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Malignancy Induced Weight Loss

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Malignancy Induced Weight Loss. N. Joseph Espat MD MS FACS ... (fasting) ... Cancer and Weight Loss. Current interventions have only been able to influence ... – PowerPoint PPT presentation

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Title: Malignancy Induced Weight Loss


1
Malignancy Induced Weight Loss
  • N. Joseph Espat MD MS FACS
  • Associate Professor
  • Hepatobiliary Surgery and Pharmacology
  • University of Illinois at Chicago

2
Surgery NutritionInflammationOncology
INTEGRATING SEVERAL DISCIPLINES
3
History Of Intravenous Nutrition
  • 1628 (Harvey)-discovery of blood circulation
  • 1869 (Menzel, Perco)-injection of oil into
    subcutaneous tissue
  • 1930s commercial IV Fluid
  • 1952 (Aubaniac) reports subclavian access
  • 1968 Dudricks work with puppies
  • 1977 HAL for radiation patients (Copeland)

4
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5
Weight Loss Patients with Cancer
Lungsmallcell
Lung non-small cell
Non-measurable gastric
Measurablegastric
Colon
Prostate
Pancreas
14
18
20
21
14
10
28
29
32
14
15
Patients with Weight Loss
26
30
38
Weight loss in previous 6 months
DeWys et al. 1980. Am J Med. 69491
6
WHY DO CANCER PATIENTS DIE?
7
Causes of Cancer-Induced Weight Loss
  • Mechanical obstruction of ingestion
  • Treatment-related effects
  • Tumor-related effects (cancer cachexia)

Rivadeneira et al. 1998. CA Cancer J Clin. 4869
8
Tumor-Related Causesof Weight Loss
  • 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. 4869
9
Therapeutic Challenges
  • Reversible cancer-induced weight loss
  • Mechanical causes
  • Treatment-related causes
  • Tumor-related weight loss
  • Metabolic abnormalities

Provision of energy and protein can promote
weight gain
No weight gain, even when added energy and
protein are provided
Ottery FD. 1994. Cancer Practice. 2123
10
Metabolic ChangesCachexia vs. Starvation
Adapted from Kotler DP. 2000. Ann Intern Med.
133622
11
Nutrition Basics
12
Glucose
  • 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

13
FAT
  • 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

14
Protein
  • 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)

15
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.

16
Starvation (fasting)
  • Simple starvation (caloric restriction) is
    characterized by the loss of hepatic mass with
    relative sparing of peripheral proteins and lean
    body mass.

17
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 )

18
Simple Starvation ( 2nd phase)
  • Decreased urinary N loss over 20-40 days
  • Decrease metabolic rate
  • Efficient use of fat

19
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

20
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.

21
the failure of nutritional repletion despite
adequate caloric intake in patients with
malignancy Or starvation in the midst of
plenty
22
Cachexia
  • 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

23
Liver 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

24
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25
Cancer- Cachexia
  • Depends on the type of cancer
  • Lymphoma breast cancer vs. GI tumors
  • 1/3 hypermetabolic and 1/3 hypometabolic
  • Ubiquitin-proteasome pathway-(determinant?)

26
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

27
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.

28
Classic Pro-Inflammatory Cytokines
  • TNF
  • IL-1
  • IL-6
  • INF-g
  • Inflamatory stimuli induce these first-line
    mediators of the acute inflamatory response.

29
CYTOKINES
  • 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

30
WHAT 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

31
NF?B pathway in Macrophages
P38
I?B Phos-?
26S-P
NF?B-I?B
EPA
I?B-p
NF?B
mRNA
TNF
IL-1
IL-10
32
1
6
2
5
3
4
33
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34
Central Role of Cytokines
Malignant tumor cells Inflammatory
response begins
Cytokine production IL-1, IL-6 TNF-?
  • ? Proteolysis
  • inducing
  • factor

Acute phase protein response initiated (? CRP)
Depressed Appetite
Metabolism of macronutrients affected
Loss of LBM
? REE
? Food intake
Weight loss
35
Tumor-Related Weight Loss Outcomes
  • ? Quality of Life
  • ? Functional Status
  • ? Response to Therapy
  • ? Body Image
  • ? Hospital Length of Stay
  • ? Unscheduled Hospitalization
  • ? Complications/Infections

36
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

Studies have not demonstrated improvement in
nutritional status, LBM, quality of life, or
survival. Side effects are a major problem.
Current interventions are unsatisfactory.
37
Cancer 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
38
Inflammation Good or Bad ?
Immune suppressive
Anti-inflammatory
Inflammatory
Appropriate response to primary pathway
stimulus)
Exaggerated of prolonged appropriate response
to primary pathway stimulus)
39
EPA
Eicosapentaenoic Acid (EPA)
  • 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

40
Fatty Acids and Cancer Cachexia
Change in Weight kg/month
Weight change before and after a median of 3
months supplementation with fish oil in patients
with unresectable pancreatic cancer (n18)
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.
41
EPA Clinical Trials in Cancer Patients
25 20 15 10 5 0 -5 -10 -15 -20
Weight Change (kg)
EPA Started
Time (months)
Wigmore. 2000. Nutrition and Cancer. 36177
42
Summary 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

43
Hypothesis
If fish oil (EPA) stabilizes weight by
suppressing metabolic changes in cancer, EPA in
combination with energy and protein will result
in weight gain.
44
  • Effect of an oral nutritional supplement
    enriched with fish oil on weight loss in patients
    with pancreatic cancer.

Barber et al. Brit J Nutr. 19998180
45
Experimental 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)

46
Clinical Study
  • Design
  • Patients with unresectable pancreatic cancer
    (n20)
  • 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

Barber et al. Brit J Nutr. 19998180
47
Weight Change After Supplementation
Mean Intake 1.9 servings/d
supplement started
Weight Change (kg)
-10 -8 -6 -4 -2 0
2 4 6 8 10
Time (months)
Barber et al. Brit J Nutr. 19998180
48
Results of Multicenter Clinical Trial in
Pancreatic Cancer
Fearon KCH. 2001 Eur J Cancer 3727S
49
Why Study Pancreatic Cancer Patients?
  • Dramatic weight loss
  • Smaller sample size
  • Shorter study duration

-4
-3
-1
-2
1
0
2
4
3
6
5
Time (months)
Lung Cancer
Pancreatic Cancer
Wigmore SJ. British J Cancer 199775106
Staal-van den Brekel AJ. Cancer Research
1994546430
50
Study Design
  • Prospective, double-blind, randomized,
    multi-center trial
  • Unresectable pancreatic cancer (n200)
  • High protein, energy dense oral supplement with
    or without EPA and enhanced antioxidants

Fearon KCH. 2001 Eur J Cancer 3727S
51
Outcome Measures for Study
  • Body weight and body composition (LBM)
  • Quality of Life
  • Change in Acute Phase Proteins
  • Appetite and total dietary Intake
  • Functional status
  • Grip strength
  • Karnofsky performance status

52
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
  • Experimental Product
  • EPA 1.09 g
  • DHA 0.46 g
  • Enhanced antioxidants (vitamins A, C, E and Se)

53
Effect on Weight Change
pNS
n96
n88
n78
n70
n60
n50
-0.09
-0.13
-0.26
-0.38
? Weight (kg/month)
-2.92
-3.18
Fearon KCH. 2001. Eur J Cancer. 3727S
54
Change in Lean Body Mass
pNS
0.74
0.27
0.38
0.12
n90
n80
n68
n630
n56
n41
? Lean Body Mass (kg/month)
-2.01
-2.35
55
Change in Weight and Lean Body Mass at 8 Weeks
n6
n3
n8
n8
n10
n8
n26
n22
kg (change)
56
Recommended Intake (1.5-2.0 cans/day) Change in
Wt and LBM at 8 Weeks
pNS
Kilograms
n30
n28
n26
n22
57
Consumption vs. Lean Body Mass
P0.036 r0.332
Lean Body Mass (kg)
Experimental
Unit Intake (cans)
PNS
Lean Body Mass (kg)
Control
Unit Intake (cans)
Fearon KCH. 2001 Eur J Cancer 3727S
58
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

59
Effect on Physical Activity Level
pNS
p0.005
NormalSedentaryLevel
TEE/REE Physical Activity Level
Confinedto Bed
Control Group (n12)
Experimental Group (n7)
Moses et al. 2001 Clin Nutr 2021
60
Weight Change vs. QLQ-C30 Physical Function
n49, r0.33, p0.02
QLQ-C30 Physical Function
Weight Change (kg)
61
Total Energy and Protein Intake
(experimental group)
p0.001
p0.001
78
1800
63
1465
Calories (kcal)
Protein (g)
Bauer et al. Nutrition Week. 2002
62
Conclusion
  • 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

63
QUESTIONS
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