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Malignancy Induced Weight Loss

Malignancy Induced Weight Loss

N. Joseph Espat MD MS FACS

Associate Professor

Hepatobiliary Surgery and Pharmacology

University of Illinois at Chicago

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Surgery

Nutrition

Inflammation

Oncology

Surgery

Nutrition

Inflammation

Oncology

INTEGRATING SEVERAL DISCIPLINES

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History Of Intravenous NutritionHistory Of Intravenous Nutrition• 1628: (Harvey)-discovery of blood circulation

• 1869: (Menzel, Perco)-injection of oil into subcutaneous tissue

• 1930’s: commercial IV Fluid

• 1952: (Aubaniac) reports subclavian access

• 1968: Dudrick’s work with puppies

• 1977: HAL for radiation patients (Copeland)

• 1628: (Harvey)-discovery of blood circulation

• 1869: (Menzel, Perco)-injection of oil into subcutaneous tissue

• 1930’s: commercial IV Fluid

• 1952: (Aubaniac) reports subclavian access

• 1968: Dudrick’s work with puppies

• 1977: HAL for radiation patients (Copeland)

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Weight Loss: Patients with CancerWeight Loss: Patients with Cancer

-80%

-60%

-40%

-20%

0%

5-10% >10%

Weight loss in previous 6 months

Colon Prostate

Lungsmallcell

Lungnon-small

cell Pancreas

Non-measurable

gastricMeasurable

gastric

14%

14%

18%

10%

20%

14%

21%

15%

28%

26%

32%

30%

29%

38%

DeWys et al. 1980. Am J Med. 69:491

% P

atie

nts

with

Wei

ght

Loss

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WHY DO CANCER PATIENTS DIE?WHY DO CANCER PATIENTS DIE?

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Causes of Cancer-Induced Weight LossCauses of Cancer-Induced Weight Loss• Mechanical obstruction of ingestion

• Treatment-related effects

• Tumor-related effects (cancer cachexia)

• Mechanical obstruction of ingestion

• Treatment-related effects

• Tumor-related effects (cancer cachexia)

Rivadeneira et al. 1998. CA Cancer J Clin. 48:69

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Tumor-Related Causesof Weight LossTumor-Related Causesof Weight Loss• Anorexia and early satiety

• Accelerated loss of protein and fat

• Altered energy metabolism

• Increased resting energy expenditure

• Anorexia and early satiety

• Accelerated loss of protein and fat

• Altered energy metabolism

• Increased resting energy expenditure

Rivadeneira et al. 1998. CA Cancer J Clin. 48:69

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Therapeutic Challenges Therapeutic Challenges • Reversible cancer-

induced weight loss– Mechanical causes

– Treatment-related causes

• Reversible cancer-induced weight loss

– Mechanical causes

– Treatment-related causes

• Tumor-related weight loss– Metabolic abnormalities

• Tumor-related weight loss– Metabolic abnormalities

Provision of energy and protein can promote

weight gain

Provision of energy and protein can promote

weight gain

No weight gain, even when added energy and

protein are provided

No weight gain, even when added energy and

protein are provided

Ottery FD. 1994. Cancer Practice. 2:123

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Metabolic Changes:Cachexia vs. StarvationMetabolic Changes:Cachexia vs. Starvation

Cachexia Starvation

Body Weight – /

Body Cell Mass (Lean Body Mass)

Body Fat

Caloric Intake

Total Energy Expenditure (EE)

Resting EE

Protein Synthesis /

Protein Degradation

Proteolysis-Inducing Factor (PIF) –

Adapted from Kotler DP. 2000. Ann Intern Med. 133:622

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Nutrition BasicsNutrition Basics

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GlucoseGlucose• 1 gram = 3.4 Kcals

• 1200 Kcals stored in the as glycogen– 800Kcals in muscle

– 400Kcals in liver

• Only form of energy used under usual conditions by brain and blood cells

• Enters cells under the control of insulin and trapped by phosphorylation except in the kidney and liver

• 1 gram = 3.4 Kcals

• 1200 Kcals stored in the as glycogen– 800Kcals in muscle

– 400Kcals in liver

• Only form of energy used under usual conditions by brain and blood cells

• Enters cells under the control of insulin and trapped by phosphorylation except in the kidney and liver

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FATFAT

• 1gram =9 calories

• 15 Kg in body as fat ( 135,000 Kcals)

• Transported as free fatty acids, converted to ketones in starvation

• Released by cathecholamines and decreased release by insulin

• Made in the liver and adipose tissue-requires protein to remove from the liver

• 1gram =9 calories

• 15 Kg in body as fat ( 135,000 Kcals)

• Transported as free fatty acids, converted to ketones in starvation

• Released by cathecholamines and decreased release by insulin

• Made in the liver and adipose tissue-requires protein to remove from the liver

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ProteinProtein• 1 gram of nitrogen =6.25 grams protein = 30

grams of muscle

• GI absorbed protein: 57% urea, 6% plasma, 23% free AA and 14% liver

• Nitrogen balance =

gms N intake – (gms urine urea N +4)

• 1 gram of nitrogen =6.25 grams protein = 30 grams of muscle

• GI absorbed protein: 57% urea, 6% plasma, 23% free AA and 14% liver

• Nitrogen balance =

gms N intake – (gms urine urea N +4)

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SARCOPENIA (this is normal)SARCOPENIA (this is normal)• diminished reserves of muscle or lean body

mass leading to reduced strength , power and endurance .

• 40% of lean body mass is lost between ages 25-70.

• diminished reserves of muscle or lean body mass leading to reduced strength , power and endurance .

• 40% of lean body mass is lost between ages 25-70.

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Starvation (fasting)Starvation (fasting)

Simple starvation (caloric restriction) is characterized by the loss of hepatic mass with relative sparing of peripheral proteins and lean body mass.

Simple starvation (caloric restriction) is characterized by the loss of hepatic mass with relative sparing of peripheral proteins and lean body mass.

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Simple Starvation ( 1st phase)Simple Starvation ( 1st phase)• 2-4 days increased urine N loss

• Use of glycogen

• Insulin falls, glucagon increases– Protein-glucose

– Fat-FFA

Increased loss of Na and water (180-300 gms muscle + 150-250 gms fat )

• 2-4 days increased urine N loss

• Use of glycogen

• Insulin falls, glucagon increases– Protein-glucose

– Fat-FFA

Increased loss of Na and water (180-300 gms muscle + 150-250 gms fat )

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Simple Starvation ( 2nd phase)Simple Starvation ( 2nd phase)• Decreased urinary N loss over 20-40 days

• Decrease metabolic rate

• Efficient use of fat

• Decreased urinary N loss over 20-40 days

• Decrease metabolic rate

• Efficient use of fat

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Simple Starvation (3rd phase)Simple Starvation (3rd phase)• Keto-adaptation

• N loss falls to 2-4 grams QD

• Obligate tissues like brain adapt to ketones

• DEATH is by respiratory failure – Intercostal muscles

– pneumonia

• Keto-adaptation

• N loss falls to 2-4 grams QD

• Obligate tissues like brain adapt to ketones

• DEATH is by respiratory failure – Intercostal muscles

– pneumonia

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Cachexia

The loss of lean body mass, peripheral proteolysis with sparing of hepatic mass and selectively increased protein synthesis seen with trauma, sepsis, and malignancy is termed cachexia.

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“the failure of nutritional repletion despite adequate caloric

intake in patients with malignancy”

Or

“starvation in the midst of plenty”

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CachexiaCachexia• Losses are in excess of caloric restriction alone

(anorexia, inanition)

• Accompanied by other metabolic derangements such as anemia, acute-phase induction, alterations in plasma lipid profile

• Losses are in excess of caloric restriction alone (anorexia, inanition)

• Accompanied by other metabolic derangements such as anemia, acute-phase induction, alterations in plasma lipid profile

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Liver Cirrhosis-CachexiaLiver Cirrhosis-Cachexia• Reduction in total body nitrogen

• Reduction in total body cell mass

• Increased total body water

• PIC and endotoxemia involved

• Hypermetabolic

• TNF I and II receptors, CD14

• Reduction in total body nitrogen

• Reduction in total body cell mass

• Increased total body water

• PIC and endotoxemia involved

• Hypermetabolic

• TNF I and II receptors, CD14

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Cancer- CachexiaCancer- Cachexia• Depends on the type of cancer

• Lymphoma & breast cancer vs. GI tumors

• 1/3 hypermetabolic and 1/3 hypometabolic

• Ubiquitin-proteasome pathway-(determinant?)

• Depends on the type of cancer

• Lymphoma & breast cancer vs. GI tumors

• 1/3 hypermetabolic and 1/3 hypometabolic

• Ubiquitin-proteasome pathway-(determinant?)

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Cytokines Mediate Acute Phase Protein Response (APPR)

Cytokines Mediate Acute Phase Protein Response (APPR)• APPR – hormonal, cytokine-mediated response

to stress, trauma, inflammation or cancer

protein synthesis in liver (CRP, haptoglobin, ceruloplasmin)

• Some of acute phase proteins are composed of amino acids derived from muscle tissue

• APPR – hormonal, cytokine-mediated response to stress, trauma, inflammation or cancer

protein synthesis in liver (CRP, haptoglobin, ceruloplasmin)

• Some of acute phase proteins are composed of amino acids derived from muscle tissue

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Acute Inflammatory Response• the soluble protein mediators of the acute phase

inflammatory response are termed cytokines.

• Tumor Necrosis Factor (TNF) and Interleukin-1 (IL-1) are the principal mediators of this response. Both induce IL-6, which is the key regulatory cytokine of hepatic acute phase protein synthesis.

• End organ level regulators of the inflammatory response continue to be a focus of study.

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Classic Pro-Inflammatory Cytokines• TNF

• IL-1

• IL-6

• INF-

Inflamatory stimuli induce these first-line mediators of the “acute inflamatory

response”.

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CYTOKINESCYTOKINES• small, non-structural proteins which serve as

chemical messengers between cells

• involved in processes such as normal growth and development

• Immune response to acute and chronic inflammation

• small, non-structural proteins which serve as chemical messengers between cells

• involved in processes such as normal growth and development

• Immune response to acute and chronic inflammation

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WHAT WE KNOWWHAT WE KNOW• Lean body mass is the most consistent predictor

of survival in cancer patients

• Hepatic uptake of nutrients is modified during inflammatory states

• Cachexia is a complex of clinical syndromes

• Inducible COX-2 enzymes are at the center of inflammation

• Lean body mass is the most consistent predictor of survival in cancer patients

• Hepatic uptake of nutrients is modified during inflammatory states

• Cachexia is a complex of clinical syndromes

• Inducible COX-2 enzymes are at the center of inflammation

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mRNA

NFB

NFB-IB

TNF

IL-1

IB-p

IB Phos-

26S-PEPA

NFB pathway in Macrophages

P38

IL-10

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2

11

3

4

5

66

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FIGURE 1Ubiquitin-Associated Proteolytic System

E1 Activating Enzyme

UbiquitinE2-carrier

enzyme

E3 Protein LigaseEnzyme

Protein

20S Proteasome

Peptide Fragments

PA700

ATP ADP

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Central Role of CytokinesCentral Role of CytokinesMalignant tumor cells Inflammatory response begins

Cytokine production IL-1, IL-6 TNF-

Metabolism of macronutrients

affectedLoss of LBM

Acute phaseprotein response

initiated( CRP)

Weight loss

REE Food intake

Proteolysis inducing

factor

Depressed Appetite

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Tumor-Related Weight Loss: OutcomesTumor-Related Weight Loss: Outcomes Quality of Life

Functional Status

Response to Therapy

Body Image

Hospital Length of Stay

Unscheduled Hospitalization

Complications/Infections

Quality of Life

Functional Status

Response to Therapy

Body Image

Hospital Length of Stay

Unscheduled Hospitalization

Complications/Infections

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Cancer and Weight Loss Current Treatments: Summary

Cancer and Weight Loss Current Treatments: Summary• Progestins: Megestrol acetate/Medroxyprogesterone

acetate

• Dronabinol: results worse

• Corticosteroids: short term appetite only

• Supplements/Dietary Counseling also not effective

• Progestins: Megestrol acetate/Medroxyprogesterone acetate

• Dronabinol: results worse

• Corticosteroids: short term appetite only

• Supplements/Dietary Counseling also not effective

Studies have not demonstrated improvement in nutritional status, LBM, quality of life, or survival.

Side effects are a major problem.

Studies have not demonstrated improvement in nutritional status, LBM, quality of life, or survival.

Side effects are a major problem.

Current interventions are unsatisfactory.Current interventions are unsatisfactory.

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Cancer and Weight LossCancer and Weight Loss

• Current interventions have only been able to influence appetite but notmajor clinical outcomes

• There is a critical need to identify new interventions which can favorably influence clinically relevant outcomes

Treatment should address the underlying mechanism

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Inflammatory

Immune suppressive

Appropriate response to “primary pathway” stimulus)

Exaggerated of prolonged“appropriate” response to “primary pathway” stimulus)

Inflammation: Good or Bad ?

Anti-inflammatory

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EPAEPA

• Long-chain polyunsaturated fatty acid of the -3 family

-3 fatty acids are essential dietary components

• Main source is oily fish

• Typical intake around 0.1 g per day

• Long-chain polyunsaturated fatty acid of the -3 family

-3 fatty acids are essential dietary components

• Main source is oily fish

• Typical intake around 0.1 g per day

Eicosapentaenoic Acid (EPA)

C OHO

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Reprinted from Nutrition Vol. 12, Wigmore SJ, Ross JA, Falconer JS, et al. The effect of polyunsaturated fatty acids on the progress of cachexia in patients with pancreatic cancer, p. S27-S30, 1996, with permission from Elsevier Science.

Fatty Acids and Cancer CachexiaFatty Acids and Cancer Cachexia

Weight change before and after a median of 3 months supplementation with fish oil in patients with unresectable pancreatic cancer (n=18)

Cha

nge

in W

eigh

t kg

/mon

th

-8

-7

-6

-5

-4

-3

-2

-1

0

1

2

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

Before EPA

EPA

E012672D 41

Wigmore. 2000. Nutrition and Cancer. 36:177

EPA: Clinical Trials in Cancer PatientsEPA: Clinical Trials in Cancer Patients

EPAStarted

Time (months)

25

20

15

10

5

0

-5

-10

-15

-20

Wei

ght

Cha

nge

(kg)

-10 -8 -6 -4 -2 0 108642 12 14 16 18

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Summary: Roles of EPASummary: Roles of EPA Inflammatory response

Pro-inflammatory cytokine production

• Attenuates APPR

Level/activity of proteolysis-inducing factor (PIF)

• Attenuates tumor-related weight loss

• Increases survival

Inflammatory response

Pro-inflammatory cytokine production

• Attenuates APPR

Level/activity of proteolysis-inducing factor (PIF)

• Attenuates tumor-related weight loss

• Increases survival

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HypothesisHypothesis

If fish oil (EPA) stabilizes weight by suppressing metabolic changes in

cancer, EPA in combination with energy and protein will result in weight gain.

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“Effect of an oral nutritional supplement enriched with fish oil

on weight loss in patients with pancreatic cancer.”

“Effect of an oral nutritional supplement enriched with fish oil

on weight loss in patients with pancreatic cancer.”

Barber et al. Brit J Nutr. 1999;81:80

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Experimental ProductExperimental Product• 240 mls per serving

• 301 kcal (1.26 kcal/ml)

• Protein: 16 g

• Carbohydrate: 44 g

• Fiber: 5 g (2.4 g FOS)

• Fat: 6 g– EPA: 1.09 g– DHA: 0.44 g

• Enhanced with antioxidants (vitamins A, C, E and Se)

• 240 mls per serving

• 301 kcal (1.26 kcal/ml)

• Protein: 16 g

• Carbohydrate: 44 g

• Fiber: 5 g (2.4 g FOS)

• Fat: 6 g– EPA: 1.09 g– DHA: 0.44 g

• Enhanced with antioxidants (vitamins A, C, E and Se)

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Clinical StudyClinical StudyDesign

• Patients with unresectable pancreatic cancer (n=20)

• 2 servings per day for up to 7 weeks

Design

• Patients with unresectable pancreatic cancer (n=20)

• 2 servings per day for up to 7 weeks

Outcome Measures

• Patients weighed at baseline, and wks 3 and 7

• Nutritional intake

• Performance and appetite

• Resting energy expenditure

• C-reactive protein

Outcome Measures

• Patients weighed at baseline, and wks 3 and 7

• Nutritional intake

• Performance and appetite

• Resting energy expenditure

• C-reactive protein

Barber et al. Brit J Nutr. 1999;81:80

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Weight Change After SupplementationWeight Change After Supplementation

-5

0

5

10

15

20

25

30

35

supplementstarted

Time (months)

-10 -8 -6 -4 -2 0 2 4 6 8 10

Barber et al. Brit J Nutr. 1999;81:80

Mean Intake 1.9 servings/dMean Intake 1.9 servings/d

Wei

ght C

hang

e (k

g)

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Results of Multicenter Clinical Trial in Pancreatic

Cancer

Results of Multicenter Clinical Trial in Pancreatic

Cancer

Fearon KCH. 2001; Eur J Cancer 37:27S

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Why Study Pancreatic Cancer Patients?Why Study Pancreatic Cancer Patients?• Dramatic weight loss• Smaller sample size• Shorter study duration

• Dramatic weight loss• Smaller sample size• Shorter study duration

-35

-30

-25

-20

-15

-10

-5

0

Wei

ght L

oss

(kg)

PancreaticCancer

LungCancer

Wigmore SJ. British J Cancer 1997;75:106 Staal-van den Brekel AJ. Cancer Research 1994;54:6430

-4 -3 -1-2 10 2 43 65 Time (months)

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Study DesignStudy Design• Prospective, double-blind, randomized,

multi-center trial

• Unresectable pancreatic cancer (n=200)

• High protein, energy dense oral supplement with or without EPA and enhanced antioxidants

• Prospective, double-blind, randomized, multi-center trial

• Unresectable pancreatic cancer (n=200)

• High protein, energy dense oral supplement with or without EPA and enhanced antioxidants

Fearon KCH. 2001; Eur J Cancer 37:27S

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Outcome Measures for StudyOutcome Measures for Study1. Body weight and body composition (LBM)

2. Quality of Life

3. Change in Acute Phase Proteins

4. Appetite and total dietary Intake

5. Functional status– Grip strength

– Karnofsky performance status

1. Body weight and body composition (LBM)

2. Quality of Life

3. Change in Acute Phase Proteins

4. Appetite and total dietary Intake

5. Functional status– Grip strength

– Karnofsky performance status

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Study Supplement Comparison Study Supplement Comparison Control/Experimental

• 300 kcal per serving

• Protein – 16 g

• Carbohydrate – 50 g

• Fiber – 5 g (2.6 g FOS)

• Fat – 6 g

Control/Experimental

• 300 kcal per serving

• Protein – 16 g

• Carbohydrate – 50 g

• Fiber – 5 g (2.6 g FOS)

• Fat – 6 g

Experimental Product

• EPA – 1.09 g

• DHA – 0.46 g

• Enhanced antioxidants (vitamins A, C, E and Se)

Experimental Product

• EPA – 1.09 g

• DHA – 0.46 g

• Enhanced antioxidants (vitamins A, C, E and Se)

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Effect on Weight ChangeEffect on Weight Change

Wei

ght (

kg/m

onth

)

Fearon KCH. 2001. Eur J Cancer. 37:27S

-4

-3

-2

-1

0

1

2

Baseline 4 Weeks 8 Weeks

Control

ProSure

n=96 n=88 n=78 n=70 n=60 n=50

-3.18-2.92

-0.13 -0.09-0.38 -0.26

p=NS

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Change in Lean Body MassChange in Lean Body Mass

Lean

Bod

y M

ass

(kg/

mon

th)

-3

-2

-1

0

1

2

Baseline 4 Weeks 8 Weeks

Control

ProSure

n=90 n=80

n=68 n=630 n=56 n=41

-2.35

-2.01

0.380.74

0.12 0.27

p=NS

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Change in Weight and Lean Body Mass at 8 WeeksChange in Weight and Lean Body Mass at 8 Weeks

kg (

chan

ge)

-6

-5

-4

-3

-2

-1

0

1

2

0-0.5 can 0.5-1.0 can 1.0-1.5 can 1.5-2.0 can

Weight

Lean Body Mass

n=6 n=3 n=8 n=8 n=10

n=8 n=26 n=22

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Recommended Intake (1.5-2.0 cans/day) Change in Wt and LBM at 8 Weeks

Recommended Intake (1.5-2.0 cans/day) Change in Wt and LBM at 8 Weeks

0.46

0.09

1.21

1.46

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

Wt LBM

Control

ProSure

0.46

0.09

1.21

1.46

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

Wt LBM

Control

ProSure

p=NS

Kilo

gram

s

n=30 n=28n=26 n=22

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Consumption vs. Lean Body MassConsumption vs. Lean Body Mass

-10-8-6-4-202468

10

0 0.5 1 1.5 2

-10-8-6-4-202468

10

0 0.5 1 1.5 2

Fearon KCH. 2001; Eur J Cancer 37:27S

Unit Intake (cans)

Lea

n B

ody

Mas

s (k

g)

Unit Intake (cans)

Lea

n B

ody

Mas

s (k

g)

P=0.036 r=0.332

P=NS

Experimental

Control

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Parallel Study of Physical Activity Level As an Objective Measure of Quality of Life

Parallel Study of Physical Activity Level As an Objective Measure of Quality of Life

• Total energy expenditure/Resting energy expenditure = Physical activity level

• TEE – measured using doubly labeled water

• REE – measured by indirect calorimetry

• Physical activity level– ~1.1 Morbid– ~1.5 Normal– ~1.8 Active

• Total energy expenditure/Resting energy expenditure = Physical activity level

• TEE – measured using doubly labeled water

• REE – measured by indirect calorimetry

• Physical activity level– ~1.1 Morbid– ~1.5 Normal– ~1.8 Active

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Effect on Physical Activity LevelEffect on Physical Activity Level

TE

E/R

EE

Phy

sica

l Act

ivity

Lev

el

Control Group (n=12) Experimental Group (n=7)

1.23

1.321.29

1.48

1.0

1.1

1.2

1.3

1.4

1.5

1.6

Baseline 8 Weeks Baseline 8 Weeks

NormalSedentary

Level

Confinedto Bed

p=NS p=0.005

Moses et al. 2001 Clin Nutr 20:21

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Weight Change vs. QLQ-C30 Physical FunctionWeight Change vs. QLQ-C30 Physical Function

-60

-40

-20

0

20

40

60

-10 -5 0 5 10

-60

-40

-20

0

20

40

60

-10 -5 0 5 10

Weight Change (kg)

QL

Q-C

30 P

hysi

cal F

unct

ion

n=49, r=0.33, p=0.02

E012672D 61

Total Energy and Protein Intake (experimental group)Total Energy and Protein Intake (experimental group)

0

500

1000

1500

2000

Baseline 8 Weeks

p=0.001

Bauer et al. Nutrition Week. 2002

p=0.001

Cal

orie

s (k

cal)

0

20

40

60

80

Baseline 8 Weeks

Pro

tein

(g)

78

63

1800

1465

E012672D 62

ConclusionConclusion• It appears to be the combination of energy and

protein with EPA and antioxidants is effective in improving nutritional status in patients with cancer-induced weight loss

• Need for biological markers of oral supplement consumption

• Need for further randomized trials

• It appears to be the combination of energy and protein with EPA and antioxidants is effective in improving nutritional status in patients with cancer-induced weight loss

• Need for biological markers of oral supplement consumption

• Need for further randomized trials

E012672D 63

QUESTIONSQUESTIONS