June 4, 2010, 3:57PM

By Linda Perrett

Posted in: Supportive care | survivorship | treatment

Tags: antidepressants, cancer-related fatigue, corticosteroids, hematopoietics, psychostimulants

People are surviving cancer in greater numbers than ever before thanks to treatment options that include surgery, chemotherapy, radiation therapy, immunotherapy, and medication. But during or after treatment patients are often hit with a common side-effect of the disease—a debilitating and whole-body exhaustion that cannot be relieved by rest or sleep—called cancer-related fatigue.

Research has been conducted to test the characteristics and properties of drugs currently used to enhance alertness, treat depression, arthritis—and even narcolepsy—for their effectiveness in treating cancer-related fatigue. NCI-supported investigators conducted a review of literature on 32 clinical trials that were held in the U.S., Canada, and Europe, to better understand how these treatment options work.

Jennifer K. Carroll, M.D., of the James P. Wilmot Cancer Center in Rochester, N.Y., and her colleagues compiled information from  trials that ranged from seven days to two years in duration, with most lasting four months. These trials tested the effects of hematopoietics, psychostimulants, antidepressants, corticosteroids, L-carnitine, and modafinil [see descriptions below] against cancer related fatigue. Seventy five percent of the trial participants had one or more types of cancer.

After compiling of results, it was found that hematopoietics, psychostimulants, antidepressants, and corticosteroids may have a beneficial effect on cancer related fatigue, while, in special populations of cancer patients, L-carnitine and the modafinil may also be beneficial.

Although the results are intriguing, Carroll’s team cautions that there were limitations to the 32 clinical trials. First, sample sizes varied in many of the studies; some were quite small. Second, many of the studies were open-label/non-blinded rather than blinded, placebo-controlled studies. Third, side-effects were not consistently reported. Finally, many of the studies were funded by pharmaceutical companies with few head-to head or comparative effectiveness studies done.  More research is needed to address these methodological limitations of these therapies.

Assessment of Drugs Tested for Treatment of Cancer-Related Fatigue

Hematopoietics

Hematopoietics are used to treat anemia. Anemia, or lack of healthy red blood cells, can occur in patients with cancer as a consequence of either disease-related processes or cancer treatment. Twelve clinical trials (38 percent of total) tested epoetin alfa (Procrit®), and the longer-acting version, darbepoetin alfa (Aranesp®) against cancer-related fatigue. Of the 12, seven were randomized controlled clinical trials. Overall results provide evidence that these drugs decreased fatigue and improved the quality of life in patients with cancer-related anemia. There were significant improvements in energy level, activity level, and overall quality of life, as well as decreases in fatigue.

In these studies, the improvements in energy level and quality of life correlated with the increase in hemoglobin concentrations and were seen in patients with stable disease and in those who responded well to chemotherapy.

Psychostimulants

Psychostimulants are used to enhance alertness. Sleep disorders, including insomnia and excessive daytime sleepiness, are common in patients with cancer. Seven clinical trials (22 percent of total) tested the psychostimulants methylphenidate and dexmethylphenidate against cancer-related fatigue.

Methylphenidate (Ritalin®) is a central nervous system stimulant that is structurally related to amphetamines. Researchers theorize that methylphenidate could be effective in treating cancer-related fatigue because it has been found to produce enhanced alertness, attention, vigilance, and reduce fatigue in patients with other chronic conditions, such as multiple sclerosis and HIV infection. In these studies, methylphenidate was shown to improve fatigue in patients with cancer but its effect was not significantly different from that of placebo in a double-blind study.

Dexmethylphenidate (Focalin®) is a drug commonly used to treat attention deficit hyperactivity disorder. In a randomized placebo-controlled trial, in non-anemic patients with cancer who had completed chemotherapy, dexmethylphenidate was associated with significantly greater improvements in fatigue than placebo.

Given that relatively few randomized, placebo-controlled clinical trials have been conducted specifically to evaluate the use of psychostimulants in patients with cancer-related fatigue, adverse effects of psychostimulants, such as irritability, anorexia, insomnia, fluctuations in mood, nausea, and heart beat irregularities must be considered when making treatment decisions.

Antidepressants

Antidepressants are used to manage depression. Many patients with cancer experience depression. Two clinical trials (6 percent of total) examined the antidepressant Bupropion Sustained-Release (SR) for cancer-related fatigue. Bupropion (Wellbutrin-SR®) is an antidepressant that has been used to treat chronic fatigue syndrome, as well as fatigue associated with multiple sclerosis. Bupropion SR was associated with improvement in fatigue scores within two to four weeks of the start of treatment. Further placebo-controlled studies were considered necessary to establish the efficacy of Bupropion SR in cancer-related fatigue.

Two double-blinded, placebo-controlled randomized trials (6 percent of total) of the selective serotonin re-uptake inhibitor (a newer type of antidepressant) paroxetine (Paxil®) report this antidepressant improved depression but had no effect on fatigue in patients receiving chemotherapy, suggesting that the underlying causal mechanisms for depression and cancer-related fatigue are distinct.

Corticosteroids

Corticosteroids, which are hormones produced in the adrenal cortex to respond stress and inflammation, are used to treat pain, nausea and vomiting. Cancer patients often have pain and low energy levels. Three clinical trials (9 percent of total) tested corticosteroids (including methylprednisolone, prednisone, and megestrol acetate) against cancer related fatigue. Two of the studies were randomized trials.

The studies found corticosteroids improved cancer symptoms, especially pain, and reduced fatigue in patients with metastatic cancer. For example, in one study scientists demonstrated a significantly greater reduction in the severity of pain in patients with terminal cancer after 14 days of treatment with methylprednisolone compared with placebo. In another, megestrol acetate was found to decrease fatigue and increase energy levels, appetite, and feelings of well-being in patients with advanced cancer.

Corticosteroid studies were generally of short duration (10–14 days). Since the study durations were short, there is no information about corticosteroid therapy long-term for cancer-related problems. However, adverse effects of long-term corticosteroid use are well-documented for many other conditions. Corticosteroids may be most helpful to patients who are in the terminal phases of advanced cancer and have cancer-related fatigue.

L-carnitine

L-carnitine is used to manage effects of chemotherapy. Chemotherapy treatment often causes anemia and nausea and robs the body of carnitine—an important protein derived from an amino acid that is found in nearly all cells of the body. L-carnitine is one of two forms of the substance. Three clinical trials (9 percent of total) tested L-carnitine in the treatment of cancer-related fatigue. L-carnitine, commonly used as an energy nutrient, is used to treat patients who do not make enough carnitine as way to prevent tissue damage caused by chemotherapy. Treatment with with–L-carnitine significantly improved fatigue.

Modafinil

Modafinil is a mood-brightening and memory-enhancing psychostimulant which improves wakefulness and is used to treat narcolepsy, obstructive sleep apnea, and shift-work sleep disorder. Two clinical trials (6 percent of total) tested modafinil (Provigil®) against cancer related fatigue. Short-term clinical studies have shown improved wakefulness in patients with other conditions such as multiple sclerosis, major depression, and Parkinson’s disease.

The first study found positive effects on fatigue that had persisted for an average of two years following breast cancer treatment, with fatigue severity and other measures of quality of life significantly improved after one month of treatment. In the second study of 30 patients with malignant and benign brain tumors who were treated with surgery, radiotherapy, and/or chemotherapy, modafinil was associated with significant improvements in fatigue scores.

Randomized clinical trials of modafinil are under way to investigate its effect on cancer-related fatigue in patients receiving chemotherapy and those who have completed chemotherapy or radiation therapy.

Cancer Related Fatigue Presentations at the American Society of Clinical Oncology (ASCO)

Several clinical science symposiums, including one titled Cancer Fatigue and Contributing Factors: Recognition and Treatment, and another titled Pharmacologic Treatment of Cancer Related Fatigue: Does it Make a Difference, will be held the American Society of Clinical Oncology (ASCO) annual meeting in Chicago, June 2010.

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