Breast Cancer, Hot Flashes, Menopausal Symptoms, Unspecified Adult Solid Tumor, Protocol Specific
Conditions
Keywords
menopausal symptoms, hot flashes, breast cancer, unspecified adult solid tumor, protocol specific
Brief summary
RATIONALE: Estrogen can relieve the symptoms of menopause, but can also cause the growth of breast cancer cells. Flaxseed may reduce the number of hot flashes and improve mood and quality of life in postmenopausal women not receiving estrogen therapy. PURPOSE: This randomized phase III trial is studying flaxseed to see how well it works in treating postmenopausal women with hot flashes who have a history of breast cancer or other cancer or who do not wish to take estrogen therapy.
Detailed description
OBJECTIVES: * To evaluate the efficacy of flaxseed on hot flash scores in women with a history of breast cancer or other cancer or in women who do not wish to take estrogen therapy for fear of increased risk of breast cancer as measured by a daily prospective hot flash diary. * To evaluate the side effect profile of flaxseed in this population. * To evaluate the effects of flaxseed on mood (per the Profile of Mood States) and broader menopausal symptoms (per the MENQOL), daily interference from hot flashes (per the HFRDIS), and perception of benefit (per Global Impression of Change). OUTLINE: Patients are stratified according to age (18-49 years vs ≥ 50 years); treatment with tamoxifen citrate, selective estrogen receptor modulators, or aromatase inhibitors (yes vs no); duration of hot flashes (≤ 9 months vs \> 9 months); and daily frequency of hot flashes (4-9 vs ≥ 10). Patients are randomized to 1 of 2 treatment arms. * Arm I: Patients receive oral flaxseed in the form of a bar similar to a granola bar once daily. * Arm II: Patients receive oral placebo bar once daily. In both arms, treatment continues for 6-12 weeks. Patients in arm II may crossover to receive treatment as in arm I after 6 weeks. Patients complete questionnaires (Hot Flash Diary, Side Effect Experience Questionnaire, Profile of Mood States, Hot Flash Related Daily Interference Scale, and Menopause Specific Quality of Life) at baseline and periodically during treatment. Patients are contacted by telephone at the end of weeks 2, 4, 5, and 7 to assess product tolerability, document compliance, encourage completion of questionnaires, and address problems.
Interventions
DIETARY_SUPPLEMENTflaxseed
Given orally
OTHERplacebo
Given orally
Sponsors
National Cancer Institute (NCI)
Alliance for Clinical Trials in Oncology
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Bothersome hot flashes, defined by their occurrence ≥ 28 times per week and of sufficient severity to make the patient desire therapeutic intervention * Presence of hot flashes for ≥ 1 month * Meets 1 of the following criteria: * History of breast cancer or other cancer (currently without malignant disease) * No history of breast cancer and wishes to avoid estrogen due to a perceived increased risk of breast cancer * Hormone receptor status not specified * Postmenopausal as defined by 1 of the following\*: NOTE: \*Women with ≥ 1 ovary but without a uterus should be deemed postmenopausal by either age \> 55 OR a combination of estrogen within a postmenopausal range (per local lab) and follicle-stimulating hormone \> 40 mIU/mL * Absence of a period in the past 12 months * Bilateral oophorectomy * ECOG performance status 0-1 * Life expectancy ≥ 6 months * Able to complete questionnaire(s) alone or with assistance * No diabetes requiring oral or injectable antihyperglycemics * No hypotension * No history of allergic or other adverse reaction to flaxseed * No irritable bowel syndrome, colitis, Crohn disease, or any gastrointestinal condition where the patient should not consume and/or has an intolerance/allergies to seeds or nuts * At least 4 weeks since prior and no concurrent or planned androgens, estrogens, or progestational agents * Tamoxifen, raloxifene, or aromatase inhibitors are allowed provided the patient has been on a constant dose for ≥ 4 weeks and is not expected to stop the medication during study treatment • At least 4 weeks since prior and no concurrent anti-cancer therapies of any kind * Trastuzumab allowed * No concurrent treatment with other anti-cancer therapies of any kind except for trastuzumab or endocrine therapies * No concurrent (≤ 7 days prior to registration) or planned use of other agents for treating hot flashes (i.e., gabapentin, clonidine, antidepressants, estrogen treatment, megestrol acetate, or Bellergal) * Stable dose of vitamin E (as a general vitamin supplement) allowed provided it is ≤ 800 IU/day, it was started \> 30 days before study initiation, and is to be continued through study period * Patients who have been using antidepressants for mood and have been on a stable dose for over a month and meet the eligibility criteria for hot flash frequency and duration are eligible • No concurrent anticoagulants or anti-platelets (1 mg of Coumadin for central line patency allowed) * Aspirin allowed (≤ 81 mg) * No concurrent anti-hypertensives * No other concurrent herbal supplements for any reason, including soy and soy supplements (i.e., powders, pills, or milk)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| To Evaluate the Efficacy of Flaxseed on Hot Flash Scores in Women as Measured by a Daily Prospective Hot Flash Diary. | Baseline and 7 weeks | The intra-patient difference in hot flash activity between baseline (study week 1) and treatment termination (study week 7) is the primary endpoint. The hot flash activity will be measured by the weekly average hot flash score which is a composite entity of both frequency and severity of hot flashes. The hot flash severities are graded from 1 to 4, ranging from mild, to moderate, to severe to very severe. The daily hot flash score is computed by multiplying the mean grade of severity by the frequency during every 24 hour period. Therefore, a score of zero is the lowest possible score and can be interpreted as having no hot flashes. The average daily hot flash score during the baseline week was compared to the average daily value during week 7. The primary method of analysis will be the independent sample t-test to examine the change of weekly average hot flash score from baseline to treatment termination between flaxseed and placebo arms. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Toxicity as Measured by CTCAE v3.0 | Up to 7 weeks | Frequency and severity of adverse events were reported by patients weekly evaluated through clinical assessment by NCI CTCAE v3.0. The number of patients reporting grade 3 or higher events are reported in this outcome measure. For a full list of all events, please refer to the Adverse Events section of this report. |
| Change of Mood as Measured by the Profile of Mood States (POMS) | Baseline and up to 7 weeks | Profile of Mood States (POMS) was used to look at total mood disturbance as well as the subscales of tension-anxiety, fatigue-inertia, and vigor-activity. The POMS is a well known, well validated, reliable measure of psychological distress which includes 6 subscales of fatigue-inertia, vigor-activity, tension-anxiety, depression-dejection, anger-hostility, and confusion-bewilderment. The entire scale can be scored to provide a measure of total mood disturbance. The measure contains adjectives related to mood which are scored from 0 (not at all) to 4 (extremely). Individual scores were converted to a 0-100 scale where 100 is best quality of life. The change of mood as measured by the POMS from baseline to treatment termination between flaxseed versus placebo arms was compared using Kruskal-Wallis test. The mean change in total score for each arm is reported. |
| Change of Menopause Specific Quality of Life as Measured by the Menopause Specific Quality of Life (MENQOL) | Baseline and up to 7 weeks | The change in quality of life as measured by the MENQOL from baseline to treatment termination between flaxseed versus placebo arms was evaluated. On a 0-6 scale, patients were asked to answer questions in in each of 4 domain scores (Vasomotor, Psychosocial, Physical, Sexual) Scores were converted to a 0-100 scale where 100 is best QOL. The change in score from baseline to end of treatment were analyzed separately for each domain. Here we report the mean change in score for each category. |
| Change of Daily Interference as Measured by the Hot Flash Related Daily Interference Scale (HFRDIS) | Baseline and up to 7 weeks | The change of daily interference as measured by the HFRDIS from baseline to treatment termination between flaxseed versus placebo arms was evaluated with an independent t-test for continuous data. On a 0-10 scale, patients were asked to describe how hot flashes interfered with 10 different aspects of their life (work, social activities, leisure activities, sleep, mood, concentration, relationships with others, sexuality, enjoyment of life and overall quality of life). Scores were converted to a 0-100 scale where 100 is best QOL.The HFRDIS total score was the average of the 10 individual questions. The change in total score from baseline to end of treatment was analyzed between the groups using a Kruskal-Wallace test. |
Countries
United States
Participant flow
Pre-assignment details
One-hundred-five patients were randomized to each of the Flaxseed arm and the Placebo arm. After unblinding, all patients had the option of continuing Flaxseed treatment for 6 additional weeks to obtain longer term information about the effects of flaxseed for the management of hot flashes and to allow the placebo arm to try the flaxseed.
Participants by arm
| Arm | Count |
|---|---|
| Flaxseed Patients receive 1 Nutrigrad™ flaxseed bar containing 7.5 grams flaxseed, 410 mg lignans,once daily. | 105 |
| Placebo Patients Identical looking bar with same calorie and total fat content but without flaxseed or lignans once daily. | 105 |
| Total | 210 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Flaxseed and Placebo | Ineligible | 3 | 1 |
| Flaxseed and Placebo | Withdrawal by Subject | 5 | 4 |
Baseline characteristics
| Characteristic | Flaxseed | Placebo | Total |
|---|---|---|---|
| Age, Customized Flaxseed and Placebo Period <50 | 25 Participants | 24 Participants | 49 Participants |
| Age, Customized Flaxseed and Placebo Period >=50 | 80 Participants | 81 Participants | 161 Participants |
| Age, Customized Optional Flaxseed Continuation <50 | 25 Participants | — | 25 Participants |
| Age, Customized Optional Flaxseed Continuation >=50 | 55 Participants | — | 55 Participants |
| Region of Enrollment United States | 105 participants | 105 participants | 210 participants |
| Sex: Female, Male Flaxseed and Placebo Period Female | 105 Participants | 105 Participants | 210 Participants |
| Sex: Female, Male Flaxseed and Placebo Period Male | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Optional Flaxseed Continuation Female | 80 Participants | 0 Participants | 80 Participants |
| Sex: Female, Male Optional Flaxseed Continuation Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 61 / 101 | 71 / 102 | 32 / 76 |
| serious Total, serious adverse events | 0 / 101 | 0 / 102 | 0 / 76 |
Outcome results
Primary
To Evaluate the Efficacy of Flaxseed on Hot Flash Scores in Women as Measured by a Daily Prospective Hot Flash Diary.
The intra-patient difference in hot flash activity between baseline (study week 1) and treatment termination (study week 7) is the primary endpoint. The hot flash activity will be measured by the weekly average hot flash score which is a composite entity of both frequency and severity of hot flashes. The hot flash severities are graded from 1 to 4, ranging from mild, to moderate, to severe to very severe. The daily hot flash score is computed by multiplying the mean grade of severity by the frequency during every 24 hour period. Therefore, a score of zero is the lowest possible score and can be interpreted as having no hot flashes. The average daily hot flash score during the baseline week was compared to the average daily value during week 7. The primary method of analysis will be the independent sample t-test to examine the change of weekly average hot flash score from baseline to treatment termination between flaxseed and placebo arms.
Time frame: Baseline and 7 weeks
Population: Per protocol, the study was powered for 77 patients on each arm. With 20% over-accrual, the analysis began after 94 patients registered to each arm. 25 patients from Flaxseed were not used (4 cancel, 2 ineligible, 12 refused further treatment, 5 due to adverse events, 2 noncompliance). 17 from the placebo arm were not used (3,1,5,7,1 respective)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Flaxseed | To Evaluate the Efficacy of Flaxseed on Hot Flash Scores in Women as Measured by a Daily Prospective Hot Flash Diary. | -4.9 units on a scale | Standard Deviation 6.41 |
| Placebo | To Evaluate the Efficacy of Flaxseed on Hot Flash Scores in Women as Measured by a Daily Prospective Hot Flash Diary. | -3.5 units on a scale | Standard Deviation 6.47 |
p-value: 0.29t-test, 2 sided
Secondary
Change of Daily Interference as Measured by the Hot Flash Related Daily Interference Scale (HFRDIS)
The change of daily interference as measured by the HFRDIS from baseline to treatment termination between flaxseed versus placebo arms was evaluated with an independent t-test for continuous data. On a 0-10 scale, patients were asked to describe how hot flashes interfered with 10 different aspects of their life (work, social activities, leisure activities, sleep, mood, concentration, relationships with others, sexuality, enjoyment of life and overall quality of life). Scores were converted to a 0-100 scale where 100 is best QOL.The HFRDIS total score was the average of the 10 individual questions. The change in total score from baseline to end of treatment was analyzed between the groups using a Kruskal-Wallace test.
Time frame: Baseline and up to 7 weeks
Population: Per protocol, the study was powered for 77 patients on each arm. With 20% over-accrual, the analysis began after 94 patients registered to each arm. 25 patients from Flaxseed were not used (4 cancel, 2 ineligible, 12 refused further treatment, 5 due to adverse events, 2 noncompliance). 17 from the placebo arm were not used (3,1,5,7,1 respective)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Flaxseed | Change of Daily Interference as Measured by the Hot Flash Related Daily Interference Scale (HFRDIS) | 13.9 units on a scale | Standard Deviation 18.57 |
| Placebo | Change of Daily Interference as Measured by the Hot Flash Related Daily Interference Scale (HFRDIS) | 9.8 units on a scale | Standard Deviation 19.65 |
p-value: 0.089Kruskal-Wallis
Secondary
Change of Menopause Specific Quality of Life as Measured by the Menopause Specific Quality of Life (MENQOL)
The change in quality of life as measured by the MENQOL from baseline to treatment termination between flaxseed versus placebo arms was evaluated. On a 0-6 scale, patients were asked to answer questions in in each of 4 domain scores (Vasomotor, Psychosocial, Physical, Sexual) Scores were converted to a 0-100 scale where 100 is best QOL. The change in score from baseline to end of treatment were analyzed separately for each domain. Here we report the mean change in score for each category.
Time frame: Baseline and up to 7 weeks
Population: Per protocol, the study was powered for 77 patients on each arm. With 20% over-accrual, the analysis began after 94 patients registered to each arm. 25 patients from Flaxseed were not used (4 cancel, 2 ineligible, 12 refused further treatment, 5 due to adverse events, 2 noncompliance). 17 from the placebo arm were not used (3,1,5,7,1 respective)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Flaxseed | Change of Menopause Specific Quality of Life as Measured by the Menopause Specific Quality of Life (MENQOL) | Change in Vasomotor score | 22.5 units on a scale | Standard Deviation 20.13 |
| Flaxseed | Change of Menopause Specific Quality of Life as Measured by the Menopause Specific Quality of Life (MENQOL) | Change in Psychosocial score | 9.9 units on a scale | Standard Deviation 12.49 |
| Flaxseed | Change of Menopause Specific Quality of Life as Measured by the Menopause Specific Quality of Life (MENQOL) | Change in Physical Score | 9.3 units on a scale | Standard Deviation 13.44 |
| Flaxseed | Change of Menopause Specific Quality of Life as Measured by the Menopause Specific Quality of Life (MENQOL) | Change in Sexual Score | 14.4 units on a scale | Standard Deviation 18.27 |
| Placebo | Change of Menopause Specific Quality of Life as Measured by the Menopause Specific Quality of Life (MENQOL) | Change in Sexual Score | 14.4 units on a scale | Standard Deviation 22.05 |
| Placebo | Change of Menopause Specific Quality of Life as Measured by the Menopause Specific Quality of Life (MENQOL) | Change in Vasomotor score | 18.7 units on a scale | Standard Deviation 22.04 |
| Placebo | Change of Menopause Specific Quality of Life as Measured by the Menopause Specific Quality of Life (MENQOL) | Change in Physical Score | 11.8 units on a scale | Standard Deviation 15.19 |
| Placebo | Change of Menopause Specific Quality of Life as Measured by the Menopause Specific Quality of Life (MENQOL) | Change in Psychosocial score | 11.1 units on a scale | Standard Deviation 15.02 |
Comparison: Testing the change in score from baseline to treatment completion for vasomotor-related questions in the MENQOL form.p-value: 0.19Kruskal-Wallis
Comparison: Testing the change in score from baseline to treatment completion for Psychosocial-related questions in the MENQOL form.p-value: 0.78Kruskal-Wallis
Comparison: Testing the change in score from baseline to treatment completion for Physical-related questions in the MENQOL form.p-value: 0.238Kruskal-Wallis
Comparison: Testing the change in score from baseline to treatment completion for Sexually-related questions in the MENQOL form.p-value: 0.497Kruskal-Wallis
Secondary
Change of Mood as Measured by the Profile of Mood States (POMS)
Profile of Mood States (POMS) was used to look at total mood disturbance as well as the subscales of tension-anxiety, fatigue-inertia, and vigor-activity. The POMS is a well known, well validated, reliable measure of psychological distress which includes 6 subscales of fatigue-inertia, vigor-activity, tension-anxiety, depression-dejection, anger-hostility, and confusion-bewilderment. The entire scale can be scored to provide a measure of total mood disturbance. The measure contains adjectives related to mood which are scored from 0 (not at all) to 4 (extremely). Individual scores were converted to a 0-100 scale where 100 is best quality of life. The change of mood as measured by the POMS from baseline to treatment termination between flaxseed versus placebo arms was compared using Kruskal-Wallis test. The mean change in total score for each arm is reported.
Time frame: Baseline and up to 7 weeks
Population: Per protocol, the study was powered for 77 patients on each arm. With 20% over-accrual, the analysis began after 94 patients registered to each arm. 25 patients from Flaxseed were not used (4 cancel, 2 ineligible, 12 refused further treatment, 5 due to adverse events, 2 noncompliance). 17 from the placebo arm were not used (3,1,5,7,1 respective)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Flaxseed | Change of Mood as Measured by the Profile of Mood States (POMS) | 6.6 units on a scale | Standard Deviation 9.92 |
| Placebo | Change of Mood as Measured by the Profile of Mood States (POMS) | 5.7 units on a scale | Standard Deviation 9.41 |
p-value: 0.93Kruskal-Wallis
Secondary
Toxicity as Measured by CTCAE v3.0
Frequency and severity of adverse events were reported by patients weekly evaluated through clinical assessment by NCI CTCAE v3.0. The number of patients reporting grade 3 or higher events are reported in this outcome measure. For a full list of all events, please refer to the Adverse Events section of this report.
Time frame: Up to 7 weeks
Population: All patients treated during the Double-blinded period of the study were included in this analysis
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Flaxseed | Toxicity as Measured by CTCAE v3.0 | Grade 3+ Adverse Event | 0 Participants |
| Flaxseed | Toxicity as Measured by CTCAE v3.0 | Grade 4+ Adverse Event | 0 Participants |
| Placebo | Toxicity as Measured by CTCAE v3.0 | Grade 3+ Adverse Event | 1 Participants |
| Placebo | Toxicity as Measured by CTCAE v3.0 | Grade 4+ Adverse Event | 0 Participants |