cancer cachexia

1. Cancer Cachexia
Dr Gebrekirstos Hagos
Clinical Oncology R-I
AAU-SoM
July 13, 2018

2. Presentation Outlines
Introduction
Definition
Pathophysiology
Epidemiology
Clinical Features
Clinical assessment
Management
References

3. Introduction
• Diet is well identified risk factor for cancer.
• Weight loss in cancer patient is associated with
 poor quality od life
 symptom distress(fatigue, social withdrawal,
depression )
 increased surgical morbidity
 pts may not be candidate for curative treatment
because of their malnutrition complications.
• Obesity contribute for 15% of cancer death in
USA

4. Definition
• Cachexia is Greek word:
Kakos-bad, and Hexus-condition
It is complex multifactorial metabolic syndrome
associated with underlying illness &
characterized by loss of muscle with or with out
fat mass that can not be fully reversed by
conventional nutritional support and lead to
progressive functional impairment.

7. Causes & pathophysiology CCS
Multifactorial
• Anorexia
• Clinical N,V,D,pain,dysphagia…
• Abnormal metabolic rate
• Altered cellular metabolism of
lipid, protein, CHO
• Change in cytokine milieu

8. Anorexia
• Anorexia of malignancy-spontaneous decrease
of food intake mediated by cytokines
• There are two sets of neurons within the
arcuate nucleus of the hypothalamus involved
in appetite regulation:
-Melanocortin system-appetite depressant
-Neuropeptide Y(NPY) system –stimulant

10. Metabolism
• REE, Resting energy expenditure increase in cancer pts
but total energy expenditure is reduced because these
pts decrease activities.
• Increased turnover of proteins and lipids is a feature of
CCS, leading to decreased skeletal muscle mass and
depleted fat stores.
• The metabolic changes seen in cachexia are a result of:
-Tumor factors
- host factors
-Interaction between the two

11. Metabolism…
• Proteolysis-inducing factor (PIF) is a major
mediator of protein catabolism in cancer
patients; it activates nuclear factor kappa B
(NF-κB), which then turns on the ubiquitin
proteasome proteolysis pathway

12. Metabolism…
• Lipid-mobilizing factor (LMF) is central to
adipocytes lipolysis via regulation of hormone
sensitive lipase (HSL).
• By mass, most weight loss in cancer cachexia
is from the depletion of fat stores.
• Both proteolysis and lipolysis are not
suppressed with the administration of
exogenous nitrogen and glucose

13. Metabolism…
• Glycolysis is the main energy generation
process in cancer cells.
• This energy- is insufficient & leads to an
increase in hepatic gluconeogenesis and can
cause the normal tissues to be energy starved.

15. Cytokine & hormones
• Both tumor cell production and host
responses contribute to the deranged
cytokine milieu
-IL-1 - TNF-α
-IL-6 -INF-Y

16. TNF-α
• Muscle breakdown
-ubiquitin proteasome pathway
- nitric oxide synthase expression
• Fat depletion
-lipolysis through the activation of HSL
-decreased lipogenesis
• anorexia
IFN-γ contribute to muscle wasting and fat loss of
the same processes

17. IL-1, IL-6
• IL-1 –anorexia
-↑ peripheral breakdown of muscle
- promotes the release of IL-6.
• IL-6 - ↑hepatic gluconeogenesis
-↑ peripheral proteolysis,
-result in more profound wasting than TNF

18. Hormones & tumor drive proteins
• leptin,
• Serotonin Host tissue
• PIF,
• LMF tumor cells

19. Leptin
• Adipocyte-derived hormone
• Regulate body fat mass by ↓appetite & ↑ REE
(hypothalamic neuropeptides)
--appetite stimulants ghrelin and
neuropeptide Y (NPY)
++ appetite suppressors corticotrophin-
releasing factor (CRF) and melanocortin.

20. Causes

22. Stage of Cachexia

23. Epidemiology
• Can occur at any stage of disease but more common at
advanced stage
• It vary with cancer types, size, site , stage, age,
treatment types but most common in pancreatic and
upper GIT cancers
• occurs - 40% new
-80 % of advanced cancer pts
• Breast & sarcoma-40%
• Lung ca-60%
• Stomach &pancreas -85%
• Causes 20% of cancer death

24. Clinical Features
• Correlates with poor performance status, poor
quality of life, and a high mortality rate
• Include weight loss, anorexia, fatigue, anemia,
early satiety, social isolation and hypo albumin
• Its prominent feature is weight loss in adult
corrected for fluid retention and growth failure in
children excluding endocrine disorders

25. Nutritional Screening & Assessment
• Nutrition screening -
identify ca pts at risk for
malnutrition
• Nutrition assessment-
elucidate their nutrient
requirements
→are the first step in the
nutrition care of ca pts.

27. Management of CCS
• Goal of therapy is often to improve symptoms
and quality of life.
• The primary endpoints of optimal treatment of
cancer cachexia are improvements:
- lean body mass
-resting energy expenditure
-fatigue, anorexia, quality of life
-performance status
- reduction in pro-inflammatory cytokines

28. Management of Cancer Cachexia
• Cancer treatment
• Nutritional intervention
• Pharmacological treatment
-Anabolic
-Cytokine inhibitors
-Anti inflammatory
-Antidepressant

29. Treatment of cancer
• Treatment cancer or cancer treatment related
symptoms( nausea, vomiting, diarrhea, and
constipation ) is best option for CCS
management.

30. Nutritional intervention
• A nutritional assessment to seek reversible causes of
weight loss is the first step in management in cachectic
patients.
• Concept of parallel pathway:
-nutritional issue
- has strong impact on the cancer out come &
quality of life
- should be considered from the beginning the
cancer natural history!
• Nutritional intervention have better weight
maintenance if pts are treated in the “precachexia”
phase

31. Nutritional intervention
• In well nourished ca pts on Rx (CT, RT, Sx),
nutrition support is not indicated
• It should be reserved for pts with
malnutrition or at high risk to be
malnourished for next 7-14 days because of
inability to take oral feeding.

32. Route of supplementation

33. Immunonutrition Supplements
• Nutritionally modify the metabolic milieu by
providing anti-inflammatory substances, such
as eicosapentaenoic acid (EPA)-a long-chain
PUFA of the omega-3(n-3) family.

34. Eicosapentaenoic Acid(EPA)
.It replaces arachidonic acid (AA), n-6 PUFA, in
cell membrane phospholipids in the production
of prostaglandins & leukotriene.
• Eicosanoids synthesized from EPA rather than
AA have lower potential in promoting
inflammation.
• Analysis of RCTs did not show any differences
between EPA supplementation and placebo

35. Progestational agents
• Megestrol acetate and medroxyprogesterone
- ↑ appetite
- ↓weight loss by IL-6 level
-↑ non-fluid body mass alteration
*but not improved quality of life
-160 to 1600 mg per day) in part,

36. Corticosteroids
• Produce transient improvement in :
-Nutritional parameters
-Appetite
• Continued use is associated with :
-Negative nitrogen balance
-Glucose intolerance
-Immunosuppression
-GI ulceration
• Good choices in patients with thrombophlebitis &
pre terminal stage

37. Cytokine-directed therapies
• Animal studies are promising potentially
reversing cancer cachexia but non of them
are clinically effective in human.
• Thalidomide and pentoxifylline which inhibit
TNF-α, not demonstrated clear efficacy in
clinical trials.

38. Cytokine-directed therapies
• Specific anti TNF-α agents (etanercept and
infliximab) did not show any positive effect on
appetite or body weight in RCTs

39. Potential Therapeutic Targets.
• Focused on melanocortin system of appetite
regulation
• Activation of the Melanocortin-4- receptor
(MC4R) in murine models :
- decreases food-seeking behavior
- increases basal metabolic rate
-decreases lean body mass .
• Treatment with a MC4R antagonist attenuated
these responses .

40. Antidepressant
• Depression occurs in 25% to 45% of ca pts
and can lead to appetite & weight loss.
• Antidepressant medications can help

41. Combination therapy
 Mantovani (2010) randomized 332 pts with CCS
assigned in to 5 arms:
(1) medroxyprogesterone/megestrol acetate
(2) Eicosapentaenoic acid (EPA)
(3) L-carnitine
(4) thalidomide
(5) a combination of the above for total of 4 months
 Significant improvements were observed in arm 5 in
LBM Appetite
Fatigue Negligible toxicity

42. Management

46. Recommendations
1) Adding weight(W) to the new pt form
& baseline pts weight …… BMI
2) Health Educations to pts at the waiting area
3) Working with dep’t of Nutrition
4) Pts card demography
5) Research on cachexia in our set up?

47. References
• Devita ---------------------10th e
• Uptodate-------------------21.6
• Web search

48. Thank you!