Symptom management: An important part of cancer care

CANCER-RELATED FATIGUE: COMMON BUT NOT INEVITABLE

Most cancer patients report fatigue. Although it is one of the most common symptoms in advanced cancer,⁵ it is not necessarily inevitable or untreatable.⁶

Cancer-related fatigue is multidimensional and develops over time, diminishing energy, mental capacity, and psychological condition.⁷ Patients may report feeling tired or being unable to complete their activities of daily living. People who were previously very active may be frustrated by their inability to participate in favorite leisure activities, which has a big impact on quality of life. Fatigue can be physical, emotional, or mental. It is important to distinguish physical weakness from dyspnea on exertion, which is commonly reported as fatigue. Depression may also cause or exacerbate fatigue.

Unlike fatigue in the general population, cancer-related fatigue does not improve with rest, and patients often report large amounts of unrestorative sleep.

Look for reversible causes of fatigue

First, conduct a thorough assessment to identify any reversible causes, such as:

• Anemia
• Insomnia, sleep disturbance
• Malnutrition
• Pain
• Depression
• Medical comorbidities: renal, cardiac, or pulmonary disease
• Hypothyroidism
• Hypogonadism.

In many cases, however, a reversible cause cannot be found.

Treating cancer-related fatigue

Nonpharmacologic interventions have been evaluated for this application, but evidence of efficacy is limited and mixed. The National Cancer Comprehensive Network guidelines⁸ suggest that energy conservation and education about cancer-related fatigue are central to management. Patients should be advised that fatigue has a fluctuating course and that they have a limited pool of energy, which they should conserve and use judiciously.

In a meta-analysis by Schmitz et al,⁹ physical activity interventions were found to be beneficial. Sixty-three percent of those studied were undergoing active treatment, so whether this population reflects advanced cancer is unclear. A small pilot study in advanced cancer found a trend toward benefit with exercise.¹⁰

Comment. The strategies of rest and exercise are complementary. The key point is to plan them per personal preference.

Psychostimulants include methylphenidate (Ritalin). A randomized placebo-controlled trial in patients with acquired immunodeficiency syndrome (AIDS) found methylphenidate 15 to 60 mg/day to have a positive effect.¹¹ Prospective studies have shown similar results in cancer patients,¹² and a Cochrane review in 2008 showed a small but significant benefit in cancer-related fatigue.¹³

Methylphenidate is usually started at a dose of 5 mg given at 8:00 am and at noon, and then titrated. Benefit, when experienced, is typically noted within 24 to 48 hours. Possible adverse effects include anorexia, insomnia, anxiety, confusion, tremor, and tachycardia.

Stimulants should be used with caution in patients with cardiac disease or delirium.

Modafinil (Provigil), a nonstimulant agent, has been less studied, but it may also help.^14,15 The usual dosage is 50 to 200 mg daily.

Corticosteroids may have a role in advanced cancer, as suggested by anecdotal reports.¹⁶ They should be used judiciously, as their adverse effects (insomnia, muscle wasting, edema) are themselves burdensome and may outweigh their benefits.

ANOREXIA CAN BE DISTRESSING TO THE FAMILY AND THE PATIENT

Most patients with advanced cancer experience anorexia, which is a marker of poor prognosis.¹

Appetite loss may occur in isolation or as a part of the anorexia-cachexia syndrome. This syndrome is a wasting state seen in chronic, advanced diseases including cancer, AIDS, chronic obstructive pulmonary disease, chronic renal insufficiency, and congestive heart failure.¹⁷ The associated weight loss is involuntary and includes both muscle and fat.

Appetite loss alone is usually not bothersome. In fact, anorexia frequently causes more distress to the family than to the patient.¹⁸ The ramifications of decreased appetite, on the other hand, can be devastating. Decreased caloric intake coupled with the hypermetabolic state of malignancy leads to rapid, dramatic changes in body habitus. This outward sign of the ravages of cancer can be psychologically damaging to patients and their loved ones as they contemplate advanced disease and limited life expectancy. They may be concerned about starvation, in which case education about and attempts to normalize the anorexia-cachexia syndrome are essential.

Look for reversible causes of anorexia

The first step in the management of anorexia is to identify any reversible causes, such as:

• Stomatitis
• Constipation
• Uncontrolled severe symptoms such as pain or dyspnea
• Delirium
• Nausea, vomiting
• Depression
• Gastroparesis.

Managing cancer-related anorexia

Nonpharmacologic measures include nutritional counseling and increased physical activity. Patients may be counseled to eat calorie-dense foods and supplemental high-calorie, high-protein, high-fat drinks. Some may be able to take advantage of a diurnal variation in appetite, usually an increased appetite in the morning.

Megestrol acetate (Megace) improved appetite and induced weight gain when used in a dosage of 800 mg daily in a randomized controlled trial in AIDS patients.¹⁹ Case studies have shown doses as low as 80 to 160 mg daily to be beneficial.²⁰ Most of the added weight is fat, not lean muscle mass. Unfortunately, the addition of testosterone to megestrol did not increase the accumulation of lean muscle mass in another randomized trial.²¹ But the addition of olanzapine (Zyprexa) to megestrol was associated with improved appetite and weight gain in a significant percentage of advanced cancer patients.²² Rates of adverse effects with megestrol are low; the most significant adverse effect is thromboembolism.

Corticosteroids. While much of the support for corticosteroids is anecdotal, a prospective study of dexamethasone 4 to 16 mg daily showed improvement in several symptoms, including appetite.²³ Because of the multiple adverse effects of corticosteroids, careful attention to dose, duration, and tolerability is essential. Corticosteroids should be discontinued if the desired positive effects are not observed within 3 to 5 days. If prolonged survival is expected, wean to the lowest effective dose.

Cannabinoids. Dronabinol (Marinol), a synthetic formulation of delta-9-tetrahydrocannabinol (THC), the active agent of marijuana, has been beneficial in AIDS anorexia. Fewer studies have been done in advanced cancer.

In a small, open-label case series, doses of 7.5 to 15 mg of dronabinol daily improved appetite and were well tolerated.²⁴ On the other hand, in a multicenter, randomized, double-blind, placebo-controlled trial, neither cannabis extract nor THC (5 mg daily) significantly improved appetite over a 6-week period.²⁵

A large randomized study found megestrol acetate 800 mg to be superior to dronabinol 5 mg daily for treating anorexia.²⁶

Neurotoxicity, anxiety, nervousness, dizziness, euphoria, and somnolence from dronabinol can be severe and intolerable for some.

Enteral tube feeding and parenteral nutrition do not improve survival or comfort in terminally ill patients.²⁷ On the contrary, they are associated with complications, including aspiration pneumonia, sepsis, abdominal pain, vomiting, and diarrhea. Nevertheless, in some patients with mechanical impediments to nutrition (eg, esophageal fistula, obstruction, or proximal small bowel obstruction) or in those who are hungry and unable to take food by mouth, tube feeding may be appropriate.