- Email: [email protected]
Fluoxetine may reduce hot flashes in women with a history of breast cancer
TREATMENT
Fluoxetine may reduce hot flashes in women with a history of breast cancer Abstracted from: Loprinzi C, Sloan J, Perez E,Quella S, Stella P, Mailliard J, Halyard M, Pruthi S, Novotny P, RummansT. Phase III evaluation of £uoxetine for treatment of hot £ashes. J Clin Oncol 2002; 20: 1578^1583.
BACKGROUND Hormonal therapies may not be the best treatment for hot £ashes in women with a history of breast cancer because of possible tumorpromoting e¡ects. The value of non-hormonal anti-depressants such as £uoxetine (Prozac) remains uncertain. OBJECTIVE To examine the e⁄cacy of £uoxetine for hot £ashes in women with a history of breast cancer or high breast cancer risk.
reduction in placebo group). Bene¢ts held after crossover analysis (p = 0.02).
AUTHORS’ CONCLUSIONS There was a modest improvement in hot £ashes among women with a history of breast cancer treated with short-term £uoxetine.
METHOD NOTES SETTING Setting not reported; recruitment July 1998 to May 2000.
Power
METHOD Randomized cross-over trial. PARTICIPANTS Seventy-two women with a history of breast cancer or increased risk of breast cancer. All reported an average of at least 14 hot £ashes per week for a minimum of 1 month prior to study entry. There was no menopausal status requirement.Women receiving a stable dose of tamoxifen or raloxifene were eligible. Exclusion criteria were current malignant disease; anti-neoplastic chemotherapy; previous use of £uoxetine; use of other anti-depressants within 2 years, concurrent treatment for hot £ashes or treatment with androgens, coumadin, estrogens or progestational drugs. INTERVENTION Four weeks of 20 mg/day oral £uoxetine or placebo followed by a 4 week cross-over phase.
Blinding Allocation concealment Generation of allocation sequence Balanced groups
Analysis Other
With a sample size of 80, the study would have 80% power to detect a di¡erence of 1.3 hot £ashes per day using a two-sided test at the 5% level of signi¢cance.The study did not achieve planned power (n = 72) Adequate: Double blind Adequate Adequate Adequately balanced for age, duration of hot £ash symptoms, tamoxifen use and frequency of hot £ashes Intention to treat There was no washout period between the crossover phase of the trial
OUTCOMES Composite hot £ash frequency and hot £ash score (frequency average severity). Sources of funding: Notspeci¢ed.
182
MAIN RESULTS Fluoxetine was well tolerated. After 4 weeks, hot £ash scores were more likely to have reduced in the £uoxetine group (50% reduction vs 36%
Correspondenceto: Charles Loprinzi, Division of Medical Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, (E-mail: [email protected]).
Evidence-based Oncology (2002) 3,182^184 doi:10.1054/ebon.2002.0050, available online at http://www.idealibrary.com.on
1363 - 4054/02/$ - see front matter & 2002 Elsevier Science Ltd. All rights reserved
Commentary 1 Hot flashes are a significant problem for many postmenopausal women. Although estrogen relieves hot flashes, resulting in an 80% to 90% reduction, hormone replacement therapy is contraindicated in women with a history of breast cancer.Furthermore, hormone replacement may increase the risk of breast cancer and heart disease.1 Women may therefore seek alternatives to estrogen for menopausal symptoms. Lower doses of estrogen have been found to be as effective as conventional doses of hormone replacement therapy for relieving hot flashes.2 The long-term effects on breast cancer and cardiovascular disease risk remain unclear. Several alternatives to estrogen have been evaluated for treating hot flashes, including clonidine, progestins and phytoestrogens. Results are mixed. The effect of selective serotoninreuptake inhibitor antidepressants has also been assessed. Loprinzi and colleagues report on the largest randomized, placebo-controlled trial to date evaluating fluoxetine for hot flashes. The strength of the study is the cross-over design where each participant serves as her own control (thereby increasing the power of the study). Although fluoxetine was better at relieving hot flashes than placebo, the effect was modest (50% vs 36%).The significant placebo effect is typical of most hot flash studies. Complete data were only available for 68 participants, somewhat decreasing the power of the study. The authors used statistical approaches to handle missing data. They also controlled for potential confounding using linear model analysis and found that the effect of fluoxetine remained after adjusting for age and tamoxifen use. Venlafaxine is the most extensively studied antidepressant for relieving hot flashes. In a previous trial, the same study group found that venlafaxine (75 mg/day) reduced hot flashes by 60%,3 but was associated with increased adverse effects such as dry mouth, decreased appetite, nausea and constipation. In contrast, in this study fluoxetine was well tolerated. Fluoxetine appears to be as effective as venlafaxine and may have fewer adverse effects. A direct comparison is needed to assess this. The treatment effect of fluoxetine was evident within a few weeks. Longer-term studies are needed to evaluate the duration of the effect. Furthermore, the authors used a single dose of
fluoxetine. A dose-response trial is needed to examine whether 20 mg/day is the optimal dose of fluoxetine for relief of hot flashes. In conclusion, this study found that fluoxetine is an effective alternative to hormone replacement therapy for hot flashes in women who choose not to take estrogen or where hormones are contraindicated.The effect is modest and only slightly better than placebo, however.The search continues for an effective, safe alternative to estrogen.
Quality assessment (scale 1 = fair, 4 = excellent) Relevance Validity Applicability Feasibility Impact Knowledge context
3 3 3 3 2 2
Paula Amato MD Department of Obstetrics and Gynecology Baylor College of Medicine Texas, USA
Literature cited 1. Writing group for the Women’s Health Initiative investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002; 288: 321^333. 2. Utian WH, Shoupe D, Bachmann G, Pinkerton JV, Pickar JH. Relief of vasomotor symptoms and vaginal atrophy with lower doses of conjugated equine estrogens and medroxyprogesterone acetate. Fertil Steril 2001; 75: 1065^1079. 3. Loprinzi CL, Krugler JW, Sloan JA et al.Venlafaxine in management of hot flashes in survivors of breast cancer: a randomized controlled trial. Lancet 2000; 356: 2059^2063.
Evidence-based Oncology (2002) 3,182^184
183
Commentary 2 Hot flashes are a significant clinical problem for women with a history of breast cancer. Loprinzi and colleagues investigated the antidepressant fluoxetine (Prozac) for women with a history of breast cancer and women at high risk of breast cancer. The authors do not provide information about how many participants of each type were enrolled.This may be important as one cannot assume that the physiological mechanism of hot flashes is the same in healthy women as in women who have been treated for breast cancer. The choice of intervention is questionable for two reasons. First, no known or hypothesised mechanism of action is discussed. Physiologically, hot flashes occur as elevations in core body temperature within a reduced thermoregulatory null zone. They are most likely due to elevated central norepinephrine.1 Unlike venlafaxine, fluoxetine has not been shown to act on norepinephrine.2 These drugs are pharmacologically distinct and should not be expected to have the same effect on hot flashes. Second, fluoxetine is known to inhibit cytochrome P450 isoenzymes involved in the metabolism of tamoxifen and other medications.3,4 Fluoxetine may raise levels of tamoxifen and other medications and should be used with caution. The study design does not allow an adequate test of the study hypotheses. Positive findings may have been underestimated due to potential carryover effects.Fluoxetine and its metabolite, norfluoxetine, have relatively long half-lives of elimination: 4 to 6 days, and 4 to16 days respectively.5 The 4 week treatment period and no washout period may therefore be problematic. In contrast, positive findings may have been overestimated due to reliance on self-report measures of depressive symptoms and hot flashes. Beck Depression Inventory data indicate that a significant number of participants may have been clinically depressed.6 Objective measures of depression are routinely used in studies of antidepressants, however, none was included in this study to verify the Beck Depression Inventory scores. In addition, there may be problems with compliance and the accuracy of paper and pencil symptom diaries,7 particularly compared to objective measurement of hot flashes.8 Self-reported night-time hot flashes may have been under-reported by participants due to the sleeppromoting qualities of fluoxetine. Thus, the decrease in hot flashes shown over time may have been due to relief of depressive symptoms, improved sleep or decreasing compliance and accuracy in maintaining the daily diaries over time, rather than a physiological change in hot flashes.
184
Evidence-based Oncology (2002) 3,182^184
Non-hormonal treatments for hot flashes are needed for women with a history of breast cancer and those at high risk of developing breast cancer. Unfortunately, fluoxetine is not likely to be a feasible option for women in this group because of the high potential for drug interactions. Methodological limitations make the positive findings of this study questionable. Janet S Carpenter PhD, RN Assistant Professor School of Nursing and Research Deputy Director Vanderbilt University and the Vanderbilt-Ingram Comprehensive Cancer Center Nashville, USA
Literature cited 1. Freedman RR, Krell W. Reduced thermoregulatory null zone in postmenopausal women with hot flashes. Am J Obstet Gynecol 1999; 181: 66^70. 2. Sanchez C, Hyttel J. Comparison of the effects of antidepressants and their metabolites on reuptake of biogenic amines and on receptor binding. Cell Mol Neurobiol 1999; 19: 467^ 489. 3. Cheer SM, Goa KL. Fluoxetine: a review of its therapeutic potential in the treatment of depression associated with physical illness. Drugs 2001; 61: 81^110. 4. Crewe HK, Notley LM, Wunsch RM, Lennard MS, Gillam, EM. Metabolism of tamoxifen by recombinant human cytochrome P450 enzymes: formation of the 4 -hydroxy, 40-hydroxy and n-desmethyl metabolites and isomerization of trans- 4 -hydroxytamoxifen. Drub Metab Dispos 2002; 30: 869^ 874. 5. Medical Economics. Physician’s Desk Reference. US: Medical Economics Company, 2001. 6. Kathol RG, Mutgi A,Williams J,Clamon G, Noyes R. Diagnosis of major depression in cancer patients according to four sets of criteria. Am J Psychiatry 1990; 147: 1021^1024. 7. Stone AA, Shiffman S, Schwartz JE, Broderick JE, Hufford MR. Patient non-compliance with paper diaries. BMJ 2002; 324: 1193^1194. 8. Carpenter JS, Andrykowski MA, Freedman RR, Munn R. Feasibility and psychometrics of an ambulatory hot flash monitoring device. Menopause1999; 6: 209^215. Level and Quality of Evidence: 2b
Fluoxetine may reduce hot flashes in women with a history of breast cancer Abstracted from: Loprinzi C, Sloan J, Perez E,Quella S, Stella P, Mailliard J, Halyard M, Pruthi S, Novotny P, RummansT. Phase III evaluation of £uoxetine for treatment of hot £ashes. J Clin Oncol 2002; 20: 1578^1583.
BACKGROUND Hormonal therapies may not be the best treatment for hot £ashes in women with a history of breast cancer because of possible tumorpromoting e¡ects. The value of non-hormonal anti-depressants such as £uoxetine (Prozac) remains uncertain. OBJECTIVE To examine the e⁄cacy of £uoxetine for hot £ashes in women with a history of breast cancer or high breast cancer risk.
reduction in placebo group). Bene¢ts held after crossover analysis (p = 0.02).
AUTHORS’ CONCLUSIONS There was a modest improvement in hot £ashes among women with a history of breast cancer treated with short-term £uoxetine.
METHOD NOTES SETTING Setting not reported; recruitment July 1998 to May 2000.
Power
METHOD Randomized cross-over trial. PARTICIPANTS Seventy-two women with a history of breast cancer or increased risk of breast cancer. All reported an average of at least 14 hot £ashes per week for a minimum of 1 month prior to study entry. There was no menopausal status requirement.Women receiving a stable dose of tamoxifen or raloxifene were eligible. Exclusion criteria were current malignant disease; anti-neoplastic chemotherapy; previous use of £uoxetine; use of other anti-depressants within 2 years, concurrent treatment for hot £ashes or treatment with androgens, coumadin, estrogens or progestational drugs. INTERVENTION Four weeks of 20 mg/day oral £uoxetine or placebo followed by a 4 week cross-over phase.
Blinding Allocation concealment Generation of allocation sequence Balanced groups
Analysis Other
With a sample size of 80, the study would have 80% power to detect a di¡erence of 1.3 hot £ashes per day using a two-sided test at the 5% level of signi¢cance.The study did not achieve planned power (n = 72) Adequate: Double blind Adequate Adequate Adequately balanced for age, duration of hot £ash symptoms, tamoxifen use and frequency of hot £ashes Intention to treat There was no washout period between the crossover phase of the trial
OUTCOMES Composite hot £ash frequency and hot £ash score (frequency average severity). Sources of funding: Notspeci¢ed.
182
MAIN RESULTS Fluoxetine was well tolerated. After 4 weeks, hot £ash scores were more likely to have reduced in the £uoxetine group (50% reduction vs 36%
Correspondenceto: Charles Loprinzi, Division of Medical Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, (E-mail: [email protected]).
Evidence-based Oncology (2002) 3,182^184 doi:10.1054/ebon.2002.0050, available online at http://www.idealibrary.com.on
1363 - 4054/02/$ - see front matter & 2002 Elsevier Science Ltd. All rights reserved
Commentary 1 Hot flashes are a significant problem for many postmenopausal women. Although estrogen relieves hot flashes, resulting in an 80% to 90% reduction, hormone replacement therapy is contraindicated in women with a history of breast cancer.Furthermore, hormone replacement may increase the risk of breast cancer and heart disease.1 Women may therefore seek alternatives to estrogen for menopausal symptoms. Lower doses of estrogen have been found to be as effective as conventional doses of hormone replacement therapy for relieving hot flashes.2 The long-term effects on breast cancer and cardiovascular disease risk remain unclear. Several alternatives to estrogen have been evaluated for treating hot flashes, including clonidine, progestins and phytoestrogens. Results are mixed. The effect of selective serotoninreuptake inhibitor antidepressants has also been assessed. Loprinzi and colleagues report on the largest randomized, placebo-controlled trial to date evaluating fluoxetine for hot flashes. The strength of the study is the cross-over design where each participant serves as her own control (thereby increasing the power of the study). Although fluoxetine was better at relieving hot flashes than placebo, the effect was modest (50% vs 36%).The significant placebo effect is typical of most hot flash studies. Complete data were only available for 68 participants, somewhat decreasing the power of the study. The authors used statistical approaches to handle missing data. They also controlled for potential confounding using linear model analysis and found that the effect of fluoxetine remained after adjusting for age and tamoxifen use. Venlafaxine is the most extensively studied antidepressant for relieving hot flashes. In a previous trial, the same study group found that venlafaxine (75 mg/day) reduced hot flashes by 60%,3 but was associated with increased adverse effects such as dry mouth, decreased appetite, nausea and constipation. In contrast, in this study fluoxetine was well tolerated. Fluoxetine appears to be as effective as venlafaxine and may have fewer adverse effects. A direct comparison is needed to assess this. The treatment effect of fluoxetine was evident within a few weeks. Longer-term studies are needed to evaluate the duration of the effect. Furthermore, the authors used a single dose of
fluoxetine. A dose-response trial is needed to examine whether 20 mg/day is the optimal dose of fluoxetine for relief of hot flashes. In conclusion, this study found that fluoxetine is an effective alternative to hormone replacement therapy for hot flashes in women who choose not to take estrogen or where hormones are contraindicated.The effect is modest and only slightly better than placebo, however.The search continues for an effective, safe alternative to estrogen.
Quality assessment (scale 1 = fair, 4 = excellent) Relevance Validity Applicability Feasibility Impact Knowledge context
3 3 3 3 2 2
Paula Amato MD Department of Obstetrics and Gynecology Baylor College of Medicine Texas, USA
Literature cited 1. Writing group for the Women’s Health Initiative investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002; 288: 321^333. 2. Utian WH, Shoupe D, Bachmann G, Pinkerton JV, Pickar JH. Relief of vasomotor symptoms and vaginal atrophy with lower doses of conjugated equine estrogens and medroxyprogesterone acetate. Fertil Steril 2001; 75: 1065^1079. 3. Loprinzi CL, Krugler JW, Sloan JA et al.Venlafaxine in management of hot flashes in survivors of breast cancer: a randomized controlled trial. Lancet 2000; 356: 2059^2063.
Evidence-based Oncology (2002) 3,182^184
183
Commentary 2 Hot flashes are a significant clinical problem for women with a history of breast cancer. Loprinzi and colleagues investigated the antidepressant fluoxetine (Prozac) for women with a history of breast cancer and women at high risk of breast cancer. The authors do not provide information about how many participants of each type were enrolled.This may be important as one cannot assume that the physiological mechanism of hot flashes is the same in healthy women as in women who have been treated for breast cancer. The choice of intervention is questionable for two reasons. First, no known or hypothesised mechanism of action is discussed. Physiologically, hot flashes occur as elevations in core body temperature within a reduced thermoregulatory null zone. They are most likely due to elevated central norepinephrine.1 Unlike venlafaxine, fluoxetine has not been shown to act on norepinephrine.2 These drugs are pharmacologically distinct and should not be expected to have the same effect on hot flashes. Second, fluoxetine is known to inhibit cytochrome P450 isoenzymes involved in the metabolism of tamoxifen and other medications.3,4 Fluoxetine may raise levels of tamoxifen and other medications and should be used with caution. The study design does not allow an adequate test of the study hypotheses. Positive findings may have been underestimated due to potential carryover effects.Fluoxetine and its metabolite, norfluoxetine, have relatively long half-lives of elimination: 4 to 6 days, and 4 to16 days respectively.5 The 4 week treatment period and no washout period may therefore be problematic. In contrast, positive findings may have been overestimated due to reliance on self-report measures of depressive symptoms and hot flashes. Beck Depression Inventory data indicate that a significant number of participants may have been clinically depressed.6 Objective measures of depression are routinely used in studies of antidepressants, however, none was included in this study to verify the Beck Depression Inventory scores. In addition, there may be problems with compliance and the accuracy of paper and pencil symptom diaries,7 particularly compared to objective measurement of hot flashes.8 Self-reported night-time hot flashes may have been under-reported by participants due to the sleeppromoting qualities of fluoxetine. Thus, the decrease in hot flashes shown over time may have been due to relief of depressive symptoms, improved sleep or decreasing compliance and accuracy in maintaining the daily diaries over time, rather than a physiological change in hot flashes.
184
Evidence-based Oncology (2002) 3,182^184
Non-hormonal treatments for hot flashes are needed for women with a history of breast cancer and those at high risk of developing breast cancer. Unfortunately, fluoxetine is not likely to be a feasible option for women in this group because of the high potential for drug interactions. Methodological limitations make the positive findings of this study questionable. Janet S Carpenter PhD, RN Assistant Professor School of Nursing and Research Deputy Director Vanderbilt University and the Vanderbilt-Ingram Comprehensive Cancer Center Nashville, USA
Literature cited 1. Freedman RR, Krell W. Reduced thermoregulatory null zone in postmenopausal women with hot flashes. Am J Obstet Gynecol 1999; 181: 66^70. 2. Sanchez C, Hyttel J. Comparison of the effects of antidepressants and their metabolites on reuptake of biogenic amines and on receptor binding. Cell Mol Neurobiol 1999; 19: 467^ 489. 3. Cheer SM, Goa KL. Fluoxetine: a review of its therapeutic potential in the treatment of depression associated with physical illness. Drugs 2001; 61: 81^110. 4. Crewe HK, Notley LM, Wunsch RM, Lennard MS, Gillam, EM. Metabolism of tamoxifen by recombinant human cytochrome P450 enzymes: formation of the 4 -hydroxy, 40-hydroxy and n-desmethyl metabolites and isomerization of trans- 4 -hydroxytamoxifen. Drub Metab Dispos 2002; 30: 869^ 874. 5. Medical Economics. Physician’s Desk Reference. US: Medical Economics Company, 2001. 6. Kathol RG, Mutgi A,Williams J,Clamon G, Noyes R. Diagnosis of major depression in cancer patients according to four sets of criteria. Am J Psychiatry 1990; 147: 1021^1024. 7. Stone AA, Shiffman S, Schwartz JE, Broderick JE, Hufford MR. Patient non-compliance with paper diaries. BMJ 2002; 324: 1193^1194. 8. Carpenter JS, Andrykowski MA, Freedman RR, Munn R. Feasibility and psychometrics of an ambulatory hot flash monitoring device. Menopause1999; 6: 209^215. Level and Quality of Evidence: 2b