutical/Dietary Supplement Company:

Reviewer Comments:

As stated by the authors the characteristics of the subjects that received the n3-FA and flavonoid supplementation were different than the population that did not receive the supplementation. The subjects that received supplementation were considered "High Risk" because of re-irradiation or lesions in "delicate areas" of the brain.

Limitations:

No information on standardization of sylimarin as it is a herb
No information on compliance with supplementation
No anthropometric information pre and post supplementation
No information obtained from patients daily diaries
Large range in follow-up time and does not include all patients
Timing of supplement administration not indicated
No statistical comparison of groups for significant differences

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?		No
	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?	No
	1.3.	Were the target population and setting specified?	Yes
2.	Was the selection of study subjects/patients free from bias?		No
	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?	No
	2.2.	Were criteria applied equally to all study groups?	No
	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?		No
	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?	No
	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?	Yes
	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?		No
	4.1.	Were follow-up methods described and the same for all groups?	No
	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%.)	No
	4.3.	Were all enrolled subjects/patients (in the original sample) accounted for?	Yes
	4.4.	Were reasons for withdrawals similar across groups?	???
	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?	No
	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?		No
	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?	No
	6.5.	Were co-interventions (e.g., ancillary treatments, other therapies) described?	Yes
	6.6.	Were extra or unplanned treatments described?	Yes
	6.7.	Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups?	No
	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?		No
	7.1.	Were primary and secondary endpoints described and relevant to the question?	No
	7.2.	Were nutrition measures appropriate to question and outcomes of concern?	N/A
	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?	Yes
	7.7.	Were the measurements conducted consistently across groups?	???
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?	No
	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)?	No
	8.5.	Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)?	Yes
	8.6.	Was clinical significance as well as statistical significance reported?	No
	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?	No
	10.2.	Was the study free from apparent conflict of interest?	Yes