Symptom Clusters in Patients with
Advanced Cancer:
Cachexia, Anorexia & Asthenia

Davis Wilkins, M.D. M.A.-Bioethics
 Fellow, Palliative Medicine
 May 2008
Goals
 Discuss
impact of symptom clusters on
QOL
 Review pathophysiology & current thinking
 Current treatment strategies
 Ongoing research & future directions
Definitions
 Cachexia:
involuntary profound loss of
lean body mass and adipose tissue.
 Anorexia: Loss of appetite
 Asthenia/Fatigue: listlessness, decreased
energy, decreased motivation; physical +
cognitive components
Impact of Anorexia & Cachexia
 Occurs
in up to 20% at dx; up to 80% in
advanced cancer
 Attributed as main cause of death in ~20%
patients
 Loss of >10% of premorbid weight = poor
prognostic indicator & associated w/
decreased survival
Strasser & Bruera, Hematol Oncol Clin N Am 2002
Anorexia & Cachexia, continued
 More

common in solid tumors
Exception: breast CA where fatigue more
common
 Does
not correlate well w/ tumor size or
biology
 Specific complications of tumor location &
treatments may additionally exacerbate

i.e. bowel obstruction & inflammation
Strasser & Bruera, Hematol Oncol Clin N Am 2002
Impact of Asthenia/Fatigue
 Asthenia/Fatigue
has been ranked as the
longest-lasting, most disruptive sx with the
greatest impact on QOL



95% cancer patients endorse this as chief
symptom: most common symptom
Often lasts months or years after treatments
Assessment difficult; multiple contributing
factors
• Cancer, treatment, complications of tx or ca, meds,
other physical & psychological conditions
Barnes & Bruera, Intl J Gynecol Cancer 2002
Additional impact of this sx cluster






Profound sense of loss associated with drastic
changes in body image & ability to be active
Often a cause in people’s withdrawal from social
life
Leads to increases stress around food/feeding
by patient, family, friends
Loss of functional status
Decreased performance status = decreased
treatment candidate
All 3 symptoms also very common in other lifelimiting illnesses: AIDS, COPD, CHF, CKD, RA
Importance of better recognition & treatment
 More
‘silent’ symptoms than pain or
dyspnea; often go unrecognized,
unaddressed
 No good current single therapies
 Probably a common pathway for many
diseases
 Targeted therapies may do much to
improve QOL, possibly even survival.
Concept of symptom clusters

Definition: 3 or more symptoms that occur together, are
stable, and relatively independent of other clusters

Anorexia, cachexia, fatigue: flu-like symptoms that
manifest in cancer patients

Can also be accompanied by:





Somatic complaints/aches
Depression
Chronic nausea
Early satiety
Cognitve impairment
Fan et al. Curr Oncol 2007; Gift, A. Seminar in Onc Nurs 2007
Current common treatments

Most single therapies often not very efficacious

Megesterol
Marinol
Mirtazepine
Olanzapine
SSRI’s

Exceptions:




• Corticosteroids, NSAIDs, ? methylphenidate
Del Fabbro. JAMA 2007.
It really IS all about cytokines….
Pathophysiology of cancer
cachexia & anorexia

Complex metabolic syndrome/aberrant inflammatory response

Pro-inflammatory/catabolic state; peripheral proteins & lipids
mobilized to keep up; decreased sensitivity to orexigenic
compounds

Tumor by-products formed from proteolysis inducing factor (PIF),
lipid mobilizing factor (LMF) & activation of ubiquitin-proteosome
degradative pathway

Host cytokines: IL-1, IL-6, TNF-a, interferon

Host synthesis of acute phase proteins in liver at the expense of
muscle protein, proteolysis, lipolysis, insulin resistance,
decreased lipogenesis, elevated triglycerides, decreased
HDlipoproteins

Neuroendocrine dysregulation & production of anorexigenic
compounds
Del Fabbro et al J Pall Med 2006
Cancer cachexia signaling pathways
Clinical Cancer Research 13, 1356-1361, March 2007
? Role of cytokine genetic
polymorphisms
 Cytokine
production & polymorphisms
recently implicated in severity of cancer
related pain

Ongoing research into patient cytokine gene
polymorphisms as explanation for pain
variability in lung CA patients
• Genes for TNF-alpha, IL-6, and IL-8
Reyes-Gibby et al. Cancer Epidemiol Biomarkers Prev. Dec 2007
Pathophysiology: cachexia &
fatigue
 CA
patients have abnormal muscle, even
when lean body mass = constant & caloric
intake still normal:



Excessive lactate in tumor free muscles
Animal studies show alterations in enzyme
activity and isoenzyme distribution, as well as
in synthesis & breakdown of myofibrils &
sarcoplasmic proteins
Patients w/ early impaired maximal strength
Boddaert, M. et al Curr Opin Oncol 2006
Pathophysiology, continued
 Nutritional
supplements and appetite
stimulation alone cannot overcome
progressive loss of muscle mass.
 Treatments (chemo, XRT, surgery) often
exacerbate tissue damage as well as lead
to deconditioning.
Boddaert, M. et al Curr OpinOncol 2006
Current Pharmacologic
Management: cachexia, anorexia

Goal: delay cachexia, alleviate symptom burden
w/o changing body composition


Progestational agents
• Megesterol
• Corticosteroids
Cannabinoids
• Marinol, dronabinol


Hormonal/anti-catabolic
• Testosterone,oxandrolone, GH
Psychotropics
• Antidepressants, anti-psychotics
Strasser & Bruera Hematol Oncol Clin N Am 2002
Current Pharmacologic
Management: Asthenia
 Corticosteroids
 Progestins

& androgens
Megesterol, testosterone
 Psychostimulants

Methylphenidate, modafenil, perroline
 Cholinesterase

donepezil
inhibitors
Current Research

Immune Modulator therapies




Thalidomide
Melatonin
Progestins- in combination with other drugs
Macronutrients
• (L-carnitine, Omega 3 fatty acids, fish oil)
 B-Agonists,
Antagonists
• Norepinephrine, clenbuterol

Anti-inflammatories

Corticosteroids, NSAIDS, EPA, macrolides
Synergy?
 May
be synergistic if given with other
therapies, due to targeting of multiple
pathways simultaneously

Orexigens
Corticosteroids, progestins

Anti-catabolics
Oxandrolone, testosterone, GH

Anti-inflammatories
NSAIDs, EPA, melatonin, macrolides
Yennu, Del Fabbro & Bruera, AAHPM, 2008
Corticosteroids
Mechanism unknown. ? Related to central
euphoria in combination with influence on
prostaglandin metabolism & cytokine release.
Improve appetite, food intake, sense of well-being,
performance status in advanced CA pts up to 4
weeks. NO significant weight gain.


Pred 10-40 mg/day; dex 1-8 mg bid
Longer use may induce myopathy, infxn,GIB, leading
to worsening asthenia
Lundstrom (sweden)2005, Bruera 1995
Melatonin

Most potent endogenous anti-oxidant



Direct ROS scavenger & stimulates other anti-ox’s
Has anti-tumor effects via multiple targets & may improve
survival?
Recent studies:



In many CA, melatonin production decreased
Adding melatonin enhances PPI protective effects & perhaps
decreases chemo side effects
Improves multiple sx in solid tumor pts as well as decreases TNFa serum levels, pain levels from 7-10/102-4/10.
• 20 mg/day x 4 weeks vs placebo, then crossover, then all (RCT)
• (synthetic not cow) (IR not SR)

Downside: hard to assure quality of product/not FDA
regulated. Need more trials/data.
Plissoni (Italy) 2007; Del Fabbro AAHPM 2008
Thalidomide

In-vitro:


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Modulate cytokines w/ CNS effects
Recent studies:



Inhibits TNF-a, IL-6, IL-12 @ transcriptional level.
Switches TH1->TH2 type cytokines; inhibits NFkB
100-300 mg/day significantly improves mult. Sxs
Superior to Megace for improving appetite, modest decrease in
wt. loss; side effect: + improved sleep
Downside:



Narrow therapeutic window,
Combo w/ decadron = early data suggest highly thrombogenic
Unavailable in US except in CA Rx, research setting
• Dirt cheap in rest of world, ($200/tablet here)
Bruera, AAHPM, 2008
Modafenil (Provigil)




Novel wake-promoting agent
 Increases release of monoamines, elevates histamine
in certain brain regions.
 Unlikely to have addiction potential
 May have neuroprotective effects
Well tolerated; less side effects than than
psychostimulants
Dosing: start at 50 mg qam; titrate to 100-200 mg/day.
(400 mg/d for narcolepsy)
Downside: HA, nausea, insomnia, anxiety ;
new/experimental. $$

Assessment & Management of
Cancer Related Anorexia,
Cachexia
Strasser & Bruera, Hematol Oncol Clin N Am 2002
Assessment & Management of
Cancer Related Asthenia/Fatigue
Algorithm for
assessment and
management of
cancer-related fatigue
From the NCCN 2002 cancer-related
fatigue guideline, Supportive Care
Practice Guidelines in Oncology
Non-pharmacologic measures

Nutritional support, counseling


Meta-analysis of TPN in cancer patients showed
decreased survival, increased susceptibility to
infection; some patients may maintain weight w/ oral
supplements for short time.
Palliate other major contributing symptoms &
reversible causes:

Chronic nausea, dyspnea, deconditioning,
depression, mucositis, GI obstruction, anemia,
dehydration, pain, metabolic derangements
Nonpharmacologic measures,
continued

Increase activity as able
• Benefit of resistance and endurance training on improved
mood, quality of sleep, muscle mass maintenance


Stress management, supportive counseling
Reframe family/pt. understanding
• Not: ‘starving to death’ but complex metabolic abnormalities
caused by the cancer
• Giving additional food will not result in additional fat or
muscle restoration
• Best chance may be to try and treat with multiple meds, but
need to weigh risk-benefit, pt. ability/desire to take pills
Current novel research
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Targeted therapies

Proteasome inhibitors

TNF inhibitors

Monoclonal antibodies to IL-6
Anabolic cytokines (IL-15)
Specific cannabinoid-receptor antagonists
Role of Grehlin (‘gut-brain’ hormone) , leptin
Alpha-melanocyte-stimulating hormone
Growth Hormone/IGF/IGF-I treatments
Immunonutrition

(omega 3 EFA, L-arginine, L-carnitine glutamine, nucleotides)
Anti-cytokine approaches

Anti-sense NFkappa-B

Soluble TNF-alpha receptors

Cytokine antagonists (pentoxifylline, bradykinin antagonists)
Strasser & Bruera Hematol Oncol Clin N Am 2002
Further research needed
 Need




trials with patient-centered endpoints
?Does weight gain/increased lean body mass
lead to better survival?
Function?
QOL?
Improved chemo/XRT tolerance?
Bibliography
Barnes, EA & Bruera, E. “Fatigue in patients with advanced cancer: A review.” Intl Jour
Gynecol Cancer Sept 2002; 12(5), 424-28.
Boddaert et al.” On our way to targeted therapy for cachexia in cancer?” Curr Opin
Oncolo 2006 18:335-340.
Del Fabbro. “Cachexia & Wasting: A Modern Approach.” JAMA Feb 7,2007 297(5)536—
7.
Del Fabbro et al. “ Symptom Control in Palliative Care—Part II: Cachexia, Anorexia, and
Fatigue.” Journal of Palliative Medicine 2006 9 (2); 409-421.
Fan, G, et al. “Symptom Clusters in Cancer Patients: A review of the literature.” Curr
Oncol. October 2007; 14(5)173-179.
Gift, A. Symptom Clusters Related to Specific Cancers.” Seminars in Onc Nursing, May
2007, 23(2): 136-141
Morrow et al. Management of Cancer-Related Fatigue. Cancer Investigation, 2005,
23:229-239
Reyes-Gibby et al. “Cytokine genes and pain severity in lung CA; exploring the
influence..”Cancer Epidemiol Biomarkers Prev 2007 Dec; 16(12)2745-51.
Strasser F, & Bruera, E. “ Update on Anorexia & Cachexia” Hematol Oncol Clin N AM
2002 (16) 589-617.
Swarnali, A, & Guttridge, D. “Cancer Cachexia Signaling Pathways Continue to Emerge
Yet Much Still Points to the Proteasome” Clinical Cancer Research 13, 1356-1361,
March 2007
Yennurajalingam S, and Bruera E. “Palliative management of fatigue at the close of life:
“It feels like my body is all worn out!” JAMA 2007; 297 (3): 295-304