EAL

ONC: Pancreatic Cancer (2006)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

1. to determine if the decreased total energy expenditure (TEE) and physical activity level (PAL) observed in lung cancer patients is also observed in patients with pancreatic cancer

2. to test if an EPA-enriched energy and protein dense supplement was associated with stabilization or gain in weight and improved TEE/PAL as a potential objective measure of quality of life.

Inclusion Criteria:

Patients with unresectable pancreatic cancer referred to Royal Infirmary of Edinburgh with

weight loss > 5% of preillness stable weight in the previous 6 months and
Karnofsky index > 60 and
life expectancy > 2 months

[OF NOTE: these patients were a subset of patients ifrom the published study Fearon KCH, et al. Gut 2003;52:1479-1483.]

Exclusion Criteria:

Major surgery, endoscopic stenting, radiotherapy, chemotherapy in the previous 4 weeks
Other active medical conditions (e.g. major GI disease, chronic renal failure, uncontrolled diabetes, HIV disease)
BMI > 30 kg/m²
Received medication could profoundly modulate metabolism or weight, in particular fish oil or n-3 fatty acid preparations exceeding 200 mg EPA/d or 1 capsule of fish oil/d in the previous 90 days

Description of Study Protocol:

Recruitment: A subset of patients from a multicenter, randomized, double-blinded, clinical trial at 1 of the study sites, Royal Infirmary of Edinburgh.

Design: Patients were asked to consume 2, 8-oz cans of an n-3 fatty acid containing oral nutritional supplement or an identical supplement without n-3 fatty acids daily during the 8 week study period. (Per can: 310 Kcal, 16g protein with or without 1.1g n-3 fatty acid)

Patients were randomized after stratification for study site and histological proof of diagnosis to permutation blocks of 2 using numbered, sealed envelopes containing computer generated random assignments. Randomization envelopes were opened by personnel shipping the product.

At enrollment the following measurements were made:

weight
height
body composition via BIA
TEE measured over 14 days using doubly labeled water
3-day diet diary

On day 14 (the baseline visit) the following measurements were made:

REE via indirect caloriemetry
weight
plasma EPA by gas chromatography

Over the next 8 weeks, patients consumed up to 2, 8-oz cans of supplement/d.

At the start of week 7, patients underwent repeat measurement of TEE using the doubly labelled water protocol (which ran for the next 14 days to the end of week 8). They completed another 3-day diet diary during this period.

At the end of week 8 the following measurements were made:

physical examination
weight
body composition
REE
plasma EPA levels

Blinding used: Double-blinded

Intervention: Patients were asked to consume 2, 8-oz cans of the experimental n-3 fatty acid containing oral nutritional supplement or an isocaloric, isonitrogenous control product each day during the 8 week study period.

Statistical Analysis:

Student's unpaired t-test for independent samples (differences between groups)

Paired Student's t-test (differences within a group)

Fisher's exact test

Wilcoxon's test

Power 80%, A sample size of 16 was calculated to detect a 20% difference in PAL between gorups with a significance level of 0.05 and a power of 0.8. Target sample size was increased to 30 patients to account for possible of attrition. Patients lost to follow up were not replaced as the initial N had been inflated to deal with expected attrition in this severely ill population. 9 control patients and 5 experimental patients completed the 8 week study.

P < 0.05

Data Collection Summary:

Timing of Measurements:

At enrollment the following measurements were made:

weight
height
body composition via BIA
TEE measured over 14 days using doubly labeled water
3-day diet diary

On day 14 (the baseline visit) the following measurements were made:

REE via indirect caloriemetry
weight
plasma EPA by gas chromatography

Week 7:

TEE measured over 14 days using doubly labeled water

3-day diet diary

Week 8:

physical examination
weight
body composition
REE
plasma EPA levels

Dependent Variables

Weight and Body Composition-preillness stable weight and duration of weight loss were self reported. Body weight measured by spring balance scales with light clothing, no shoes. Body composition was measured via BIA using acceptd methods.
REE- measured via indirect calorimetry following an overnight fast, using accepted methods.
TEE-Labeled ²H and ¹⁸O were measured using an accepted doublly labeled water protocol. TEE was calculated from these measurements using accepted equations.
PAL was calculated using the equation PAL = TEE/REE. A PAL of 1.5 for healthy sedentary adults was derived from research reports on PAL.
Energy Expenditure of Activity (EEA) was calculated using the equation EEA = TEE-REE and includes dietary-induced thermogenesis and nonexercise activity thermogenesis.
Dietary Intake-Dietitians instructed patients on how to record food and beverage intake. Mean total energy intake and macronutrient intakes were calculated.
Plasma EPA Concentration-Plasma phospholipids were analyzed using accepted methods.
Physician-assessed Physical Function Score-Assessed using the Karnofsky performance score.

Independent Variable:

Quantity of EPA consumed

Description of Actual Data Sample:

Initial N: 24 [Control n=15 (4 males, 11 females); EPA n=9 (6 males, 3 females)]

*mismatch in sample size due to the larger study being stratified and investigators blinded until the study was complete).

Attrition (final N): 19 [Control n=12, EPA n=7]

1 patient died in each group,

1 control pateint withdrew,

1 patient in each group dropped out due to change in medical status.

Age: Mean 68 years + 2

Ethnicity: Not described

Other relevant demographics: (N=24)

Cancer stage:

15 stage II,

4 stage III,

5 stage IV

Karnofsky performance score: 2 had score of 60, 12 had score of 70, 5 had score of 80, 3 had score of 9.

Anthropometrics: (N=24)

Mean BMI=20+1 kg/m²

Percent weight loss from usual 19 + 1%.

Location: Subset of patients at the Royal Infirmary of Edinburgh site from a larger multicenter study.

Summary of Results:

There was no significant difference in supplement intake between groups. Only significant findings are reported below.

Variables

Treatment Group

Measures and confidence intervals

Control group

Measures and confidence intervals

Statistical Significance of Group Difference

TEE

Change from baseline

286 Cal + 79

99 + 132

EPA p<0.05, Control NS

PAL

Change from baseline

01.8 + 0.05

0.01 + 0.1

EPA p<0.05, Control NS

EEA

Change from baseline

287 + 66

114 + 131

EPA p<0.05, Control NS

Dietary Intake:

Change in total energy intake

Change in total protein intake

474 Cal + 106

27 + 6

166 Cal + 122

4 + 6

EPA p<0.05, Control NS

EPA p<0.05. Control vs EPA p< 0.05.

Plasma EPA

Baseline EPA (&)

Patients (N) with baseline EPA > 1.6%

Final EPA%

Patients (N) with final EPA >1.6%

0.94 + 0.09

5.57 + 0.7

0.91 + 0.21

1.70 + 0.49

p=0.001

Other Findings: Because EPA analysis at 8 weeks showed that 4 control patients had had high EPA levels, a post hoc analysis was done where these 4 patients were included in the high EPA group. Significant findings are reported below.

Variables

High EPA Group

Measures and confidence intervals

Low EPA Group

Measures and confidence intervals

Statistical Significance of Group Difference

REE

Change from baseline

23 + 30

-55 + 23

EPA p<0.05

Control NS

TEE

Change EPA vs control

340 + 92

-68 + 134

p< 0.05

Author Conclusion:

The study demonstrates that

REE is increased, TEE and PAL is reduced in cachectic cancer patients
Reduced TEE may be associated with reduced PAL
Caution must be used in interpreting data from diet diaries in studies where chachectic patients may want to please their physician or relatives by systematically overestimating their food intake.
Weight and LBM remained stable in both groups. The net increase in protein and energy intake in the exp group seemed to translate into an almost parallel increase in TEE wih a consequent rise in PAL. Similar findings were not seen in the control group.
These data are unique in documenting with objective methodology an improvement in the physical function of cachectic patients with advanced cancer following institution of EPA in combination with an energy and protein dense oral supplement.
LBM did not change significantly in the overall trial although there was a positive, direct, signifiicant relationship between experimenal supplement intake and change in LBM in the experimetal but not in the control group.
- It is not clear in this study if the increased TEE and PAL is necessarily accompanied by an increase in the mass rather than in the function/quality of the LBM.
Post hoc analysis has to be treated with caution and will require confirmation in further studies. the numbers of patietns in the present study are relatively small and fell short of the intended recrutment. Analysis was further hampered by the randomization proecss from the larger study that allocated more paeints to the control group compaed with the experimental group.

Nevertheless, the present study provided pilot data suggesting that the exp supplement results in an increse in PAL. Further work is required to confirm these results and clarify the relationship between PAL and overall quality of life.

Documentation of TEE and PAL using the DLW technique is labour intensive and costly. Howver, the data obtained are unique and highlight the potential of such objective methodology to provide a focus for therapeutic intervention in the complex syndrome of cancer cachexia.

Funding Source:

Industry:

Ross Products

Food Company:

University/Hospital:

Royal Infirmary of Edinburgh (UK)

In-Kind support reported by Industry:

Yes

Reviewer Comments:

These are preliminary findings from what, because of short comings noted by the authors, is essentially a pilot study. It is hypothesis generating. Further, larger, controlled studies are needed.

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)	Yes
	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?	???
	6.6.	Were extra or unplanned treatments described?	???
	6.7.	Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups?	Yes
	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?	Yes
	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)?	???
	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?		No
	10.1.	Were sources of funding and investigators' affiliations described?	Yes
	10.2.	Was the study free from apparent conflict of interest?	Yes