2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

Table 3. Etiology of Cancer-Related Fatigue
Peripheral component: negative energy imbalance
● Cancer itself or therapy for cancer
● Treatment for cancer: chemotherapy, radiation therapy, surgery, hormone
therapy, targeted kinase inhibitors
● Systemic infections
● Hypothyroidism
● Anemia
● Malnutrition
● Metabolic abnormalities
● Sleep disorders
● Psychological factors: depression, anxiety
Central component
● Hyperactivity of the hypothalamic-pituitary-adrenal axis from stress (i.e.,
increase in cortisol or corticotrophin-releasing factor
● Decreased gonadotropin levels
● Increase in the numbers of circulating T-lymphocytes
● Increased interleukin-1 receptor antagonist
● Increased soluble tumor necrosis factor receptor type II
● Increased neopterin levels
Currently, no proven pharmacologic treatments are available
for established chemotherapy-associated peripheral
neuropathy. Discontinuation of the causative agent or dose
reductions may help. Pharmacologic agents that have been
tried include topical amitriptyline with ketamine, topical
lidocaine, selective serotonin norepinephrine uptake inhibitors,
and antiepileptics. Because chemotherapy-associated
peripheral neuropathy is only partially reversible and
maybe permanent, several studies have focused on prevention
of the disorder. 45 Calcium and magnesium infusions
and glutathione have been shown to prevent neurotoxicity
from oxaliplatin and cisplatin, respectively. Clinical trials
involving patients receiving oxaliplatin or paclitaxel have
demonstrated that glutamine substantially reduces neuropathy
symptoms along with decreased incidence of motor
weakness and gait disturbances.
Cancer-Related Fatigue
The NCCN defines cancer-related fatigue as a distressing
persistent subjective sense of tiredness or exhaustion that is
not proportional to recent activity and interferes with usual
functioning. Cancer-related fatigue may be an early symptom
of malignant disease and is reported by as many as 40%
of patients at the time of diagnosis. In addition, as many as
90% of patients receiving radiation therapy and as many as
80% of patients receiving chemotherapy experience fatigue.
One study demonstrated no association between fatigue and
age. 45 A number of studies found an association between
hemoglobin levels, pain, and nonpain symptoms with fatigue.
In the Health and Retirement Study, 67% of the
patients with cancer were 65 and olderand approximately
50% had one or two coexisting medical conditions. 46 Patients
with cancer had a substantially higher risk for fatigue,
depression, and pain. Table 3 provides information on the
etiology and possible pathophysiology of cancer-related fatigue.
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To date, there is no U.S. Food and Drug Administration
(FDA) approved drug for the treatment of cancer-related
fatigue. [In addition, there are no studies that have been
conducted to study CRF specifically in elderly patients with
cancer.] If fatigue is secondary to low hemoglobin, erythropoietin
stimulating agents (ESA) may be used to treat the
underlying anemia. However, ESAs must be used with
caution given the risk of thromboembolic disease, and they
continue to be contraindicated in patients receiving myelosuppressive
therapy for curative cancers. A randomized
study of methylphenidate (target dose, 54 mg/d) in 148 adult
patients with cancer did not significantly improve cancerrelated
fatigue (p � 0.35). 48 A subset analysis suggested
that patients with more severe fatigue and/or with more
advanced disease did have some improvement in fatigue.
Patients in the methylphenidate arm reported more nervousness
and appetite loss. Several studies have shown no
benefit of selective serotonin reuptake inhibitors (sertraline
or paroxetine) for the treatment of cancer-related fatigue in
patients with cancer. Modafinil, a wakefulness drug, improved
severe cancer-related fatigue in a large randomized
study. 49
Nonpharmacologic interventions have also been studied
for their effect on cancer-related fatigue. 50 A Cochrane
review demonstrated that exercise improves cancer-related
fatigue during and after cancer therapy. 51 Caution in developing
the exercise prescription is recommended for patients
with bone metastases or myelosuppression andpatients who
are febrile. Exercise interventions included moderately intense
(55% to 75% of heart rate) aerobic exercise (e.g.,
walking, cycling), ranging from 10–90 minutes 3 to 7 days
per week. Psychological and behavioral interventions 47 that
have been evaluated for cancer-related fatigue include support
groups, yoga, and cognitive behavioral interventions.
These interventions have improved cancer-related fatigue
and vitality in most studies. These interventions also can
be combined with exercise for maximizing benefit, as was
demonstrated in the GROUP-HOPE trial. 52
Conclusion
MOHILE, KLEPIN, AND RAO
The incidence of cancer increases with age. An older
patient’s chronologic age does not always reflect his or her
overall health status. Therefore, oncologists need to be adept
at assessing physiologic and functional capacity in older
patients. The CGA is the criterion standard for evaluation of
an older patient. The combined data from the CGA can be
used to stratify patients into risk categories to better predict
chemotherapy toxicity and survival. More research is
needed on the best ways to incorporate the CGA into
decision making for cancer treatment, implement novel
treatment dosing options, and develop interventions to improve
symptoms of sarcopenia, cachexia, chemotherapyassociated
peripheral neuropathy, and cancer-related
fatigue in older patients with cancer.