Oncology

Randomized Controlled Trial

A - Click here for explanation of classification scheme.

POSITIVE: See Quality Criteria Checklist below.

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.

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.]

• 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

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

 

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

     

 

 

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.

 

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 0   5.57 + 0.7   7	0.91 + 0.21 2   1.70 + 0.49   4	NS     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

 

 

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.

Industry:	Ross Products Food Company:
University/Hospital:	Royal Infirmary of Edinburgh (UK)
In-Kind support reported by Industry:	Yes

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.