Malignancy Induced Weight Loss

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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 NutritionInflammationOncology
INTEGRATING SEVERAL DISCIPLINES
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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)

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Weight Loss Patients with Cancer
Lungsmallcell
Lung non-small cell
Non-measurable gastric
Measurablegastric
Colon
Prostate
Pancreas
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21
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10
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Patients with Weight Loss
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Weight loss in previous 6 months
DeWys et al. 1980. Am J Med. 69491
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WHY DO CANCER PATIENTS DIE?
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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
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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
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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
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Metabolic ChangesCachexia 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.
133622
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Nutrition Basics
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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

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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

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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)

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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.

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Starvation (fasting)

• 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)

• 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)

• Decreased urinary N loss over 20-40 days
• Decrease metabolic rate
• Efficient use of fat

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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

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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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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

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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

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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?)

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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

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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-g
• Inflamatory stimuli induce these first-line
  mediators of the acute inflamatory response.

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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

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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

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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
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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
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Tumor-Related Weight Loss Outcomes

• ? 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

• 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.
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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
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Inflammation Good or Bad ?
Immune suppressive
Anti-inflammatory
Inflammatory
Appropriate response to primary pathway
stimulus)
Exaggerated of prolonged appropriate response
to primary pathway stimulus)
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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

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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.
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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
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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

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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.
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• 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
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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)

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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
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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
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Results of Multicenter Clinical Trial in
Pancreatic Cancer
Fearon KCH. 2001 Eur J Cancer 3727S
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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
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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
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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

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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)

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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
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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
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Change in Weight and Lean Body Mass at 8 Weeks
n6
n3
n8
n8
n10
n8
n26
n22
kg (change)
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Recommended Intake (1.5-2.0 cans/day) Change in
Wt and LBM at 8 Weeks
pNS
Kilograms
n30
n28
n26
n22
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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
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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

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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
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Weight Change vs. QLQ-C30 Physical Function
n49, r0.33, p0.02
QLQ-C30 Physical Function
Weight Change (kg)
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Total Energy and Protein Intake
(experimental group)
p0.001
p0.001
78
1800
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1465
Calories (kcal)
Protein (g)
Bauer et al. Nutrition Week. 2002
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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

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QUESTIONS