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Key Words

Fatigue, chemobrain, chemotherapy, dexmethylphenidate (Focalin® or d-MPH). (Definitions of many terms related to cancer can be found in the Cancer.gov Dictionary.)

Summary

Cancer patients diagnosed with chemotherapy-related fatigue and cognitive impairment ("chemobrain") were treated with the central nervous system stimulant dexmethylphenidate (Focalin®) for eight weeks. Compared to those receiving a placebo, patients taking the drug experienced significantly less fatigue and possibly better memory function.

Source

American Society of Clinical Oncology annual meeting, Orlando, Florida, May 17, 2005.

Background

Most regimens of systemic chemotherapy send a cocktail of chemicals into a patient’s bloodstream to kill cancer cells, but the process can be a major assault on the entire body. Many such cancer patients report similar subjective sensations - they say they are not thinking as clearly, are overly forgetful, are always tired, or just don’t feel right. Clinicians now recognize a condition called chemobrain, which includes a complex mix of symptoms such as fatigue, mental confusion, memory loss, and lack of focus.

Cancer-related fatigue may affect as many as seven in ten cancer patients, and is normally not relieved by rest. Some 99 percent of breast and lung cancer patients report fatigue, and 61 percent of patients receiving chemotherapy or radiotherapy report that their fatigue persists after treatment has stopped.

Over the long course of a patient’s disease and treatment, it is hard for doctors to untangle these symptoms, and recognize or treat them individually. For example, does foggy thinking result from fatigue or are the two symptoms independent of each other?

Drugs in the class of central nervous system stimulants are being tested in this population, but there is currently no approved treatment for any of the chemobrain symptoms.

The Study

In this phase II trial testing the safety and efficacy of dexmethylphenidate (d-MPH), 154 cancer patients with a life expectancy of more than six months were enrolled at 21 centers over 14 months. All patients had completed at least four cycles of cytotoxic chemotherapy at least two months before the study began. The patients’ median age was about 53 years old; 94 percent of them were female (76 percent of them with breast cancer and 14 percent with ovarian cancer), 79 percent were white, and nine percent were African-American.

All of the patients were diagnosed with chemotherapy-related fatigue and cognitive impairment, as measured by a variety of tests. For one week, they took a 5 milligram (mg) pill twice a day which doctors, but not the patients themselves, knew was a placebo. Those patients whose symptoms persisted or worsened were then randomly assigned to receive either a placebo or d-MPH for eight weeks. This part of the trial was double-blinded; that is, neither doctors or patients knew who was receiving which treatment. Patients in the two groups were well balanced in terms of physical and mental health characteristics.

Based on the patients’ symptoms, doctors were allowed to adjust the amount of treatment as they saw fit, either decreasing it or raising it by as much as 10 mg a day for the first six weeks, up to a maximum of 50 mg a day. Twenty-two patients left the study because of adverse events or other reasons, which meant that 132 completed the full eight-weeks course: 59 in the drug group and 73 in the placebo group.

The study was designed primarily to determine whether the drug proved beneficial in treating chemotherapy-related fatigue. To measure this, doctors relied most on a test called the Functional Assessment of Chronic Illness Therapy-Fatigue Subscale (FACIT-F) Total Score. Secondary goals of the trial were to see whether the drug improved cognitive function (as determined by a test called the High Sensitivity Cognitive Screen or HSCS, which measures memory and other kinds of cognitive activity) and to find out what dose range was effective and safe. Doctors administered the fatigue and cognitive tests both before and after treatment so they could measure any change.

The primary author was Elyse Lower, M.D. at the University of Cincinnati Medical Center.

Results

At the end of eight weeks, patients on d-MPH were significantly less fatigued than those in the placebo group, as measured by FACIT-F. The drug also helped patients do significantly better on the memory portion of the HSCS test, though none of the other cognitive functions appeared to improve. However, the trial was not designed to reach definitive conclusions about cognitive functions.

More patients receiving d-MPH had at least one adverse event compared to those on placebo (90 percent versus 78 percent), though the only two serious adverse events of the trial occurred in the placebo group. Common mild-to-moderate side effects were headache (40.8 percent of patients in the d-MPH group versus 33.3 percent in the placebo group) and nausea (27.6 percent d-MPH versus 7.7 percent placebo).

Comments

Lower concludes that d-MPH “significantly reduced chemotherapy-related fatigue in this adult population, and that doses up to 50 mg/day are safe and well-tolerated.” She and her colleagues suggest the drug should be recommended to treat both the fatigue and the memory impairment associated with chemobrain.

Limitations

Kathleen M. Foley, M.D., a neurologist with the Pain and Palliative Care Service at the Memorial Sloan Kettering Cancer Center, said at the ASCO discussion that this study “was not powered to look at [the complex functions of] chemobrain, and is really a fatigue study.”

Ted Trimble, M.D., Associate Chief of Surgery in NCI’s Division of Cancer Treatment and Diagnosis, believes that the study design does not account for the possibility that, while effective against fatigue, d-MPH could have no impact or even negative effects on other aspects of the chemobrain complex of symptoms.

The great majority of patients in this study were treated for breast cancer, and questions were raised at the ASCO meeting about whether the results apply to other groups of cancer patients. Lower said the study had been open to all, but enrolled the patients predominant at the participating sites. She saw no data to indicate the d-MPH advantage would not apply to all groups. Trimble agreed: “The drugs we use for breast cancer are routine for treating other common cancers. It’s fair to assume this drug will probably work in any setting where patients report fatigue and cognitive deficits after chemotherapy.”

Trimble pointed out that most clinicians would want to see these results replicated in a larger study before adopting d-MPH routinely into practice.

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