Symptom Control in Palliative Care—Part II: Cachexia

Palliative Care Reviews
JOURNAL OF PALLIATIVE MEDICINE
Volume 9, Number 2, 2006
© Mary Ann Liebert, Inc.
Feature Editors: Robert M. Arnold and Solomon Liao
Symptom Control in Palliative Care—Part II:
Cachexia/Anorexia and Fatigue
EGIDIO DEL FABBRO, M.D., SHALINI DALAL, M.D., and EDUARDO BRUERA, M.D.
INTRODUCTION
I
we addressed general symptom assessment, constipation, and chronic nausea. This part discusses cachexia/anorexia and fatigue, and once again most of the available
research is cancer-related.
N THE FIRST PART
CACHEXIA/ANOREXIA
Cachexia may occur in up to 80% of patients
with advanced cancer.1 This complex metabolic
syndrome, characterized by profound loss of lean
body mass, is the main cause of death in 20% of
patients. Cachexia (involuntary loss of more than
10% of premorbid weight) is a marker for poor
prognosis2 and is associated with anorexia (loss
of appetite), asthenia and changes in body image.
Cancer cachexia tends to occur in patients with
solid tumors, in children, and in elderly patients.
Cachexia is also common in acquired immune deficiency syndrome (AIDS), chronic obstructive
pulmonary disease (COPD), congestive heart failure (CHF)3–6 and other chronic illnesses, such as
dementia, tuberculosis, malaria,7 chronic kidney
disease, liver disease,8 and rheumatoid arthritis.
MECHANISMS
Cachexia is caused by a complex interaction between tumor by-products (proteolysis inducing
factor, lipid mobilizing factor) and host cytokines
(including interleukin [IL]-1, IL-6, tumor necrosis
factor, interferon). Cachexia in experimental animal models can be relieved by specific cytokine
antagonists, such as monoclonal antibodies to IL6.9 The metabolic abnormalities are characterized
by synthesis of acute phase proteins in the liver
at the expense of muscle protein, proteolysis,
lipolysis, insulin resistance, decreased lipogenesis, elevated triglycerides and decreased high
density lipoproteins (Fig. 1). Neuroendocrine abnormalities and the production of anorexigenic10
compounds may further contribute to the development of cachexia. Nutritional supplementation
and appetite stimulation alone cannot overcome
the block in accretion of muscle mass. Similar
mechanisms for cachexia in CHF, chronic kidney
disease,11 COPD,12 and rheumatoid arthritis13
have been described.
ASSESSMENT
The patient’s subjective loss of appetite can be
assessed with a numerical rating scale such as the
Edmonton Symptom Assessment System (ESAS),
or one of the other tools previously described.
The clinical assessment includes a careful history
that is focused on nutritional issues and a physical examination. Body weight is the only test
commonly used outside the research setting.
Measuring mid upper arm circumference may
have prognostic value.14 Whole-body impedence
and electroconductivity is based on the principle
that lean tissue conducts electricity better than fat.
This has the potential for more widespread clinical use as the equipment becomes more easily
Department of Palliative Care and Rehabilitation Medicine, University of Texas M. D. Anderson Cancer Center,
Houston, Texas.
409
410
DEL FABBRO ET AL.
FIG. 1.
Metabolic abnormalities in primary cachexia.
available. For research and for follow-up, the effect of any intervention on related symptoms,
such as fatigue and dyspnea, would be useful, as
well as quality of life and functional assessments.
MANAGEMENT
The management of major contributors to this
syndrome, such as chronic nausea, constipation,
early satiety, taste alteration, dyspnea, deconditioning, and depression may result in significant
improvement. Established pharmacologic treatment currently comprises either megestrol or corticosteroids, which predominantly stimulate appetite, however will not reverse cachexia in most
patients. Weight gain may be necessary to alleviate distress associated with changes in body image. The other therapies described below may
delay or reverse the cachexia component, or alleviate the symptom burden without major effects
on body composition.
Pharmacologic treatment
Progestational agents. Megestrol acetate has
demonstrated dose dependent improvements
(starting at 160 mg/d) in appetite, fatigue, and
general well-being in more than 60% of patients.15–17 Approximately 480–800 mg/d is optimal for weight gain, but it is prudent to start at
a lower dose and titrate upward, since adverse
effects18 and expense are dose-related. Symptomatic improvement in appetite occurs in less than
1 week; however, weight gain may take several
weeks and it happens in less than one quarter of
treated patients. In a comparison study, megesterol acetate (MA; 800 mg/d) was found to have
fewer side effects than dexamethasone (0.75 mg
four times daily [qid]), with a trend toward better weight gain.19 The authors concluded that for
planned long-term use (weeks to months) it
might be preferable to choose megestrol acetate.
Consideration should also be given to cost (up to
20 times more expensive) and the higher risk for
deep vein thrombosis (DVI).
A recent review of the literature on MA20
showed that this drug was safe and effective in
patients with cancer and AIDS. Megestrol has
also been used in other noncancer conditions. A
randomized double-blinded placebo controlled 8
week trial21 of either megestrol 800 mg daily or
placebo in underweight patients with COPD
demonstrated significant weight gain (mostly fat
mass) in the megestrol group. Ventilation was
stimulated (PaCO2 decreased), but there was no
change in the 6-minute walk test. Side effects of
megestrol include edema, hyperglycemia, and elevated liver enzymes.
Medroxyprogesterone22 at doses of 1000 mg/d
(equivalent to megestrol 160 mg/d) has demonstrated significant improvements in appetite and
body weight.
Corticosteroids may stimulate appetite and
decrease nausea as well.23,24 Randomized clinical trials have demonstrated that compared to
placebo, corticosteroids can improve appetite and
food intake.25 The effects of corticosteroids on ap-
SYMPTOM CONTROL: CACHEXIA, ANOREXIA, FATIGUE
petite and food intake are usually limited to a
couple of weeks, and the side effects of these
drugs increase dramatically over time. Therefore,
corticosteroids should be considered most useful
for patients with a life expectancy of less than 6
weeks. Most authors have used prednisone doses
ranging from 20–40 mg, or dexamethasone at an
equivalent dosage.
Cannabinoids. Dronabinol, a synthetic cannabinoid, is Food and Drug Administration (FDA) approved for anorexia related to AIDS and chemotherapy-induced nausea and emesis. In a study
of patients with AIDS-related cachexia, dronabinol showed significant improvement in nausea,
appetite, and mood but no weight gain.26 Although some studies found beneficial effects of
dronabinol on appetite in patients with advanced
cancer,27,28 the effects of dronabinol on cachexia
appear to be limited. In a more recent study comparing dronabinol with megesterol acetate, the
latter drug was found to be more beneficial as an
orexigenic agent.29 A combination of both drugs
was not better than MA alone. The use of dronabinol is also limited by undesirable central nervous side effects, such as sedation, confusion, and
perceptual disturbances.30
Thalidomide has immunomodulatory and antineoplastic effects and its use is being explored
in a variety of conditions.31 Recent trials in patients with advanced cancer have been encouraging. Thalidomide was found to improve appetite, nausea and well-being32 after 10 days
of treatment (100 mg daily) in patients with
advanced cancer. A recent randomized placebo
controlled trial33 of 50 patients with pancreatic
cancer demonstrated that a dose of 200 mg
daily for 24 weeks was well-tolerated and effective at attenuating loss of weight and lean body
mass. There was no significant difference in appetite symptom scores between thalidomide and
placebo. Two patients developed peripheral neuropathy that resolved on cessation of the drug.
Another open-label trial of thalidomide for 2
weeks in patients with esophageal cancer34 appeared to reverse loss of lean body mass, and although sedation was experienced by all patients,
daytime somnolence was transitory and disappeared after 2 or 3 days.
Thalidomide also appears to benefit patients
without cancer with cachexia. Patients with human immunodeficiency virus (HIV) with aph-
411
thous ulcers have demonstrated weight gain on
doses of 200 mg daily.35 Low-dose (100 mg)
thalidomide36 for 8 weeks in AIDS-associated
cachexia was also associated with significant
weight gain, half of which was fat-free mass. A
trial of thalidomide in patients with active pulmonary tuberculosis37 was well tolerated and resulted in significant weight gain and reduction of
tumor necrosis factor (TNF)-.
Testosterone and its derivatives, such as oxandrolone,38 have been studied in patients with
AIDS, neuromuscular disorders, and alcoholic
cirrhosis. A recent review of oxandrolone concluded that improvements in body composition
and muscle strength are significant in the majority of well-designed trials. Long-term safety ( 1
year) and dosage titration still need to be determined. A prospective open-label study39 demonstrated a preferential increase of lean body mass
in patients with COPD after 2 months of oxandrolone. There was an increase in 6 minute walking distance of more than 65 m in the majority of
patients. Eighteen percent of patients withdrew
because of side effects. Nandrolone has shown
similar benefits in patients with COPD40 and
AIDS, however, it can only be given parenterally
and this limits its use.
Other hormones, such as growth hormone,
have demonstrated increases in lean body mass
in patients with AIDS,41 and may have future applications in the syndrome of frailty42 in the elderly, but the cost is prohibitive. Ghrelin, a novel
growth hormone-releasing peptide isolated from
the stomach, may have future therapeutic potential for cachexia43 of different causes (cardiac or
cancer).
Melatonin may inhibit cancer cell growth, improve survival and decrease chemotherapy induced side effects. In two studies with a large
number of patients (total 1640), the frequency
of cachexia, asthenia, and thrombocytopenia was
significantly lower in patients treated with 20 mg
of melatonin at night.44 A randomized pilot trial
in patients with cancer of fish oil, melatonin, or
their combination did not induce major biochemical changes suggestive of a strong anticachectic effect, but may have produced a weightstabilizing effect.45 This well-tolerated drug
deserves further placebo-controlled trials.
-3 fish oil has few adverse effects and several
benefits, including an immunomodulatory action and an antidepressant effect. Despite its
412
promise,46 there was no nutritional or symptomatic benefit in two randomized double-blinded
controlled trials of advanced cancer patients.47,48
-Antagonists and agonists. The possible role of
the sympathetic nervous system in cardiac
cachexia was illustrated by a study49 that measured body weight, plasma norepinephrine, leptin, and insulin in both cachectic and noncachectic chronic heart failure patients. After 6 months
of -blocker therapy, patients with baseline
cachexia demonstrated significantly greater
weight gain, increase in leptin levels, and decrease in norepinephrine levels compared to noncachectic patients. The -agonist Clenbuterol has
an anabolic effect in normal and wasted muscles
of animals. A single double-blinded placebo controlled trial50 of healthy postoperative orthopedic
patients demonstrated increased muscle strength
in the group treated with clenbuterol.
Immunologic. A review51 of six clinical trials of
various monoclonal antibodies to IL-6 in the
treatment of cancer showed that the therapy was
well tolerated and decreased the cancer-related
symptoms of cachexia, pain, and fever. In most
patients C-reactive protein levels decreased below detectable limits. A recent trial52 of a low-cost
oral therapeutic HIV vaccine (V1) in patients with
AIDS prolonged survival and increased body
mass.
Psychotropics. Antidepressants, such as mirtazapine, and atypical antipsychotics, such as
olanzapine, may be useful for the management of
anorexia, nausea, and other symptoms in patients
with cancer.53 Tricyclics, such as amitriptylline,
may improve appetite but unfortunately have
side effects, especially in the elderly.
Nonpharmacologic treatment
Nutritional support and counseling. Those patients with a predominant starvation component
resulting from obstructive gastrointestinal tumors or painful mucositis as a result of head and
neck cancer treatment may benefit from nutritional interventions.
Artificial nutrition via the enteral or parenteral
routes is inappropriate for most patients with advanced cancer and may hinder the transition to
hospice. A meta-analysis54 of total parenteral nutrition (TPN) in patients with cancer undergoing
DEL FABBRO ET AL.
chemotherapy showed decreased survival and
increased susceptibility to infection. A review of
70 prospective randomized trials of enteral and
parenteral nutrition in cancer patients55 concluded that if there is any therapeutic benefit it is
small and confined to a small subset of patients.
In rare cases, home TPN can be associated with
long-term survival. A retrospective single institution study of home TPN56 identified 16 patients
with cancer over a 20-year period who survived
a year or longer. Most of the tumors were carcinoid and quality of life data were not assessed.
One recent randomized prospective study57 of
patients with primarily gastrointestinal tumors
suggested a trend toward increased survival in
patients who received TPN.
Counseling. Compassionate communication is required to address the benefits and burdens of nutrition and to reframe the condition from that of
“starving to death” to the more complex one of irreversible (usually) metabolic abnormalities. The
psychological component is also important to consider, because eating meals together is important
for social integration. Families of patients who are
able to eat should be advised that frequent small
meals may be more tolerable than three large meals
daily. Nutritional counseling has been reported to
improve nutritional intake in patients undergoing
chemotherapy but not to influence symptom distress or survival.58 In patients with advanced cancer, this increased nutritional intake may last for
only a few weeks.59 Unfortunately, there has been
only limited research on the value of nutritional
counseling in palliative care.
FATIGUE
Fatigue is one of the most common symptoms
encountered in palliative care patients.60,61 It has
been ranked as the longest lasting and most disruptive of symptoms,62 having the greatest impact on quality-of-life parameters.63 Fatigue, similar to other symptoms, is a subjective sensation,
which manifests with varying dimensions of impaired physical, cognitive, and affective functioning.64 The physical dimension is usually described as a perception of muscle weakness or
decreased energy. The cognitive and affective dimensions include difficulty in concentrating or
maintaining attention and lack of motivation or
interest in activities.
413
SYMPTOM CONTROL: CACHEXIA, ANOREXIA, FATIGUE
Frequency rates as high as 96% for fatigue have
been reported in association with chemotherapy
and radiotherapy,65 and severe fatigue is almost
universal in patients receiving biological response modifiers, such as interferon- and IL2.66–68 In cancer survivors, fatigue has also been
reported as a disruptive symptom months or
years after cancer treatment ends.69–71 A qualitative study of patients with severe heart failure revealed difficulties with walking and extreme fatigue similar to that of patients living with
advanced cancer.72 In a study of 427 ambulatory
patients with AIDS,73 fatigue was found to be
present in 54%, and its presence correlated
strongly with the number of AIDS-related physical symptoms, anemia and pain. The patients
with fatigue were also observed to have relatively
poorer physical functioning and quality of life
and greater psychological distress than those
with no fatigue.
MECHANISMS
Multiple etiological factors may coexist and be
interrelated. The common contributors to fatigue in advanced cancer include the tumor, the
treatments and the proinflammatory cytokines
produced (interleukin-1, IL-6, and TNF-). Cytokines are the likely mediators of anemia, fever,
FIG. 2.
pain, cachexia, and depression. Comorbidities
such as congestive heart failure, kidney, and
liver failure exacerbate fatigue as do electrolyte
endocrine and mood disorders These factors are
shown in Figure 2.
ASSESSMENT
Fatigue is assessed much like any other symptom, namely by characterizing the severity, temporal features (onset, course, duration, and daily
pattern), exacerbating and relieving factors, associated distress, and impact on daily life,74 while
searching for contributing factors. Additional information is obtained from the history and physical examination and laboratory data. In palliative care practice, patients present with multiple
symptoms, which can be simultaneously assessed
by the ESAS. The presence of other symptoms
such as pain, sleep, depression, and anxiety, are
strongly correlated with fatigue.
A more rigorous method, used for research
purposes and validated for internal consistency,
Functional Assessment of Cancer Therapy-Fatigue Subscale (FACT-F).75 The Brief Fatigue Inventory (BFI) has also been used and validated
as a measure of fatigue in patients with cancer,76
as has the Memorial Symptom Assessment ScaleShort Form (MSAS-SF). A study of patient re-
Contributors to fatigue.
414
DEL FABBRO ET AL.
sponses to BFI, FACT-F, and the lack of energy
item yielded similar information for assessing fatigue.77
MANAGEMENT
Figure 3 shows an approach to management of
fatigue and is discussed below.
Specific measures
Anemia is frequent in patients with cancer and
may be secondary to bleeding, treatment-related
FIG. 3.
myelosuppression, chronic disease, and malnutrition. Severe anemia (hemoglobin 8 g/dL) is
known to cause profound fatigue; however, a
higher hemoglobin may also be associated with fatigue. Using a hemoglobin value of 12 g/dL or less
to define anemia, anemic cancer patients requiring
chemotherapy were found to have significantly
higher levels of fatigue and impaired physical and
functional well-being.78 There is a clear relationship
between anemia and fatigue in patients with cancer receiving chemotherapy,79 and treatment of
these patients with red blood cell transfusion
and/or erythropoetin alpha80 has shown to im-
Approach to fatigue management in palliative care.
SYMPTOM CONTROL: CACHEXIA, ANOREXIA, FATIGUE
prove quality of life and energy.81 Although therapy with erythropoetic agents is relatively safe, the
disadvantages include the cost and the delay of 4–8
weeks before an increase of 1–2 g/dL and symptom improvement occurs. Recent data suggest that
erythropoietin leads to an increase risk of deep venous thrombosis and may, in certain populations,
increase mortality. Moreover, data82 supporting
erythropoetin’s usefulness in patients not on chemotherapy are less clear. In a recent retrospective
study of 147 patients with cancer receiving palliative care, anemia was not found to be independently associated with fatigue. Because the number and severity of other comorbid conditions
increase with advancement of disease, the relative
contribution of anemia to fatigue likely decreases
progressively.83
Infection. Fatigue is frequently associated with infection. It may predate the episode of infection and
may outlast the infection by weeks or months.
Anxiety, depression, or other mood disturbances are common in patients with cancer.84
There is an association between depression and
fatigue in patients with cancer; however, a causal
relationship has not been established
Hypogonadism may also contribute to fatigue.
Much of the research on the role of hypogonadism in fatigue has been done on HIV-positive
men. Testosterone deficiency is associated with
loss of muscle mass, fatigue, reduced libido, and
anemia.85 In patients with HIV with testosterone
deficiency, treatment with androgenic anabolic
steroids, including testosterone and its derivatives, has been found to increase muscle mass,
energy levels, and libido.86–89 A randomized 10week trial of 47 patients with COPD with testosterone deficiency showed that testosterone plus
resistance training had additive benefits.90 Both
lean body mass and leg muscle strength increased
significantly. Recently published studies have
found a high prevalence of hypogonadism in patients with cancer91 and in patients receiving high
doses of opioids.92 In both these studies, the presence of hypogonadism was associated with fatigue. Therapeutic trials of androgen replacement
therapy in these patients for fatigue management
are currently in progress.
Pharmacologic
Medications such as MA and dexamethasone
may alleviate some of the symptoms of fatigue in
415
patients with advanced cancer.93,94 Corticosteroids have been shown to decrease fatigue via unknown mechanisms.95 The duration of benefit is
between 2–4 weeks, and treatment may be suitable for patients with a short life expectancy. Prolonged use may induce myopathy and infection,
thereby further contributing to fatigue. The usual
starting dose in most studies is prednisone 20–40
mg per day or its equivalent.
Psychostimulant medications have been
shown in studies to ameliorate fatigue in patients
with AIDS and multiple sclerosis.96,97 In a randomized double-blinded placebo-controlled trial
of ambulatory patients with HIV, two psychostimulants—pemoline and methylphenidate—
were shown to improve fatigue scores and quality of life. In patients with cancer, the most
commonly used psychostimulant is methylphenidate. Dextroamphetamine, pemoline, and
modafinil have also been used, although there
have been no controlled comparisons of any of
these drugs. Methylphenidate has been used in
cancer patients to treat opioid induced somnolence, reduce pain intensity, treat depression, and
improve cognition.98 Preliminary evidence suggests that psychostimulants may have a role in
fatigue management in patients with cancer.99
Clinical trials are in progress. Modafinil, which is
licensed for treatment of narcolepsy, is a novel
psychostimulant that has been shown to be effective for management of fatigue in multiple
sclerosis.100 Further research is warranted to evaluate its role in fatigue management in advanced
chronic disease.
Donepezil, a centrally acting acetylcholinesterase (AChE) inhibitor approved for use in
Alzheimer’s disease, may have a role in some patients with fatigue. Preliminary studies in patients with cancer have suggested at least shortterm benefit in treating opiate-related sedation,101
as well as improvement in fatigue scores.102
Randomized controlled trials are currently in
progress.
Nonpharmacologic approaches
A multidisciplinary approach to management
benefits patients with advanced cancer and other
disease such as CHF.103
Patients with heart failure have a wide array of
options104 should standard medical therapy (diuretics, angiotensin-converting enzyme [ACE]inhibitors, beta blockers, aldosterone antagonists,
416
digoxin) fail to improve fatigue and functional
capacity. However, more invasive emerging
therapies, such as ventricular assist devices or resynchronization pacing should be carefully discussed with the primary team before implementation, because of their considerable impact on
complexity of care and hospital discharge.
Patient education. Patients with symptoms of fatigue need to be counseled about the nature of
symptoms, likely etiology of their fatigue, options
for management, and the expected outcome. This
will help patients and their families set realistic
expectations. As the disease progresses, patients
will need to adapt to progressive limitations in
physical function and activity. Patient preferences for information and willingness to participate in exercise and other treatment options
should be ascertained.
Exercise programs. In patients with cancer, muscle abnormalities have been found even when lean
body mass is constant and caloric intake normal.
Excessive amounts of lactate have been found in
tumor-free muscle tissues and it is unclear whether
lactate is part of the pathogenic mechanism or consequent to it.105 Tumor-free muscle from tumorbearing animals show alterations in the activity of
various enzymes, distribution of isoenzymes, and
synthesis and breakdown of myofibrillar and sarcoplasmic proteins.106 Patients with breast cancer
who underwent electrical stimulation of the abductor pollicis muscle via the ulnar nerve were
found to have impaired maximal strength, decreased relaxation velocity, and increased fatigue
compared to normal controls.107 In addition, medications such as corticosteroids and cyclosporine
may contribute to myopathy.108 Deconditioning
resulting from inactivity and prolonged bed rest
results in loss of muscle mass and reduced cardiac
output. This in turn decreases endurance and activities of daily living.109,110 There is good evidence111 to support the effectiveness of exercise in
patients with fatigue.112–117 Exercise improves fatigue through an adaptive cardiorespiratory response, maintenance of muscle mass, improvement in mood, and quality of sleep. Several studies
have shown that endurance exercise training improves fatigue and physical performance in patients with cancer undergoing chemotherapy or in
those who have undergone bone marrow or stem
cell transplantation.118–120 Patients with multiple
sclerosis121 who underwent an 8-week progressive
DEL FABBRO ET AL.
resistance training program reported decreased fatigue and disability. There are also similarities122
between COPD and CHF with regard to muscle
dysfunction and the impact of exercise.
Although there is abundance of data to support exercise, selection of the most appropriate
program for patients with various types of advanced disease and different levels of performance status are not well defined. Any exercise
program should be initiated gradually.
Psychosocial interventions. Patients should be
counseled about stress management and methods
to deal with depression and anxiety, which are
commonly associated with fatigue. Clinical studies testing interventions to reduce stress and increase psychosocial support in cancer patients
have shown reduction in fatigue levels, although
in many of these studies fatigue was a secondary
endpoint.123–126
Nutrition and hydration. Patients may have decreased oral intake due to a variety of causes related to their illness or treatment. Referral to a nutritionist for dietary planning may be indicated if
decreased intake is judged to be one of the causes
of fatigue.
Future treatment approaches
Several promising approaches to fatigue management have been identified. Cytokine antagonists may be exploitable in combating the components of cancer-related fatigue and may also
inhibit tumor growth.127 Pentoxifylline and
bradykinin antagonists inhibit the release of cytokines, while others, such as COX-2 inhibitors,
nonselective COX inhibitors, -melanocytes–
stimulating hormone, and monoclonal antibodies,128 inhibit cytokine action. Thalidomide has
been shown to improve the sensation of well-being in patients with cancer cachexia, and may also
be helpful in cancer-related fatigue.129 Other potential treatment approaches that warrant research include human growth hormone, and Lcarnitine130 supplementation.
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Address reprint requests to:
Eduardo Bruera, M.D.
Department of Palliative
and Rehabilitation Medicine
University of Texas M. D. Anderson Cancer Center
Box 008
1515 Holcombe Boulevard
Houston, TX 77030
E-mail: [email protected]