Chapter 9: Fatigue: Clarifying the Research Questions

Recent surveys of cancer-related fatigue have documented substantial unmet needs related to poor assessment and a limited focus on treatment (Vogelzang et al., 1997; Curt et al., 2000). This type of survey is needed in other seriously ill populations. Additional epidemiologic surveys are needed in all these populations to better clarify the nature of fatigue (including prevalence, severity, time course, and phenomenology), to identify syndromes, and to document impact. With the advent of improved sophistication in fatigue assessment methodologies, these surveys promise to yield a strong foundation for clinical trials and studies of fatigue mechanisms.

There have been very few studies of management approaches for fatigue. At the present time, treatment is based largely on clinical experience. This has been codified in an algorithm for the management of cancer-related fatigue (Portenoy and Itri, 1999).

Figure 4.1 Algorithm for the Management of Cancer-related Fatigue

Patient with Cancer Related Fatigue

Leads to

Evaluation of Fatigue which includes the following:
Assess Characteristics/Manifestations (Severity; Onset, duration, pattern, and course; Exacerbating and palliative factors; Distress and impact; Manifestations (which may include Lack of energy, Weakness, Somnolence, Impaired thinking, Mood disturbance)
Assess Related Constructs (Overall quality of life and Symptom distress)

This leads to

Evaluation of Predisposing Factors/Etiologies

Physiologic Factors (Underlying disease; Treatments; Intercurent disease processed (e.g. infection, anemia, electrolyte disturbance or other metabolic disorder, neuromuscular disorder); Sleep disorder; Possible polyphamacy

Psychological Factors (Mood disorder; stress)

This leads to:

Management of Fatigue
Establishing reasonable expectations
Plans to assess repeatedly

This leads to either

Correction of Potential Etiologies or Symptomatic Therapies

For Correction of Potential Etiologies includes:

Depression or Pain
Antidepressants (Selective serotonin reuptake inhibitors; Secondary amine tricyclics; Bupropion) or Analgesics

Anemia
Exclude common causes of anemia (Iron deficiency, Bleeding, Hemolysis, Nutritional deficiency)
Severeanemia (Transfuse)

Mild to moderate anemia (Consider epoetin alfa 40,000 units subcutaneously weekly and Evaluate after 4 weeks:

if increase in Hgb is > 1 g/dL, continue therapy
If increase in Hgb is < 1g/dL, increase dosage to 60,000 units weekly
If no response, discontinue epoetin alfa

Provide supplemental iron as necessary

Sleep Disorder
Sleep hygiene and Careful use of hypnotics

Deconditioning
Energy conservation and Consider referral to rehabilitation specialist

Other Conditions
Correct fluids/electrolytes
Calcium, thyroid or cortcosteroid replacement
Give oxygen
Treat infection
Reduce or eliminate nonessential medications
Treat hypogonadism

Symptomatic Therapies lead to either Pharmacologic Treatment or Nonpharmacologic Treatment

Pharmacologic Treatment
Psychostimulants including Methylphenidate, Pemoline, Dextroamphetamine, Modafinil
or Low-dose conticosteroid including Dexamethasone, Prednisone

Nonpharmacologic Treatment
Patient education, Exercise, Modify activity and rest patterns, Stress management and cognitive therapies, Adequate nutrition and hydration

Both Pharmacologic and Nonpharmacologic treatments lead to investigation of:

Fatigue Nonresponsive to Other Interventions
Empiric trial of antidepressant (Selective serotonin reuptake inhibitors, Secondary amine tricyclics, Bupropion)
Empiric trial of amantadine

The algorithm for cancer-related fatigue is useful in clarifying a broader research agenda for clinical trials targeted to fatigue in medical illness. For example, the algorithm notes that the initial approach to the management of fatigue typically involves efforts to correct potential etiologies, if it is possible and appropriate given the goals of care. This may include elimination of nonessential centrally-acting drugs, treatment of a sleep disorder, reversal of anemia or other metabolic abnormalities, improvement in nutrition, or management of major depression. All of these interventions deserve systematic clinical study.

The reversal of fatigue in successfully treated patients with depression lends credence to the hypothesis that a subtype of fatigue is related to the neurobiological substrate of depression. Studies of antidepressant drugs with varied profiles in fatigued patients with and without depressed mood would be illuminating.