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Key Words

Breast cancer, hot flashes, gabapentin (Neurontin®), supportive care. (Definitions of many terms related to cancer can be found in the Cancer.gov Dictionary ⁴.)

Summary

The drug gabapentin (Neurontin) effectively reduced the intensity and duration of hot flashes in a clinical trial of more than 400 breast cancer patients. While it remains to be learned how the drug compares to other hot flash remedies currently in use, gabapentin appears to be a viable nonhormonal alternative for breast cancer patients experiencing this common side effect of treatment.

Source

The Lancet, September 3, 2005 (see the journal abstract).

Background

Hot flashes occur when changes in hormone levels interfere with the body’s ability to regulate its temperature. Hot flashes often afflict younger women treated with chemotherapy (which can shut down their ovaries), and also is one of the main side effects of the commonly prescribed hormone therapies, such as tamoxifen (Nolvadex®) or an aromatase inhibitor such as anastrozole (Arimidex®) Many men undergoing hormone treatments for prostate cancer also get hot flashes.

Hormone replacement therapy (HRT) has been prescribed to women suffering from menopause-related hot flashes. But HRT is not recommended for breast cancer patients, whose tumors may grow in response to estrogen.

Gabapentin is a promising nonhormonal therapy for hot flashes. It was originally approved by the FDA to control epileptic seizures, but has since become more widely used to reduce pain. Gabapentin effectively reduced both the frequency and severity of hot flashes in a 2003 randomized clinical trial of 59 healthy postmenopausal women, and in a 2004 pilot study of breast cancer patients.

Other nonhormonal treatments for hot flashes include such drugs as venlafaxine (an antidepressant) and clonidine (a drug to treat hypertension).

The Study

This phase III clinical trial enrolled 420 women with breast cancer between June 2001 and July 2003 at 18 centers that are part of the Rochester Community Clinical Oncology Program (CCOP) in New York State. None of the patients were currently undergoing chemotherapy, though about 9 percent had received chemotherapy earlier; about 8 percent had been previously treated with radiation. Most patients were taking tamoxifen at the time and all were experiencing between two and 54 hot flashes a day. Their median age was 55 and most were white.

The study was double-blinded. Researchers randomly assigned patients to one of three arms: 144 patients took 900 milligrams (mg) daily, 139 took 300 mg daily, and 137 took a placebo. All patients received their medication in the form of three pills each day. Most continued for eight weeks, though some withdrew because of side effects and for other reasons: 49 (12 percent) by week 4 and another 24 (5 percent) by week 8.

Patients kept a diary to record their hot flashes, rating each for intensity and duration; they were also asked by researchers about other symptoms. Data was collected to provide a profile before they began, and again during weeks 4 and 8.

The lead author was Kishan J. Pandya, M.D., from the University of Rochester Cancer Center, Rochester, New York. The study was funded under the National Cancer Institute CCOP, and Pfizer, Inc. supplied the study drug.

Results

After four weeks, the 900mg/daily group experienced a 49 percent reduction in the severity of hot flash symptoms, compared to 33 percent with the lower (300 mg) dose and 21 percent on placebo. Patients taking the higher dose also had 41 percent fewer hot flashes, compared to 28 percent with the lower dose and 18 percent on placebo. All of these measures were statistically significant. The results for all three groups further improved only slightly between week 4 and week 8.

Patients rated the severity of symptoms they experienced during treatment. Only pain and appetite showed any significant difference among the three study arms, with those taking 900 mg/daily reporting less appetite and less pain during the fourth week. In week 8, these differences disappeared, and no other significant differences among the groups were seen for distress, drowsiness, fatigue, sleep, memory, shortness of breath, nausea or vomiting.

The age of the patients and whether they were currently taking tamoxifen – and if so for how long – had no significant effect on the results.

Comments

Controlling hot flashes can be an important benefit to many women, but the long-standing use of hormone therapy is no longer an easy answer, especially in those who have – or are at increased risk of – breast cancer, explained Jennifer Eng-Wong, M.D., a clinical physician with the National Cancer Institute’s Center for Cancer Research. “Thus, we now prefer to use nonhormonal treatments for hot flashes,” and avoid the estrogen system altogether.

Lead author Pandya said gabapentin is very well tolerated, and “should be considered a viable nonhormonal alternative….

Limitations

Currently, said Eng-Wong, hot flashes in breast cancer patients are often effectively treated with the antidepressant drug venlafaxine. Clinical trials have shown that hot flash severity scores have been reduced by 45-60 percent with this drug, with minimal side effects.

“To consider gabapentin as the preferred treatment,” she said, “I would like to see head to head trials with venlafaxine and studies of how it might interact with tamoxifen or the aromatase inhibitors that many patients receive for their cancer.” The current study was conducted before use of aromatase inhibitors as an adjuvant hormonal treatment for breast cancer became widespread.

Lead author Pandya agreed about the need for more trials, saying, “until we run a clinical trial [comparing gabapentin with other hot flash remedies] we can’t know which [one] is most effective and how the side effects would compare.” The authors note, however, that previous studies have found clonidine to reduce hot flashes by 37 percent and venlafaxine by 61 percent, compared to the 46 to 48 percent found here for gabapentin.

Glossary Terms

A drug that prevents the formation of estradiol, a female hormone, by interfering with an aromatase enzyme. Aromatase inhibitors are used as a type of hormone therapy for postmenopausal women who have hormone-dependent breast cancer.

A clinical trial in which the medical staff, the patient, and the people who analyze the results do not know the specific type of treatment the patient receives until after the clinical trial is over.

A statistics term. The middle value in a set of measurements.

A study to compare the results of people taking a new treatment with the results of people taking the standard treatment (for example, which group has better survival rates or fewer side effects). In most cases, studies move into phase III only after a treatment seems to work in phases I and II. Phase III trials may include hundreds of people.

The initial study examining a new method or treatment.

Having to do with the time after menopause. Menopause (“change of life”) is the time in a woman's life when menstrual periods stop permanently.

A study in which the participants are assigned by chance to separate groups that compare different treatments; neither the researchers nor the participants can choose which group. Using chance to assign people to groups means that the groups will be similar and that the treatments they receive can be compared objectively. At the time of the trial, it is not known which treatment is best. It is the patient's choice to be in a randomized trial.

Describes a mathematical measure of difference between groups. The difference is said to be statistically significant if it is greater than what might be expected to happen by chance alone. Also called significant.

Care given to improve the quality of life of patients who have a serious or life-threatening disease. The goal of supportive care is to prevent or treat as early as possible the symptoms of a disease, side effects caused by treatment of a disease, and psychological, social, and spiritual problems related to a disease or its treatment. Also called comfort care, palliative care, and symptom management.