Cancer Anorexia - Cachexia Syndrome: Yanti Muliawati, Harlinda Haroen, Linda W.A. Rotty
Cancer Anorexia - Cachexia Syndrome: Yanti Muliawati, Harlinda Haroen, Linda W.A. Rotty
ABSTRAK
Sindroma anoreksia-kaheksia karena kanker/cancer anorexia-cachexia syndrome (CACS) adalah suatu
keadaan yang merusak dan melemahkan pada setiap tahap keganasan. Manifestasi sindroma ini terutama
berupa anoreksia, penurunan berat badan dan berkuangnya massa otot akibat asupan oral yang tidak adekuat
dan perubahan metabolik. Sindroma ini sering terjadi pada pasien kanker dan mempunyai dampak besar pada
morbiditas, mortalitas dan kualitas hidup pasien. Mekanisme patogenik CACS adalah mutifaktorial. Diduga
akibat dari interaksi tumor – pejamu dan sitokin mempunyai peran yang bermakna dalam hal ini. Diagnosis
kaheksia kanker adalah kompleks, ditinjau dari banyak segi dan membutuhkan ketelitian pada pemeriksaan klinis
pasien. Tantangan bagi klinisi adalah mengetahui bagaimana penatalaksanaan terbaik untuk mengatasi gejala
penurunan berat badan dan anoreksia sehingga dapat memperoleh hasil yang optimal. Artikel ini meguraikan
tentang diagnosis kaheksia kanker, meninjau kembali dampaknya pada kualitas hidup dan kelangsungan hidup
pasien serta memperbarui terapi potensial yang dapat mengatasi sindroma ini.
ABSTRACT
Cancer anorexia-cachexia syndrome (CACS) is a devastating and debilitating aspect at any stage of
malignancy. It presents primarily as anorexia, weight loss and muscle wasting secondary to inadequate oral
intake and metabolic changes. This syndrome is highly prevalent among cancer patients, has a large impact
on morbidity and mortality, and impinges on patient quality of life. The pathogenic mechanisms of CACS are
multifactorial. It is suggested to be the result of tumor-host interactions and cytokines have a siginificant role.
Diagnosis of cancer cachexia is complex and multifaceted and requires meticulous clinical examination of the
patient. The challenge for clinicians is to know how best to manage the symptoms of weight loss and anorexia
for optimal patient outcome. This article outlines the diagnosis of cancer cachexia, reviews its impact on patient
quality of life and survival, and updates the reader on potential therapies that may suppress it.
155
Yanti Muliawati Acta Med Indones-Indones J Intern Med
156
Vol 44 • Number 2 • April 2012 Cancer Anorexia-Cachexia Syndrome
tissue into free fatty acids. While proteolysis- vomiting; limited food intake due to dysphagia
inducing factor and lipid-mobilzing factor are or abdominal pain or abdominal distention;
produced by the tumor, other factors are released early satiety due to an enlarged spleen or liver,
as a consequence of interactions between host an abdominal mass or abdominal distention
cells and tumor cells, represented by a number (ascites); and malabsorption resulting from tumor
of proinflammatory cytokines, including tumor invasion of the gastrointestinal tract or intestinal
necrosis factor-alpha (TNF-α), interleukin-1 (IL- resection.13
1), and interleukin-6 (IL-6).8,16
Alteration in Nutrient Metabolism
Cancer cachexia is often associated with
CLINICAL CHARACTERISTICS important changes in nutrient metabolism. Many
Cancer cachexia is characterized by patients have a constellation of findings consisting
diminished nutrient intake and progressive tissue of hyperglycemia, hypertriglyceridemia, and an
depletion, both of which lead to weight loss. exaggerated insulin response to a glucose load.
Changes in body composition, increasing debility, Hypertriglyseridemia occurs in combination
fluctuations in resting energy expenditure, loss of with increases in very low density lipoprotein
appetite, and an ability to eat for mechanical production and lipolysis and reduced activity
reasons further characterize this syndrome.13 of adipose tissue lipoprotein lipase.12,16 These
Changes in Body Composition
changes may result from the interaction between
A disproportionate and excessive loss of increased cytokine release and insulin resistance.13
lean body mass (LBM) is the hallmark of cancer Protein breakdown is increased in patients
cachexia. Weight-losing patients with solid with cancer cachexia, leading to enhanced amino
tumors suffered a loss of both fat and lean body acid release from skeletal muscle despite the
mass. However, the loss of lean body mass, most reduction in muscle mass and negative nitrogen
notably skeletal muscle, was more dramatic. The balance. The plasma concentration of certain
response contrasts with that of simple starvation amino acids tends to be elevated, perhaps in part
where the host preserves lean body mass in an because of decreased skeletal muscle uptake due
effort to survive.13 to insulin resistance.13
157
Yanti Muliawati Acta Med Indones-Indones J Intern Med
and multifaceted and requires meticulous assess patients. It is important to examine such
clinical examination of the patient (Table 2). In muscles as the gastrocnemius, vastus lateralis,
ascertaining the patient history, the presence of rectus abdominus and biceps, as experimental
unintentional weight loss of more than 5% of data and clinical observations suggest that these
premorbid weight in a 6-month period should be type II fast-twitch muscles are most commonly
noted. The presence of anorexia should also be affected in cancer cachexia. Involuntary weight
ascertained, as it is commonly associated with loss in combination with loss of LBM should alert
cancer cachexia and will contribute to decreased the clinician to the strong possibility of cancer
energy intake. Recent chemotherapy or radiation cachexia.9,18
treatment should be considered, as treatment- Screening cancer patients for cachexia has
related toxicities may worsen anorexia and/or included obtaining blood to detect low serum
cachexia.18 albumin, low hematocrit, and fibrinogen levels,
but these laboratory values are quite nonspesific
for nutritional evaluation. Measurement of
Table 2. Diagnosis of cancer cachexia.18
short half-life proteins (eg, transferrin and
Test Finding transthyretin) and urinary metabolites of protein
Clinical: breakdown (eg, creatinine) are of limited value,
-- Body Weight Unintentional weight loss (>5%
as they may be elevated in cancer patients
during preceding 6 months) with chronic malnutrition but in those with not
-- Skeletal muscle Decreases biceps, quadriceps cachexia. Increased acute-phase proteins such
mass muscle mass as CRP levels may be an especially helpful
-- Food intake recall Anorexia and/or decreased food screening test, as elevated CRP has been
or diary intake
positively correlated with weight loss and cancer
-- Fatique Increased
cachexia. Although relatively nonspecific, CRP is
-- Range of motion Usually impaired a sensitive marker for inflammation that is both
-- Quality-of-life Decreased scores inexpensive and routinely available, making it
surveys
useful in the diagnosis of cancer cachexia.4,9,18
-- Karnofsky Decreased scores
Performance
Sophisticated analytical techniques may be
Scale used to diagnose cancer cachexia. For example,
Serum:
dual energy X-ray absorptiometry (DXA) scans
-- Serum CRP Increased (acute-phase
and bioelectrical impedance analysis can assist
(C-reactive response) in determining patient body composition, which
protein) is altered in cachexia. DXA uses alternating
-- Serum fibrinogen Increased (acute-phase high-energy and low-energy X-rays to analyze
response)
the differences between bone and soft tissue
-- Serum hematokrit Decreased (anemia)
attenuating at different X-ray levels. It can
-- Serum albumin Decreased be used to determine the relative proportions
Nutritional assessment: of LBM, fat body mass, and total body water
-- Indirect Increased in REE (TBW), and exposes each patient to less radiation
calorimetry than computed tomography (CT). In cancer
-- DXA Decreased in LBM patients with cachexia, both LBM and fat body
Abbreviations: CRP, C-reactive protein; REE, resting mass will be decreased. Bioelectrical impedance
energy expenditure; DXA, dual X-ray absorptiometry; analysis can assess both the nutritional status
LBM, lean body mass.
and the fluid deficits in patients with advanced
cancer and is based on the principle that body
tissues differentially oppose the flow of a small
Physical examination may reveal skeletal alternating current.4,9,18
muscle wasting, loss of body fat, and generalized Another diagnostic tool is indirect calorimetry
weakness. Although most clinicians depend on that permits the assessment of REE and is
body weight as a general measure of nutritional an accurate and clinically feasible method of
status, skinfold thickness, and arm muscle measuring energy expenditure. Because of the
circumference and area may also be used to direct relationship between caloric burn and
158
Vol 44 • Number 2 • April 2012 Cancer Anorexia-Cachexia Syndrome
oxygen consumption, measuring the volume of A clear benefit from nutritional support may thus
oxygen uptake (VO2) will elucidate patient’s be limited to a specific, small subset of patients
caloric burn rate. Measurements of the oxygen with severe malnutrition who may require surgery
consumption rate and the carbon dioxide or may have an obstructing, but potentially
production rate can be used to calculate the therapy-responsive tumor.9
patient’s respiratory quotient and metabolic
Nutritional Counseling
rate. These measurements permit more accurate
In anorectic-cachectic cancer patients,
monitoring of patients, especially if treatment of
intensive individualized nutritional intervention
the cachexia is initiated.18
based on nutrition counseling attenuates the
deterioration of nutritional status, and accelerates
TREATMENT recovery of global quality of live and physical
The best way to treat CACS is to cure function. Food intake can be increased by
the cancer, but unfortunately this remains an providing frequent small meals and that are
infrequent achievement. Therefore, an integrated energy-dense and easy to eat. Patients should be
therapy approach is needed which includes encouraged to eat in pleasant surroundings and
both nutritional intake and counseling to attention should be given to the presentation
prevent muscle and adipose tissue wasting, and of food. It is advisable to avoid high-fat food,
pharmacologic approaches to fight anorexia and because fat delays gastric emptying and may
metabolic disturbances.8,9 exacerbate early satiety, a symptom of anorexia.
Since changes in taste and smell occur in
Hypercaloric Feeding anorectic patients, extremes in food temperature
It was hoped that enteral or parenteral and flavor should be avoided.8
nutritional support would circumvent cancer
Pharmacologic Approaches
anorexia and alleviate malnutrition. However,
Bearing in mind that anorexia and metabolic
the inability of hypercaloric feeding to increase
disturbances are involved, the development of
lean mass, especially skeletal muscle mass, has
different therapeutic strategies has focused on the
been repeatedly shown.9,17
two factors : improving appetite and neutralizing
The place of aggressive nutritional
metabolic disturbances.4
management in malignant disease also remains
ill-defined and most systematic prospective Improving Appetite
studies that have evaluated total parenteral Synthetic progestins such as megestrol
nutrition combined with chemotherapy or acetate and medroxyprogesterone were the first
radiotherapy have been disappointing. No agents studied for the treatment of CACS. The
significant survival benefit and no significant mechanism of action is not fully understood,
decrease in chemotherapy-induced toxicity however, there is evidence that these agents
have been demonstrated. Indeed, an increase reduce activity of thyrosine hydroxyls and
in infections and mechanical complications has dopamine, which are negative modulators of NPY
been reported.9 neurotransmission, and also downregulate NPY2
However, parenteral nutrition may facilitate receptors, reducing negative NPY feedback
administration of complete chemoradiation inhibition, thereby, stimulating appetite. The oral
therapy doses for esophageal cancer and may dosages of megestrol acetate range from 160 mg
have beneficial effects in certain patients with to 1600 mg per day and medroxyprogesterone is
decreased food intake because of mechanical given at doses of 300 – 4000 mg per day.4,19,20,21
obstruction of the gastrointestinal tract. Home Cannabinoids are present in marijuana.
parenteral nutrition can also be rewarding for They stimulate appetite through their effect on
such patients. If the gut can be used for nutritional hypothalamic cannabinoid-1 receptors and their
support, enteral nutrition has the advantage association with leptin. Dronabinol is an oral
of maintaining the gut-mucosal barrier and synthetic derivative of tetrahydrocannabinol
immunologic function, as well as the advantage used for the treatment of chemotherapy-induced
of having low adverse side effects and low cost.9 nausea and vomiting. Oral dronabinol 2.5 mg
The effects of caloric intake on tumor was administered three times daily, one hour after
development and growth are still being debated. meals for four weeks.4,19
159
Yanti Muliawati Acta Med Indones-Indones J Intern Med
160
Vol 44 • Number 2 • April 2012 Cancer Anorexia-Cachexia Syndrome
N-acetylcysteine can be used to increase the negatively influences survival not only by itself,
availability of cysteine in the treatment of but also by delaying initiation and/or completion
catabolic states in cancer cachexia.4,9,16 of aggressive anti-tumor therapy (Table 3).8
Non-steroidal anti-inflammatory drugs Cancer patients with cachexia-induced weight
(NSAIDs), such as ibuprofen, indomethacin, loss (≥5% body weight lost involuntary)
and cyclooxygenase (COX) inhibitors, act by experienced shorter median survival times
inhibiting prostaglandin production that may than cancer patients without weight loss. The
have an effect on tumor growth. While nitric patients with weight loss had poorer responses
oxide inhibitors (e.g. N-nitro-L-arginine), to chemotherapy and experienced more treatment
if combined with anti-oxidants, prevent the toxicities.18
decrease in body weight, the muscle wasting
and skeletal muscle molecular abnormalities.4,9,27 Table 3. Effect of weight loss expressed as % of premorbid
weight on median survival expressed in weeks.8
Angiotensin-converting enzyme (ACE)
inhibitors, like captopril, seem to act by decreasing Tumor
No 0–5% 5-10% >10%
P value
WL WL WL WL
the production of TNF-α. A highly lipohilic ACE
NSCLC 20 17 13 11 <0.01
inhibitor imidapril attenuated the development of
Prostate 46 30 18 9 <0.05
weight loss.4,16
Colorectal 43 27 15 20 <0.01
Anti-anemic drugs (i.e. erythropoietin) can
improve metabolic and exercise capacity via an Abbreviations: NSCLC, non-small-cell lung cancer; WL,
weight loss.
increased erythrocyte count together with the
decreased production of the cachexia-inducing
cytokines.4 Cachexia can have a significant effect on
Adenosine triphosphate (ATP), a directly patients with small tumor burdens. In a recent
hydrolyzable source of energy, could potentially study of early-stage (T1N0M0) renal cell
tip the balance towards weight gain and carcinoma patients, the presence of cachexia was
preservation of lean body mass. Creatine associated with markedly worse disease-spesific
administration may result in an increase in survival. The 5-year survival rate in patients with
skeletal muscle phosphocreatine content, high grade (3 or 4) tumors, with and without
which may protect the tissue during catabolic cachexia, was 55% and 75% respectively. In
conditions.4 patients with head and neck squamous cell
Proteolytic system inhibitors such as carcinoma, weight loss of greater than 10% had
peptide aldehyde, lactacystin and β–lactone can a strong prognostic impact on 1-year survival and
effectively block up to 90% of the degradation could be used to predict mortality after recurrent
of both normal and short-lived cellular proteins.4 oral cavity and oropharyngeal carcinomas.
Anti-myostatin is a promising therapeutic Survival was poorest in patients with greater than
strategy for cachectic patients. Myostatin, 10% weight loss at the time of recurrent and best
a transforming growth factor beta (TGF-β), for patients with no weight loss.18
induces cachexia through an NF-κB-independent
mechanism by antagonizing hypertrophy CONCLUSION
signaling through regulation of the AKT-FoxO1
Cancer anorexia-cachexia syndrome is
pathway.4,28
frequently seen in patients with advanced cancer.
Corticotropin-releasing factor 2 receptor
It is characterized by anorexia and loss of body
(CRF2R) has many biological activities including
weight associated with reduced muscle mass
modulation of the stress response and has
and adipose tissue. The pathogenesis of CACS
been involved in the prevention of skeletal
is multifactorial and cytokine plays a major role
muscle wasting that results from a variety of
in this disorder, thereby, representing a suitable
physiological stimuli.4
therapeutic target. Weight loss in CACS is a
marker for both progression of the syndrome
PROGNOSIS and poorer prognosis. Successful treatment of
The presence of early satiety at any stage of this syndrome may require not only nutritional
the diseases can significantly increase the risk of counseling and supplementation but also
death by 30%. The extent of body weight loss treatment with anti-cachexia agents to reverse
161
Yanti Muliawati Acta Med Indones-Indones J Intern Med
the proteolysis, lipolysis, anorexia, acute-phase 15. Ockenga J, Valentini L. Anorexia and cachexia in
response, and inappropriately elevated resting gastrointestinal cancer. Aliment Pharmacol Ther
2005;22:583-94.
energy expenditure. 16. MacDonald N, Easson AM, Mazurak VC, et al.
Understanding and managing cancer cachexia. J Am
REFERENCES Coll Surg. 2003;197(1):143-61.
17. Kotler DP. Cachexia. Ann Intern Med. 2000;133:622-
1. Loprinzi CL, Jatoi A. Pharmacologic management of
34.
cancer anorexia/cachexia. In: Rose BD, Rush JM, eds.
18. Couch M, Lai V, Cannon T, et al. Cancer cachexia
UpToDate CD room, 18.1 ed, Wallesley, MA. 2010.
syndrome in head and neck cancer patients: part 1.
2. Laviano A, Inui A, Marks DL. Neural control of the
diagnosis, impact on quality of life and survival, and
anorexia-cachexia syndrome. Am J Physiol Endocrinol
treatment. Head & Neck DOI 2007;10.1002/hed:410-
Metab. 2008;295:1000-8.
411.
3. Berenstein EG, Ortiz Z. Megestrol acetate for the
19. Daley RJ, Canada T. Managing the cancer anorexia-
treatment of anorexia-cachexia syndrome (Protocol for
cachexia syndrome: a pharmacologic review. Oncol
a Cochrane Review). The Cochrane Library. 2004;4:1-
Nutr Connect. 2004;12(4):1-6.
7.
20. Leśniak W, Bała M, Jaeschke R, et al. Effects of
4. Argiles JM, Olivan M, Busquets S, et al. Optimal
megestrol acetate in patients with cancer anorexia
management of cancer anorexia-cachexia syndrome.
cachexia syndrome – a systematic review and meta
Cancer Management and Research. 2010;2:27-38.
analysis. Pol Arch Med Wewn. 2008;118(11):636-44.
5. Harnoko K, Jusuf A, Hudoyo A, et al. Efektivitas
21. Maltoni M, Nanni O, Scarpi E. High-dose progestins for
megestrol asetat untuk pengobatan anoreksia dan
the treatment of cancer anorexia-cachexia syndrome:
penurunan berat badan penderita kanker paru jenis
A systematic review of randomised clinical trials. Ann
karsinoma bukan sel kecil. J Respir Indo. 2007;27(2):95-
Oncol. 2001;12:289-300.
107.
22. Edelman MJ, Gandara DR, Meyers FJ, et al. Serotonin
6. Uomo G, Galluci F, Rabitti PG. Anorexia-cachexia
blockade in the treatment of the cancer anorexia-
syndrome in pancreatic cancer: recent development in
cachexia syndrome. Cancer. 1999;86(4):684-8.
research and management. J Pancreas. 2006;7(2):157-
23. Dixit DV, Schaffer EM, Pyle RS, et al. Ghrelin
62.
inhibits leptin-and activation-induced proinflammatory
7. Baiti NB, Davis MP. Cytokines and cancer anorexia
cytokine expression by human monocytes and T cells.
cachexia syndrome. Am J Hospice & Paliative Med.
J Clin Invest. 2004;114(1):57-66.
2008;25(5):407-11.
24. Perboni S, Bowers C, Kojima S. Growth hormone
8. Laviano A, Meguid MM, Inui A, et al. Therapy insight:
releasing peptide 2 reverses anorexia associated with
cancer anorexia-cachexia syndrome – when all you can
chemotherapy with 5-fluorouracil in colon cancer
eat is yourself. Nat Clin Pract Oncol. 2005;2(3):158-65.
cell-bearing mice. World J Gastroenterol. 2008;14(41):
9. Inui A. Cancer anorexia-cachexia syndrome: current
6303-5.
issues in research and management. CA Cancer J Clin.
25. Mantovani G, Maccio A, Madeddu C. Randomized
2002;52:72-91.
phase III clinical trial of five different arms of treatment
10. Baiti NB, Walsh D. What is cancer anorexia-cachexia
in 332 patients with cancer cachexia. The Oncologist.
syndrome? a historical perspective. J R Coll Physicians
2010;15:200–11.
Edinb. 2009;39:257-62.
26. Wardhana, Surachmanto E, Datau EA. The role of
11. Mantovani G, Madeddu C, Maccio A, et al. Cancer-
omega-3 fatty acids contained in olive oil on chronic
related anorexia/cachexia syndrome and oxidative
inflammation. Acta Med Indones-Indones J Intern Med.
stress: an innovative approach beyond current
2011;43(2):138-43.
treatment. Cancer Epidemiol Biomarkers Prev. 2004;
27. Hamid RAH, Umbas R, Mochtar CA. Recent role of
13(10):1651-9.
inflammation in prostate diseases: chemoprevention
12. Martignoni ME, Kunze P, Friess H. Cancer cachexia. development opportunity. Acta Med Indones-Indones
Molecular Cancer. 2003;2:1-3. J Intern Med. 2011;43(1):59-65.
13. Jatoi A, Loprinzi CL. Clinical features and pathogenesis 28. Mcfarlane C, Plummer E, Thomas M, et al. Myostatin
of cancer cachexia. In: Rose BD, Rush JM, eds. induces Cachexia by activating the ubiquitin proteolytic
UpToDate CD room, 18.1 ed, Wallesley, MA. 2010. system through an NF-κB-independent, foxO1-
14. Hopkinson JB, Wright DNM, Foster C. Management of dependent mechanism. J Cell Physiol. 2006;209:501-
weight loss and anorexia. Ann Oncol. 2008;19(7):vii289- 14.
vii293.
162