Pilot Study Comparing Hypnotherapy and Gabapentin for Hot Flashes.

Study Overview
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Brief Summary
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Premenopausal women with breast cancer who receive endocrine therapy (e.g. tamoxifen) and/or chemotherapy are at risk for experiencing premature menopause because of their treatment. The resulting symptoms, most notably hot flashes, can cause significant detriment to a patient's quality of life. Treatment for menopausal symptoms with the gold standard of hormone replacement therapy is not done routinely as it is unclear whether it can increase risk of tumor recurrence. In addition, many medical oncologists feel it is contraindicated in this population, especially among women whose breast cancers have estrogen receptors. This has lead to an increased interest in options other than estrogen replacement in the treatment of hot flashes, though most investigations of alternative medications have shown a suboptimal response. Recent studies have suggested that non-drug treatments using alternative or complementary therapies may be effective. Specifically, hypnosis has been promoted as a means to control hot flashes, though it has not been tested in a randomized fashion. In accordance with the National Cancer Institute's recent initiatives to expand the goals of clinical trials to include symptom management studies, our purpose is to evaluate the role of complementary and alternative therapies for improvement of symptoms in women with breast cancer. Specifically, we plan to evaluate the use of hypnotherapy for the treatment of therapy-induced hot flashes in breast cancer survivors. We intend to recruit 60 women into a pilot feasibility trial comparing hypnotherapy to the drug gabapentin (Neurontin®) for the treatment of therapy-induced hot flashes in eligible women who are receiving care at the Breast Health Center. We have chosen gabapentin based on recent studies showing it may be an effective non-estrogen treatment for this indication. We will identify patients who are experiencing at least one daily hot flash as a result of the treatment they received for their breast cancer for participation. When enrolled, they will be randomized into either the treatment arm, in which they will receive daily gabapentin, or the experimental arm, in which they will undergo weekly hypnotherapy. Our study hypothesis is that hypnotherapy will be more effective than gabapentin in the control of hot flashes in this population.

Detailed Description
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Roughly half of women diagnosed with pre-menopausal breast cancer will have hormone receptor-positive tumors, which will make them candidates for anti-estrogen therapies. Both endocrine therapy and ovarian ablation have also been shown to improve outcomes in this population. Hot flashes are a frequent side effect in women receiving anti-estrogen therapy for breast cancer, and have been shown to have a significant impact on patients' quality of life. For example, it has been reported that hot flashes in breast cancer survivors are more severe and result in a more significant impact on quality of life measures when compared with healthy women. Hormone replacement, the gold standard for the treatment of hot flashes in postmenopausal women, is contraindicated in this population. Non-hormonal drug therapies have been explored for the treatment of hot flashes in this population of women with moderate results. In randomized controlled trials, venlafaxine has been shown to reduce self-reported hot flashes in patients with breast cancer by 25-61%. However, selective serotonin re-uptake inhibitors (SSRIs) and selective norepinephrine re-uptake inhibitors (SNRIs) may interfere with the metabolism of tamoxifen, a common treatment for estrogen-receptor positive breast cancers, by inhibiting the cytochrome P450 2D6 (CYP2D6) enzyme. Gabapentin is a gamma-aminobutyric acid (GABA) analogue commonly used for the treatment of seizure disorders and neuropathic pain. There is some evidence to demonstrate its efficacy in hot flashes to be equivalent to estrogen and superior to antidepressants in postmenopausal women. In a pilot study of 22 women with breast cancer on tamoxifen, the use of gabapentin for four weeks reduced the frequency of hot flashes by 44.2%, and decreased the hot flash severity scores by 52.6%. These results were confirmed in a larger study of 420 breast cancer survivors who were randomized to receive gabapentin 300mg/d, gabapentin 900mg/d, or placebo. The 900mg/d dose of gabapentin was the most effective; decreasing the frequency of hot flashes by 49% at four weeks. In the group receiving 900mg of gabapentin daily, there was a 12% withdrawal rate at 4 weeks, and 17% at 8 weeks, owing to side effects and subjective inefficacy. Hypnosis or hypnotherapy, defined as the induction of a deeply relaxed condition that allows the patient to suspend critical faculties and allow suggestibility, has been shown to be effective in not only reducing the daily frequency of hot flashes (by 59%), but also in improving quality of life variables such as insomnia in patients with breast cancer. However, this therapy has never been compared directly to pharmacotherapy in the treatment of therapy-induced hot flashes in patients with breast cancer. In response to the NCI's 2006 initiatives to expand the goals of clinical trials and include symptom management studies, we are interested in evaluating the role of complementary and alternative therapies for improvement of symptoms in women with breast cancer. This trial is to determine whether hypnotherapy, administered in a standard way, can improve the frequency of hot flashes and breast cancer specific quality of life in women diagnosed with pre-menopausal breast cancer. We propose to evaluate this through a pilot feasibility study which will randomize participants to an eight week course of gabapentin or hypnosis.

Official Title
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Comparison of Hypnotherapy Versus Gabapentin in the Treatment of Hot Flashes in Breast Cancer Survivors or Women at Risk of Developing Breast Cancer.

Conditions
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Breast Cancer, Hot Flashes

Intervention / Treatment
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* Behavioral: Hypnotherapy
* Drug: gabapentin


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Women with histologic confirmation of a diagnosis of infiltrating carcinoma of the breast are eligible for participation. Women with non-invasive or pre-invasive lesions of the breast, including but not limited to ductal carcinoma in situ (DCIS), atypical ductal hyperplasia (ADH) or lobular carcinoma in situ (LCIS) are eligible for participation. Women with a known breast cancer susceptibility gene (eg, BRCA) mutation or strong family history of breast cancer are eligible. Any woman age 60 years or more who cannot take estrogen therapy because of a real or perceived risk of developing breast cancer are eligible. Women under the age of 60 with a Gail model score of 1.6% or more are eligible. Subjective report of at least one daily hot flash. Able to provide voluntary informed consent. ≥ 18 years-old. There will be no upper limit for age inclusion. Karnofsky performance status > 70%. Women with a history of breast cancer must have undergone treatment with curative intent. ≥ 4 weeks from completion of chemotherapy or radiation therapy, where appropriate. adequate hematopoietic function (ANC ≥ 1500/mm3; Platelets ≥ 100,000/mm3; Hemoglobin ≥ 8 g/dL) adequate renal and hepatic function [Bilirubin ≤ 1.5 times upper limit of normal (ULN), serum glutamic-oxaloacetic transaminase (SGOT) ≤ 2.5x ULN, Alkaline phosphatase ≤ 2.5x ULN, and Creatinine ≤ 2x ULN]. No clinical evidence of disease (complete remission). Patients receiving neoadjuvant therapy will be eligible following completion of all adjuvant chemotherapy if indicated. Patients receiving hormonal therapy in lieu of or following chemotherapy will be eligible to participate. Patients must have access to a compact disk player. Exclusion criteria: History or active secondary cancer within the last 5 years (except for superficial basal cell skin cancers). Any residual chemotherapy-induced CTCv3.0 Grade 2 or greater non-hematological toxicity. Unable to give informed consent or unable to adhere to protocol. Any serious medical or psychiatric illness likely to interfere with participation in this clinical study, concurrent uncontrolled illness, or ongoing or active infection will be excluded. Any history of alcohol or drug abuse. Allergy to gabapentin. History of seizure disorder.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Hypnotherapy<br>Patients randomized to the experimental arm were scheduled for three one-hour inductions by a single hypnotherapist, each one week apart. Standardized outlines were used for each induction. The second and third sessions also began with a standardized induction, followed by the establishment of an anchor, or physical reference point (forefinger to thumb), used to invoke images of coolness, which were individualized according to patient preference. Patients were also instructed by the same hypnotherapist in self-hypnosis and guided imagery techniques to be used at home with the assistance of standardized audio compact disks. Participation lasted eight weeks. | Behavioral: Hypnotherapy<br>* Patients randomized to the hypnosis arm of the study will undergo individually three one-hour sessions with a certified hypnotherapist. These sessions will be one week apart. surveys. The therapist will be prohibited from asking subjects about clinical responses to the hypnosis sessions. The patients will also be instructed on self-hypnosis techniques to be used at home.<br>* Other names: mind-body therapy;|
| Active Comparator: Gabapentin<br>Patients randomized to the gabapentin arm were prescribed 900mg of the drug daily (300 mg by mouth three times daily). | Drug: gabapentin<br>* Patients randomized to the gabapentin arm will be prescribed 900mg of the drug daily (300 mg by mouth three times daily). This dose has been shown to be more effective than 300mg daily. Larger doses have not been evaluated in this population, and may be associated with a more significant side-effect profile. The prescription for gabapentin will be provided at the patient's enrollment appointment. The patients will take gabapentin as prescribed daily for the study-enrollment period, which is 8 weeks.<br>* Other names: gabarone;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Daily Hot Flashes | Patients kept daily diaries of their hot flashes. The absolute number of hot flashes in a 24 hour period is number of daily hot flashes. The median number was calculated for each week of data. The median number of daily hot flashes for the first week (7 days) of participation is used as baseline. The median number of daily hot flashes for the fourth week (over 7 day interval) is reported for the week four time point. The median number of daily hot flashes for the eighth week (over 7 day interval) is reported for the week eight time point (study completion). Of the 13 women randomized to the hypnotherapy arm, 2 women were ineligible and therefore not included in analysis. Two women were unable to initiate treatment and did not submit diaries. An additional two women completed treatment but lost their diaries, leaving 7 diaries for analysis at baseline. Of the 14 randomized to receive gabapentin, 6 dropped out of the study and did not submit diaries. | Baseline | 
| Number of Daily Hot Flashes | Patients kept daily diaries of their hot flashes. The absolute number of hot flashes in a 24 hour period is number of daily hot flashes. The median number was calculated for each week of data. The median number of daily hot flashes for the first week (7 days) of participation is used as baseline. The median number of daily hot flashes for the fourth week (over 7 day interval) is reported for the week four time point. The median number of daily hot flashes for the eighth week (over 7 day interval) is reported for the week eight time point (study completion). A total of 15 diaries were submitted (7 hypnotherapy, 8 gabapentin). One person in each arm stopped recording in her diary before the 4 week mark. | Week 4 | 
| Number of Daily Hot Flashes | Patients kept daily diaries of their hot flashes. The absolute number of hot flashes in a 24 hour period is number of daily hot flashes. The median number was calculated for each week of data. The median number of daily hot flashes for the first week (7 days) of participation is used as baseline. The median number of daily hot flashes for the fourth week (over 7 day interval) is reported for the week four time point. The median number of daily hot flashes for the eighth week (over 7 day interval) is reported for the week eight time point (study completion). One woman in the hypnotherapy arm and 3 women in the gabapentin arm stopped keeping their diary before the 8 week mark. | Week 8 | 
| Hot Flash Severity Score | The patients kept daily hot flash diaries, including the total number of hot flashes they characterized as mild, moderate,severe and very severe. Hot flash severity scores were calculated by assigning one point to each mild hot flash, two points for each moderate hot flash, three points for each severe hot flash and four points for each very severe hot flash. The hot flash severity score for a 24 hour period was the sum of these scores. The score was calculated for each day in the diary. For each subject, median scores were calculated for each week (7 day period) of participation. The median hot flash severity score for the first week was considered the baseline. The median hot flash severity score for the fourth week is considered the week 4 time point. The median hot flash severity score for the eighth week is considered the week 8 time point. The median result for the group was then calculated at each of the timepoints. | Baseline | 
| Hot Flash Severity Score | The patients kept daily hot flash diaries, including the total number of hot flashes they characterized as mild, moderate,severe and very severe. Hot flash severity scores were calculated by assigning one point to each mild hot flash, two points for each moderate hot flash, three points for each severe hot flash and four points for each very severe hot flash. The hot flash severity score for a 24 hour period was the sum of these scores. The score was calculated for each day in the diary. For each subject, median scores were calculated for each week (7 day period) of participation. The median hot flash severity score for the first week was considered the baseline. The median hot flash severity score for the fourth week is considered the week 4 time point. The median hot flash severity score for the eighth week is considered the week 8 time point. The median result for the group was then calculated at each of the timepoints. | Week 4 | 
| Hot Flash Severity Score | The patients kept daily hot flash diaries, including the total number of hot flashes they characterized as mild, moderate,severe and very severe. Hot flash severity scores were calculated by assigning one point to each mild hot flash, two points for each moderate hot flash, three points for each severe hot flash and four points for each very severe hot flash. The hot flash severity score for a 24 hour period was the sum of these scores. The score was calculated for each day in the diary. For each subject, median scores were calculated for each week (7 day period) of participation. The median hot flash severity score for the first week was considered the baseline. The median hot flash severity score for the fourth week is considered the week 4 time point. The median hot flash severity score for the eighth week is considered the week 8 time point. The median result for the group was then calculated at each of the timepoints. | Week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hot Flash Related Daily Interference Score (HFRDIS) | The HFRDIS is a validated survey of 10 questions asking patients to rate ten symptoms on a scale of 0-10. The HFRDIS is a sum of the scores in each category, so that total score can range from 0 (no symptoms) to 100 (10 severe symptoms). These surveys were conducted at the time of enrollment (baseline), after four weeks of treatment, and at the conclusion of the study (8 weeks). All women who were randomized were included in the baseline analysis (with the exception of 2 women excluded from the hypnotherapy arm who were deemed ineligible after randomization). | Baseline | 
| Hot Flash Related Daily Interference Score (HFRDIS) | The HFRDIS is a validated survey of 10 questions asking patients to rate ten hot flash-related symptoms on a scale of 0-10. The HFRDIS is a sum of the scores in each category, so that total score can range from 0 (no symptoms) to 100 (10 severe symptoms). These surveys were conducted at the time of enrollment (baseline), after four weeks of treatment, and at the conclusion of the study (8 weeks). Of 11 eligible women in the hypnotherapy arm, 2 never initiated treatment, and 3 did not complete the survey at this time point. Of the 14 eligible women in the gabapentin arm, 3 never initiated treatment, and 3 dropped out of the study before the 4 week time point. | Week 4 | 
| Hot Flash Related Daily Interference Score (HFRDIS) | The HFRDIS is a validated survey of 10 questions asking patients to rate ten hot flash-related symptoms on a scale of 0-10. The HFRDIS is a sum of the scores in each category, so that total score can range from 0 (no symptoms) to 100 (10 severe symptoms). These surveys were conducted at the time of enrollment (baseline), after four weeks of treatment, and at the conclusion of the study (8 weeks). All nine women who initiated hypnotherapy treatment completed the survey at the end of 8 weeks. One woman in the gabapentin arm did not submit a survey at 8 weeks. | Week 8 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hot flashes, breast cancer, Hypnotherapy, Quality of Life, Gabapentin