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A pilot trial assessing the efficacy of paroxetine hydrochloride (Paxil®) in controlling hot flashes in breast cancer survivors
Annals of Oncology 11: 17-22, 2000. © 2000 Kluwer Academic Publishers. Printed in the Netherlands.
Original article A pilot trial assessing the efficacy of paroxetine hydrochloride (Paxil®) in controlling hot flashes in breast cancer survivors V. Stearns,1 C. Isaacs,1 J. Rowland,2 J. Crawford,1 M. J. Ellis,1 R. Kramer,1 W. Lawrence,3 J. J. Hanfelt4 & D. F. Hayes1 'The Breast Cancer Program, Division of Hematoiogy/ Oncology, 2Department of Psychiatry, i Cancer Prevention and Control, Department ofBiomathematics and Biostatislics, Lombardi Cancer Center, Georgetown University School of Medicine, Washington, DC, USA
A
Results: Twenty-seven women completed the six-week study period. The mean reduction of hot flash frequency was 67% Background: Many breast cancer survivors suffer debilitating (95% confidence interval (95% CI): 56%-79%). The mean hot flashes. Estrogen, the drug of choice in perimenopausal reduction in hot flash severity score was 75% (95% CI: 66%women, is generally not recommenced to breast cancer 85%). There was a statistically significant improvement in survivors. Nonhormonal treatments are mostly disappointing. depression, sleep, anxiety, and quality of life scores. FurtherAnecdotal reports in our institution suggested that the selective more, 25 (83%) of the study participants chose to continue serotonin-reuptake inhibitor, paroxetine hydrochloride, might paroxetine therapy at the end of study. The most common adverse effect was somnolence, resulting in drug discontinuabe efficacious in alleviating hot flashes. Patients and methods: Thirty women with prior breast tion in two women, and dose reduction in two women. One cancer who were suffering at least two hotflashesa day entered woman discontinued drug due to anxiety. a single institution pilot trial to evaluate paroxetine's efficacy Conclusions: Paroxetine hydrochloride is a promising new in reducing the frequency and severity of hot flashes. After treatment for hot flashes in breast cancer survivors, and completing daily diaries for one week on no therapy, the warrants further evaluation in a double-blind randomized women received open-label paroxetine, 10 mg daily for one placebo-controlled trial. week, followed by four weeks of paroxetine, 20 mg daily. The women completed hot-flash daily diaries throughout the study period, and a health-related symptom-assessment questionnaire and a quality-of-life rating scale in the first and sixth Key words: breast cancer, hot flashes, paroxetine, serotonin week of the study. uptake inhibitors, survivors Summary
suitable to individual well-informed women with a prior breast cancer or in women at a high risk of developing Treatment of symptoms commonly encountered by breast the disease. However, this treatment is often avoided in cancer survivors and quality of life have become signifi- this group of women due to the association between cant and important considerations for medical oncolo- estrogen and breast cancer [4, 5]. In a randomized gists. Hot flashes represent one of the most prominent double-blind clinical trial, the progestin, megestrol acecomplaints, encountered by approximately 55% of breast tate, reduced hot flashes in cancer survivors by 85% as cancer survivors [1]. Hot flashes may be especially compared to a 21% reduction in a placebo-controlled prominent in young women in whom adjuvant chemo- group [6]. However, due to a theoretical concern that therapy induces early menopause. Hot flashes may also low-dose progestin might increase the risk of developing be of concern for postmenopausal women in whom a new breast cancer or a recurrence, this treatment is hormone replacement therapy is discontinued following not as widely used as would otherwise be. Several nona diagnosis of breast cancer. hormonal agents have been reported to reduce hot A hot flash is a transient sensation of heat with or flashes. These agents include Bellergal® (phenobarbital, without objective signs of skin vasodilation and is often ergotamine and belladonna), clonidine, vitamin E, and accompanied with varying degrees of sweating, flushing, soy supplementation. However, prospective randomized palpitations, anxiety, irritability, and even panic [2]. clinical trials have demonstrated that these agents are Other commonly co-existing symptoms, such as depres- only moderately more effective than placebo [7-10], and sion, nervousness, agitation, insomnia, and inability to are associated with a high toxicity profile [7, 8]. Thus, a concentrate, may exacerbate hot flashes. well-tolerated non-hormonal treatment for hot flashes Estrogen replacement is the drug of choice for hot would be of great value. flashes [3]. Estrogen replacement therapy might be Selective serotonin-reuptake inhibitors (SSRIs) are Introduction
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18 Table I. Patient characteristics (n = 30). Characteristics
Age <50 50-59 3=60 Time from diagnosis (months) < 12 12-35 3=36 Type of surgery Lumpectomy Mastectomy Prior chemotherapy Yes No Prior radiation therapy Yes No Menopause Premenopausal Postmenopausal Natural Chemotherapy-induced Hot flash daily average 2-4 5-9 3=10 Hot flash duration (months) ^3 4-6 7-11 3=12 Taking Tamoxifen Yes No Taking vitamin E Yes No
Number of patients
Mean (range)
8(27) 19(63) 3(10)
52 (37-69)
13(43) 11(37) 6(20)
26(3-216)
16(53) 14 (47)
Prior to initiating the study, each woman underwent a history and physical. Laboratory studies included serum bilirubin and creatinine within six weeks prior to starting therapy, and a serum pregnancy test for all premenopausal women within two weeks prior to starting therapy. The study was approved by the Georgetown University's Institutional Review Board and participants signed informed consent prior to enrollment.
19(63) 11(37) 17(57) 13(43) 3(10) 27 (90) 17(57) 10(33) 8(26) 11(37) 11(37)
evidence of detectable disease. To be included in the study, women must have had a history of at least 14 hot flashes per week, for a period of at least 1 month, an ECOG performance status of 0-2, and a life expectancy of greater than 6 months. Women taking Tamoxifen were permitted on the study, as long as they had been taking the drug for at least one month prior to enrollment. Participants were not allowed to receive other simultaneous treatment for hot flashes, and were required to have discontinued other putative therapies for hot flashes for at least one month prior to enrollment. Because most of the breast cancer patients seen in our institution take many vitamin preparations, vitamin E was allowed, provided it was used regularly for at least six weeks prior to enrollment in the study, and was continued throughout the study period. Women were not eligible if they were receiving simultaneous cytotoxic chemotherapy, hormonal therapy other than Tamoxifen, or antidepressants. Women who were pregnant or lactating, or with a known severe renal or hepatic impairment, were excluded.
Study design
8(2.1-21)
6(20) 5(17) 2(6) 17(57) 24 (80) 6(20)
Thirty eligible women were included in the pilot trial. Prior to initiation of the study drug, each woman completed a daily diary for one week, and filled out a baseline symptom-assessment questionnaire and a linear QOL rating scale (EuroQOL survey) Each woman was then administered open-label paroxetine 10 mg a day ('A a tablet) for seven days, to assess side effects, especially somnolence. Then, the study participant started daily therapy with paroxetine 20 mg (one tablet) for four weeks. Paroxetine tablets sufficient for the treatment of 30 patients were provided by SmithKline Beecham Pharmaceuticals. The women completed daily diaries during the five weeks of drug therapy and repeated a symptom-assessment questionnaire and QOL scale during the sixth and final week of study. After completion of six weeks of study, the women returned the daily diaries, questionnaires, and any unused tablets by mail.
22 (73) 8(27) Daily diaries
commonly prescribed for the treatment of depression. Anecdotal reports from our institution and others suggested that paroxetine hydrochloride (Paxil®, SmithKline Beecham Pharmaceuticals) and other SSRIs might be effective therapy for hotflashes.Based on our observation and the presumed physiology of hot flashes we initiated a single institution pilot study to evaluate whether paroxetine reduced the frequency and severity of hot flashes in breast cancer survivors. In a secondary analysis, we evaluated at baseline and at study end symptoms commonly associated with menopause. Specifically, we evaluated depression, sleep disruption, anxiety, sexual dysfunction, and overall quality of life (QOL).
Patients and methods Subjects Subjects eligible to participate in this pilot trial were women, 18 years or older, with a history of primary breast cancer who were without
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The daily diaries of hot flash frequency and severity, as developed and described previously [6, 8, 9], were used to document the number and severity (mild, moderate, severe, and very severe) of daily hot flashes for one week with no therapy (baseline) and throughout the five weeks of paroxetine therapy. In addition, the women documented presence or absence of four common adverse effects associated with paroxetine treatment (somnolence, dizziness, tremor, nausea). At the end of five weeks of treatment with the study drug, each woman was asked to assess whether she noted an overall subjective improvement in the hot flash symptoms, and whether she would like to continue the treatment.
Symptom-assessment questionnaire and quality of life scale The symptom-assessment questionnaire was used to assess symptoms that are commonly associated with menopause and potential adverse effects to paroxetine. The questionnaire included a modified symptom checklist, that was developed for use in the National Surgical Adjuvant Breast and Bowel Project (NSABP) and used for phase II of the Women's Health Study [11], the Center for Epidemiologic Studies Depression Scale (CES-D) [12], the Medical Outcomes Study (MOS) 9-Item Sleep Scale [13]. the 7-item anxiety sub-scale items from the Hospital Anxiety and Depression Scale (HADS), a self-assessment scale designed to detect depression and anxiety in the setting of a hospital medical outpatient clinic [14], and a 4-item scale of sexual function from the MOS [13]. To measure overall health-related QOL,
19 we used the format standardized in the EuroQOL survey, a self-rating scale that is reliable, valid, brief and easy to administer [15.16].
Statistical considerations The sample size of 30 patients provided 80% power (one-sided test; a = 0.05) to detect a 50% reduction in hot flashes at week 6. A planned comparison was made to the 20%-27% reduction in hot flash frequency and severity observed as a placebo effect in previous randomized trials of anti-hot flash therapy in similar patient populations [6, 8. 9]. The power calculation was based on the assumption that the percent reduction in hot flashes was approximately normally distributed with SD = 45% Box plots of the data indicated that the percent reduction in hot flashes (using the baseline week as a reference) was approximately normally distributed. Applying simple transformations to the endpoint (e.g., taking the logarithm or square root) was unhelpful, and actually worsened the normal approximation. A one-sample, two-tail /-test was conducted to determine whether the percent reduction in hot flashes at week 6 was significantly better than 27%. Severity of hot flash symptoms was an important endpoint. Weekly Severity Score was calculated as: 1 x (incidence count of 'mild' hot flashes experienced during one week) + 2 x ("moderate' hot flashes) + 3 x ('severe' hot flashes) + 4 x ('very severe' hot flashes) [6]. We computed the ratio of severity score at week 6 to severity score at baseline, and conducted a one-sample /-test to determine whether the mean reduction in severity score was greater than the expected placebo effect. Menopause-related symptoms and QOL data were analyzed in a similar manner. However, since some patients had baseline depression and anxiety scores of zero, it would have been inappropriate to use percentage change from baseline. Instead, the effect of paroxetine on QOL was based on the simple difference in score between week 6 and week 1. For symptoms that were dichotomous (present/absent), the change between baseline and week 6 was analyzed using McNemar's test. All tests were two-sided and /'-values less than 0.05 were considered statistically significant.
Figure I. Weekly summary of hot flash frequency in 27 patients completing the study: (a) average daily number of hot flash episodes; and (b) percent reduction compared to week 1 (baseline, prior to drug therapy). At each week, the horizontal line indicates the median value for the 27 patients, the shaded box indicates the range encompassing 50% of patients, whiskers indicate the range of more extreme values, and asterisks (when present) indicate outliers.
(P < 0.0001) [6, 8, 9]. In addition, of the 26 women who completed the trial and severity score questionnaires, the mean reduction in hot flash severity scores at week 6 Patients was 75% (95% CI: 66%-85%, Figure 2). Overall, of the 30 women included in the study, 22 women (73%) noted From November 1997, through June 1998, 30 eligible a greater than 50% reduction in hot flash severity scores. women entered the pilot trial. Twenty-seven women Furthermore, 25 (83%) of the women who entered the completed the six-week study and were evaluable for study chose to continue paroxetine therapy at the end of drug efficacy. Three women discontinued drug therapy the trial period. due to adverse effects. All 30 patients were evaluable for The sample size was too small to assess differences in safety and tolerability. The patients' characteristics are response among women who have undergone natural summarized in Table 1. Mean number of daily hot flashes versus chemotherapy-induced menopause, or among prior to treatment was 8 (range 2.1-21). Mean severity women who were on Tamoxifen therapy versus not. score prior to treatment was 134 (range 29-361). Nonetheless, there did not appear to be any obvious differences in these groups. Reduction of hot flashes Safety and tolerability Of the 27 women who completed the trial, the mean reduction of hotflashesat week six was 67% with a 95% Adverse effects were minimal and included mostly confidence interval (95% CI) of 56%-79% (Figure 1). Of somnolence (Table 2). Two patients discontinued drug the 30 women included in the study, 20 women (67%) therapy due to excessive somnolence following three reported a greater than 50% reduction in the average days, and seventeen days, respectively, of drug therapy. daily number of hot flashes. The mean reduction of hot One patient discontinued the drug following twenty-three flashes suggested a significant improvement over the days of therapy due to anxiety. Two patients decreased previously reported 20%-27% reduction in hot flashes their paroxetine dose to 10 mg due to somnolence seen as a placebo-effect in similar patient populations encountered on the higher dose. Results
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20 Table 2. Paroxetine hydrochloride adverse event profile at week 6 (« = 30). Adverse effect
Baseline (week 1), number of women (%)
Week 6, number of women (%)
Somnolence Dry mouth Nausea Dizziness Tremor Anxiety (subjective) Sexual dysfunction (subjective)
11 (37) 7(23) 6(20) 7(23) 4(10) NA a
18(60) 13(43) 9(30) 7(23) 4(10) 3(10)
NA a
3(10)
a
Subjective complaint, not included in initial questionnaire, thus, data not available. Table 3. Baseline and change in menopause-related symptoms and overall quality of life (n = 27 a ).
Figure 2 Weekly summary of hot flash severity score in 26 patients with non-missing severity data: (a) average daily score; and (b) percent reduction compared to week 1 (baseline, prior to drug therapy). For an explanation of boxplots, see Figure 1.
Symptom-assessment questionnaire and quality of life scale
Measure
Baseline Week 6 Mean change mean score mean score (95% CI) (range) (range)
P-value
Depression (CES-D) b
11.2 (0-37)
7 (0-28)
-4.2 (-0.7 to -7.6)
0.02
Sleep (MOS) b
40.9 (6.8-72.7)
26.3 (6.8-61.4)
-14.6 0.0002 (-6.4 to -22.8)
Anxiety (HADS) b
5 (0-13)
3.2 (0-9)
-1.8 (-0.9 to -2.7)
0.0005
Sexual function (MOS) a - b
34.8 (0-92)
40.6 (0-100)
5.8 (-5.6 to 17.2)
0.31
Quality of life (EuroQOL) c
80.5 (50-95)
86.4 (60 d -100)
5.9 (2.1 to 9.7)
0.004
a
Thirty women completed symptom assessment and QOL questionnaires at baseline and twenty-seven women completed the questionnaires during week 6. Overall, following five weeks of paroxetine therapy, there was an improvement in the five most common menopausal symptoms encountered by the women included in this study at baseline (short temper, forgetfulness, headaches, vaginal dryness, and difficulties concentrating). However, the differences in menopausal symptoms prior to and following paroxetine therapy were not statistically significant (data not shown). In addition, up to 18 (66%) of the women noted worsening of symptoms that could be contributed to paroxetine (somnolence, dry mouth, nausea, constipation, and decreased appetite). There was an improvement in depression, sleep, anxiety, and QOL measures (Table 3). At baseline, six (20%) women had CES-D scores consistent with a depressive state (2* 16), and two (7%) had HADS scores consistent with anxiety (Js 11). None of the three women who failed to complete the second set of questionnaires were depressed or anxious at baseline. Following five weeks of therapy, only two (7%) women had CES-D scores consistent with a depressive state, and none had HADS scores consistent with anxiety. At week 6, the mean improvement in depression, anxiety, and sleep scores was 4.2 (95% CI: 0.7-7.6), 1.8 (95% CI: 0.9-2.7),
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b c d
n = 27 for all measures, except for sexual function, n = 17. Higher scores represent a worse function. 0-100 scale, a score of 100 represents best function. Related to disease recurrence, next lowest QOL score was 75.
and 14.6 (95% CI: 6.4-22.8), respectively. The mean improvement in QOL score was 5.9 (95% CI: 2.1-9.7). The effect of paroxetine was significantly different from zero for all four measures (depression, P = 0.02; anxiety, P = 0.0005; sleep, P = 0.0002; QOL, P = 0.004). Only 17 (57%) women completed the sexual function scale. The effect of paroxetine on sexual function was inconclusive perhaps due to the minimal effect in this domain or the smaller number of women reporting on function.
Discussion In this study, we observed a substantial reduction in hot flashes following five weeks of treatment with paroxetine hydrochloride (Paxil®) in a group of women with a previous diagnosis of breast cancer. Although this was a pilot study, the 67% reduction in hot flash frequency we observed appears superior to the 20-27% reduction observed with placebo in other trials [6, 8, 9]. This large difference suggests that the beneficial effects in the trial were not due to placebo-effect.
21 Paroxetine was generally well tolerated with the most commonly reported adverse effect being somnolence. An improvement in menopausal symptoms, depression, anxiety, and sleep was seen in most of the women. Moreover, there was a substantial improvement in median scores of QOL. The physiology of hot flashes is probably related to dysfunction of the thermoregulation set point [2]. Investigators have suggested that estrogen-withdrawal results in decreased levels of brain amines, such as serotonin [17]. This hypothesis might explain why estrogen withdrawal is associated not only with hot flashes, but also with alterations in sleep, anxiety and mood. Other investigators have demonstrated that blood levels of serotonin are diminished in menopausal women [18]. Moreover, estrogen replacement therapy appears to augment serotonergic activity [19]. The beneficial results observed in our study are consistent with the theory that SSRIs might be an effective therapy for hot flashes and associated perimenopausal symptoms. Recently, other investigators have reported results of a pilot evaluation of the SSRI venlafaxine hydrochloride in breast cancer survivors and in men on androgenblockade [20]. These results are markedly similar to our observations. The authors reported that 55% of the subjects included in the study had a greater than 50% reduction in hot flash frequency and 58% had a greater than 50% reduction in hot flash severity scores. However, both studies are pilot trials, and are limited by small sample size and lack of a concomitant placebo arm. This pilot trial cannot answer questions related to the optimal dose of treatment. For example, many of the study participants noted an almost immediate reduction in the frequency and severity of their hot flashes. It is therefore possible that a dose of paroxetine 10 mg daily might be sufficient in alleviating hot flashes. Also, it is possible that women who did not respond to the standard antidepressant dose of 20 mg might benefit from an increased paroxetine dose. The pilot study was not sufficiently powered to detect differences in benefit between various subgroups, such as women who suffered long versus short duration of hot flashes, younger or older women. Moreover, the pilot study does not have sufficient power to detect differences in improvement of hot flashes in women who are on Tamoxifen therapy versus these who were not, or in women who underwent natural menopause as compared to chemotherapy-induced menopause. Finally, optimal duration of treatment was also not established. Many women who suffer severe hot flashes immediately following menopause might experience an improvement over time without therapy. Of interest in this study is the large number of women who continued medication at the end of the study. In summary, the data from this pilot trial strongly suggest that paroxetine hydrochloride is an effective therapy for hot flashes in breast cancer survivors. We are now conducting a prospective randomized clinical trial to determine the effectiveness of paroxetine hydrochloride in reducing hot flashes as compared to placebo.
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Acknowledgements The trial was supported in part and Paroxetine hydrochloride (Paxil®) tablets were provided by SmithKline Beecham Pharmaceuticals. The authors wish to thank Dr C. Loprinzi for his advice and assistance. We thank the following investigators for enrolling their patients in the trial: Drs S. Baidas, C. Berg, P. Cohen, W. Dahut, E. Early, E. Gelmann, R. Kurstin, M. Lippman, T. Tsangaris, Ms A. Galassi and Mr R. Shrout. The authors would also like to thank the Fashion Footwear Association of New York/Shoes on Sale for their generous support of the study.
References 1. Ganz PA, Rowland JH, Desmond K et al Life after breast cancer: Understanding women's health-related quality of life and sexual functioning. J Clin Oncol 1998; 16: 501-14. 2. Kronenberg F. Hot flashes: Phenomenology, quality of life, and search for treatment options. Exp Gerontol 1994; 29: 319-36. 3. Halbreich U. Role of estrogen in postmenopausal depression. Neurology 1997; 48: S16-9. 4. Hormone replacement therapy. Clinical synthesis panel on HRT [published erratum appears in Lancet 1999; 354 (9181): 870]. Lancet 1999; 354: 152-5. 5. Chlebowski RT, McTiernan A. Elements of informed consent for hormone replacement therapy in patients with diagnosed breast cancer. J Clin Oncol 1999; 17: 130-42 6. Loprinzi CL, Michalak JC, Quella SK et al. Megestrol acetate for the prevention of hot flashes. N Engl J Med 1994; 331: 34752. 7. Lebherz TB, French L. Nonhormonal treatment of the menopausal syndrome A double-blind evaluation of an autonomic system stabilizer. Obstet Gynecol 1969; 33: 795-9. 8. Goldberg RM, Loprinzi CL, O'Fallon JR et al. Transdermal clonidine for ameliorating Tamoxifen-induced hot flashes (published erratum appears in J Clin Oncol 1996; 14 (8): 2411). J Clin Oncol 1994; 12: 155-8. 9. Barton DL, Loprinzi CL, Quella SK et al. Prospective evaluation of vitamin E for hot flashes in breast cancer survivors. J Clin Oncol 1998; 16: 495-500. 10. Albertazzi P, Pansini F, Bonaccorsi G et al. The effect of dietary soy supplementation on hot flushes. Obstet Gynecol 1998; 91: 6-11. 11. Day R, Ganz PA, Costantino JP et al. Health related quality of life and Tamoxifen in breast cancer prevention: A report from the national surgical adjuvant breast and bowel project P-l study. J Clin Oncol 1999; 17: 2659-69. 12. Radloff LS. The CES-D scale: A self-report depression scale for research in the general population. Appl Psychol Measurment 1977; 1: 385-401. 13. In Stewart AL, Ware JE (eds): Measuring Functioning and WellBeing: The Medical Outcomes Study Approach. Durham, NC: Duke University Press 1992. 14. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand 1983; 67: 361-70. 15. Froberg DG, Kane RL. Methodology for measuring health-state preferences. I: Measurement strategies. J Clin Epidemiol 1989; 42: 345-54. 16. Kind P. The EuroQOL instrument: An index of health-related quality of life. In Spilker B (ed): Quality of Life and Pharmacoeconomics in Clinical Trials. Philadelphia, PA: Lippincott-Raven 1996.
22 17. Shaver JL. Beyond hormonal therapies in menopause. Exp Gerontol 1994; 29: 469-76. 18. Gonzales GF, Carrillo C. Blood serotonin levels in postmenopausal women: Effects of age and serum oestradiol levels. Maturitas 1993; 17: 23-9. 19. Young RL, Kumar NS, Goldzieher JW. Management of menopause when estrogen cannot be used. Drugs 1990; 40: 220-30. 20. Loprinzi CL, Pisansky TM, Fonseca R et al. Pilot evaluation of venlafaxine hydrochloride for the therapy of hot flashes in cancer survivors. J Clin Oncol 1998; 16: 2377-81.
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Received 6 September 1999; accepted 10 November 1999. Correspondence to: D. F. Hayes, MD Research Building, Room E504 Georgetown University 3970 Reservoir Rd., N.W. Washington, DC 20007 USA E-mail: [email protected]
Original article A pilot trial assessing the efficacy of paroxetine hydrochloride (Paxil®) in controlling hot flashes in breast cancer survivors V. Stearns,1 C. Isaacs,1 J. Rowland,2 J. Crawford,1 M. J. Ellis,1 R. Kramer,1 W. Lawrence,3 J. J. Hanfelt4 & D. F. Hayes1 'The Breast Cancer Program, Division of Hematoiogy/ Oncology, 2Department of Psychiatry, i Cancer Prevention and Control, Department ofBiomathematics and Biostatislics, Lombardi Cancer Center, Georgetown University School of Medicine, Washington, DC, USA
A
Results: Twenty-seven women completed the six-week study period. The mean reduction of hot flash frequency was 67% Background: Many breast cancer survivors suffer debilitating (95% confidence interval (95% CI): 56%-79%). The mean hot flashes. Estrogen, the drug of choice in perimenopausal reduction in hot flash severity score was 75% (95% CI: 66%women, is generally not recommenced to breast cancer 85%). There was a statistically significant improvement in survivors. Nonhormonal treatments are mostly disappointing. depression, sleep, anxiety, and quality of life scores. FurtherAnecdotal reports in our institution suggested that the selective more, 25 (83%) of the study participants chose to continue serotonin-reuptake inhibitor, paroxetine hydrochloride, might paroxetine therapy at the end of study. The most common adverse effect was somnolence, resulting in drug discontinuabe efficacious in alleviating hot flashes. Patients and methods: Thirty women with prior breast tion in two women, and dose reduction in two women. One cancer who were suffering at least two hotflashesa day entered woman discontinued drug due to anxiety. a single institution pilot trial to evaluate paroxetine's efficacy Conclusions: Paroxetine hydrochloride is a promising new in reducing the frequency and severity of hot flashes. After treatment for hot flashes in breast cancer survivors, and completing daily diaries for one week on no therapy, the warrants further evaluation in a double-blind randomized women received open-label paroxetine, 10 mg daily for one placebo-controlled trial. week, followed by four weeks of paroxetine, 20 mg daily. The women completed hot-flash daily diaries throughout the study period, and a health-related symptom-assessment questionnaire and a quality-of-life rating scale in the first and sixth Key words: breast cancer, hot flashes, paroxetine, serotonin week of the study. uptake inhibitors, survivors Summary
suitable to individual well-informed women with a prior breast cancer or in women at a high risk of developing Treatment of symptoms commonly encountered by breast the disease. However, this treatment is often avoided in cancer survivors and quality of life have become signifi- this group of women due to the association between cant and important considerations for medical oncolo- estrogen and breast cancer [4, 5]. In a randomized gists. Hot flashes represent one of the most prominent double-blind clinical trial, the progestin, megestrol acecomplaints, encountered by approximately 55% of breast tate, reduced hot flashes in cancer survivors by 85% as cancer survivors [1]. Hot flashes may be especially compared to a 21% reduction in a placebo-controlled prominent in young women in whom adjuvant chemo- group [6]. However, due to a theoretical concern that therapy induces early menopause. Hot flashes may also low-dose progestin might increase the risk of developing be of concern for postmenopausal women in whom a new breast cancer or a recurrence, this treatment is hormone replacement therapy is discontinued following not as widely used as would otherwise be. Several nona diagnosis of breast cancer. hormonal agents have been reported to reduce hot A hot flash is a transient sensation of heat with or flashes. These agents include Bellergal® (phenobarbital, without objective signs of skin vasodilation and is often ergotamine and belladonna), clonidine, vitamin E, and accompanied with varying degrees of sweating, flushing, soy supplementation. However, prospective randomized palpitations, anxiety, irritability, and even panic [2]. clinical trials have demonstrated that these agents are Other commonly co-existing symptoms, such as depres- only moderately more effective than placebo [7-10], and sion, nervousness, agitation, insomnia, and inability to are associated with a high toxicity profile [7, 8]. Thus, a concentrate, may exacerbate hot flashes. well-tolerated non-hormonal treatment for hot flashes Estrogen replacement is the drug of choice for hot would be of great value. flashes [3]. Estrogen replacement therapy might be Selective serotonin-reuptake inhibitors (SSRIs) are Introduction
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18 Table I. Patient characteristics (n = 30). Characteristics
Age <50 50-59 3=60 Time from diagnosis (months) < 12 12-35 3=36 Type of surgery Lumpectomy Mastectomy Prior chemotherapy Yes No Prior radiation therapy Yes No Menopause Premenopausal Postmenopausal Natural Chemotherapy-induced Hot flash daily average 2-4 5-9 3=10 Hot flash duration (months) ^3 4-6 7-11 3=12 Taking Tamoxifen Yes No Taking vitamin E Yes No
Number of patients
Mean (range)
8(27) 19(63) 3(10)
52 (37-69)
13(43) 11(37) 6(20)
26(3-216)
16(53) 14 (47)
Prior to initiating the study, each woman underwent a history and physical. Laboratory studies included serum bilirubin and creatinine within six weeks prior to starting therapy, and a serum pregnancy test for all premenopausal women within two weeks prior to starting therapy. The study was approved by the Georgetown University's Institutional Review Board and participants signed informed consent prior to enrollment.
19(63) 11(37) 17(57) 13(43) 3(10) 27 (90) 17(57) 10(33) 8(26) 11(37) 11(37)
evidence of detectable disease. To be included in the study, women must have had a history of at least 14 hot flashes per week, for a period of at least 1 month, an ECOG performance status of 0-2, and a life expectancy of greater than 6 months. Women taking Tamoxifen were permitted on the study, as long as they had been taking the drug for at least one month prior to enrollment. Participants were not allowed to receive other simultaneous treatment for hot flashes, and were required to have discontinued other putative therapies for hot flashes for at least one month prior to enrollment. Because most of the breast cancer patients seen in our institution take many vitamin preparations, vitamin E was allowed, provided it was used regularly for at least six weeks prior to enrollment in the study, and was continued throughout the study period. Women were not eligible if they were receiving simultaneous cytotoxic chemotherapy, hormonal therapy other than Tamoxifen, or antidepressants. Women who were pregnant or lactating, or with a known severe renal or hepatic impairment, were excluded.
Study design
8(2.1-21)
6(20) 5(17) 2(6) 17(57) 24 (80) 6(20)
Thirty eligible women were included in the pilot trial. Prior to initiation of the study drug, each woman completed a daily diary for one week, and filled out a baseline symptom-assessment questionnaire and a linear QOL rating scale (EuroQOL survey) Each woman was then administered open-label paroxetine 10 mg a day ('A a tablet) for seven days, to assess side effects, especially somnolence. Then, the study participant started daily therapy with paroxetine 20 mg (one tablet) for four weeks. Paroxetine tablets sufficient for the treatment of 30 patients were provided by SmithKline Beecham Pharmaceuticals. The women completed daily diaries during the five weeks of drug therapy and repeated a symptom-assessment questionnaire and QOL scale during the sixth and final week of study. After completion of six weeks of study, the women returned the daily diaries, questionnaires, and any unused tablets by mail.
22 (73) 8(27) Daily diaries
commonly prescribed for the treatment of depression. Anecdotal reports from our institution and others suggested that paroxetine hydrochloride (Paxil®, SmithKline Beecham Pharmaceuticals) and other SSRIs might be effective therapy for hotflashes.Based on our observation and the presumed physiology of hot flashes we initiated a single institution pilot study to evaluate whether paroxetine reduced the frequency and severity of hot flashes in breast cancer survivors. In a secondary analysis, we evaluated at baseline and at study end symptoms commonly associated with menopause. Specifically, we evaluated depression, sleep disruption, anxiety, sexual dysfunction, and overall quality of life (QOL).
Patients and methods Subjects Subjects eligible to participate in this pilot trial were women, 18 years or older, with a history of primary breast cancer who were without
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The daily diaries of hot flash frequency and severity, as developed and described previously [6, 8, 9], were used to document the number and severity (mild, moderate, severe, and very severe) of daily hot flashes for one week with no therapy (baseline) and throughout the five weeks of paroxetine therapy. In addition, the women documented presence or absence of four common adverse effects associated with paroxetine treatment (somnolence, dizziness, tremor, nausea). At the end of five weeks of treatment with the study drug, each woman was asked to assess whether she noted an overall subjective improvement in the hot flash symptoms, and whether she would like to continue the treatment.
Symptom-assessment questionnaire and quality of life scale The symptom-assessment questionnaire was used to assess symptoms that are commonly associated with menopause and potential adverse effects to paroxetine. The questionnaire included a modified symptom checklist, that was developed for use in the National Surgical Adjuvant Breast and Bowel Project (NSABP) and used for phase II of the Women's Health Study [11], the Center for Epidemiologic Studies Depression Scale (CES-D) [12], the Medical Outcomes Study (MOS) 9-Item Sleep Scale [13]. the 7-item anxiety sub-scale items from the Hospital Anxiety and Depression Scale (HADS), a self-assessment scale designed to detect depression and anxiety in the setting of a hospital medical outpatient clinic [14], and a 4-item scale of sexual function from the MOS [13]. To measure overall health-related QOL,
19 we used the format standardized in the EuroQOL survey, a self-rating scale that is reliable, valid, brief and easy to administer [15.16].
Statistical considerations The sample size of 30 patients provided 80% power (one-sided test; a = 0.05) to detect a 50% reduction in hot flashes at week 6. A planned comparison was made to the 20%-27% reduction in hot flash frequency and severity observed as a placebo effect in previous randomized trials of anti-hot flash therapy in similar patient populations [6, 8. 9]. The power calculation was based on the assumption that the percent reduction in hot flashes was approximately normally distributed with SD = 45% Box plots of the data indicated that the percent reduction in hot flashes (using the baseline week as a reference) was approximately normally distributed. Applying simple transformations to the endpoint (e.g., taking the logarithm or square root) was unhelpful, and actually worsened the normal approximation. A one-sample, two-tail /-test was conducted to determine whether the percent reduction in hot flashes at week 6 was significantly better than 27%. Severity of hot flash symptoms was an important endpoint. Weekly Severity Score was calculated as: 1 x (incidence count of 'mild' hot flashes experienced during one week) + 2 x ("moderate' hot flashes) + 3 x ('severe' hot flashes) + 4 x ('very severe' hot flashes) [6]. We computed the ratio of severity score at week 6 to severity score at baseline, and conducted a one-sample /-test to determine whether the mean reduction in severity score was greater than the expected placebo effect. Menopause-related symptoms and QOL data were analyzed in a similar manner. However, since some patients had baseline depression and anxiety scores of zero, it would have been inappropriate to use percentage change from baseline. Instead, the effect of paroxetine on QOL was based on the simple difference in score between week 6 and week 1. For symptoms that were dichotomous (present/absent), the change between baseline and week 6 was analyzed using McNemar's test. All tests were two-sided and /'-values less than 0.05 were considered statistically significant.
Figure I. Weekly summary of hot flash frequency in 27 patients completing the study: (a) average daily number of hot flash episodes; and (b) percent reduction compared to week 1 (baseline, prior to drug therapy). At each week, the horizontal line indicates the median value for the 27 patients, the shaded box indicates the range encompassing 50% of patients, whiskers indicate the range of more extreme values, and asterisks (when present) indicate outliers.
(P < 0.0001) [6, 8, 9]. In addition, of the 26 women who completed the trial and severity score questionnaires, the mean reduction in hot flash severity scores at week 6 Patients was 75% (95% CI: 66%-85%, Figure 2). Overall, of the 30 women included in the study, 22 women (73%) noted From November 1997, through June 1998, 30 eligible a greater than 50% reduction in hot flash severity scores. women entered the pilot trial. Twenty-seven women Furthermore, 25 (83%) of the women who entered the completed the six-week study and were evaluable for study chose to continue paroxetine therapy at the end of drug efficacy. Three women discontinued drug therapy the trial period. due to adverse effects. All 30 patients were evaluable for The sample size was too small to assess differences in safety and tolerability. The patients' characteristics are response among women who have undergone natural summarized in Table 1. Mean number of daily hot flashes versus chemotherapy-induced menopause, or among prior to treatment was 8 (range 2.1-21). Mean severity women who were on Tamoxifen therapy versus not. score prior to treatment was 134 (range 29-361). Nonetheless, there did not appear to be any obvious differences in these groups. Reduction of hot flashes Safety and tolerability Of the 27 women who completed the trial, the mean reduction of hotflashesat week six was 67% with a 95% Adverse effects were minimal and included mostly confidence interval (95% CI) of 56%-79% (Figure 1). Of somnolence (Table 2). Two patients discontinued drug the 30 women included in the study, 20 women (67%) therapy due to excessive somnolence following three reported a greater than 50% reduction in the average days, and seventeen days, respectively, of drug therapy. daily number of hot flashes. The mean reduction of hot One patient discontinued the drug following twenty-three flashes suggested a significant improvement over the days of therapy due to anxiety. Two patients decreased previously reported 20%-27% reduction in hot flashes their paroxetine dose to 10 mg due to somnolence seen as a placebo-effect in similar patient populations encountered on the higher dose. Results
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20 Table 2. Paroxetine hydrochloride adverse event profile at week 6 (« = 30). Adverse effect
Baseline (week 1), number of women (%)
Week 6, number of women (%)
Somnolence Dry mouth Nausea Dizziness Tremor Anxiety (subjective) Sexual dysfunction (subjective)
11 (37) 7(23) 6(20) 7(23) 4(10) NA a
18(60) 13(43) 9(30) 7(23) 4(10) 3(10)
NA a
3(10)
a
Subjective complaint, not included in initial questionnaire, thus, data not available. Table 3. Baseline and change in menopause-related symptoms and overall quality of life (n = 27 a ).
Figure 2 Weekly summary of hot flash severity score in 26 patients with non-missing severity data: (a) average daily score; and (b) percent reduction compared to week 1 (baseline, prior to drug therapy). For an explanation of boxplots, see Figure 1.
Symptom-assessment questionnaire and quality of life scale
Measure
Baseline Week 6 Mean change mean score mean score (95% CI) (range) (range)
P-value
Depression (CES-D) b
11.2 (0-37)
7 (0-28)
-4.2 (-0.7 to -7.6)
0.02
Sleep (MOS) b
40.9 (6.8-72.7)
26.3 (6.8-61.4)
-14.6 0.0002 (-6.4 to -22.8)
Anxiety (HADS) b
5 (0-13)
3.2 (0-9)
-1.8 (-0.9 to -2.7)
0.0005
Sexual function (MOS) a - b
34.8 (0-92)
40.6 (0-100)
5.8 (-5.6 to 17.2)
0.31
Quality of life (EuroQOL) c
80.5 (50-95)
86.4 (60 d -100)
5.9 (2.1 to 9.7)
0.004
a
Thirty women completed symptom assessment and QOL questionnaires at baseline and twenty-seven women completed the questionnaires during week 6. Overall, following five weeks of paroxetine therapy, there was an improvement in the five most common menopausal symptoms encountered by the women included in this study at baseline (short temper, forgetfulness, headaches, vaginal dryness, and difficulties concentrating). However, the differences in menopausal symptoms prior to and following paroxetine therapy were not statistically significant (data not shown). In addition, up to 18 (66%) of the women noted worsening of symptoms that could be contributed to paroxetine (somnolence, dry mouth, nausea, constipation, and decreased appetite). There was an improvement in depression, sleep, anxiety, and QOL measures (Table 3). At baseline, six (20%) women had CES-D scores consistent with a depressive state (2* 16), and two (7%) had HADS scores consistent with anxiety (Js 11). None of the three women who failed to complete the second set of questionnaires were depressed or anxious at baseline. Following five weeks of therapy, only two (7%) women had CES-D scores consistent with a depressive state, and none had HADS scores consistent with anxiety. At week 6, the mean improvement in depression, anxiety, and sleep scores was 4.2 (95% CI: 0.7-7.6), 1.8 (95% CI: 0.9-2.7),
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b c d
n = 27 for all measures, except for sexual function, n = 17. Higher scores represent a worse function. 0-100 scale, a score of 100 represents best function. Related to disease recurrence, next lowest QOL score was 75.
and 14.6 (95% CI: 6.4-22.8), respectively. The mean improvement in QOL score was 5.9 (95% CI: 2.1-9.7). The effect of paroxetine was significantly different from zero for all four measures (depression, P = 0.02; anxiety, P = 0.0005; sleep, P = 0.0002; QOL, P = 0.004). Only 17 (57%) women completed the sexual function scale. The effect of paroxetine on sexual function was inconclusive perhaps due to the minimal effect in this domain or the smaller number of women reporting on function.
Discussion In this study, we observed a substantial reduction in hot flashes following five weeks of treatment with paroxetine hydrochloride (Paxil®) in a group of women with a previous diagnosis of breast cancer. Although this was a pilot study, the 67% reduction in hot flash frequency we observed appears superior to the 20-27% reduction observed with placebo in other trials [6, 8, 9]. This large difference suggests that the beneficial effects in the trial were not due to placebo-effect.
21 Paroxetine was generally well tolerated with the most commonly reported adverse effect being somnolence. An improvement in menopausal symptoms, depression, anxiety, and sleep was seen in most of the women. Moreover, there was a substantial improvement in median scores of QOL. The physiology of hot flashes is probably related to dysfunction of the thermoregulation set point [2]. Investigators have suggested that estrogen-withdrawal results in decreased levels of brain amines, such as serotonin [17]. This hypothesis might explain why estrogen withdrawal is associated not only with hot flashes, but also with alterations in sleep, anxiety and mood. Other investigators have demonstrated that blood levels of serotonin are diminished in menopausal women [18]. Moreover, estrogen replacement therapy appears to augment serotonergic activity [19]. The beneficial results observed in our study are consistent with the theory that SSRIs might be an effective therapy for hot flashes and associated perimenopausal symptoms. Recently, other investigators have reported results of a pilot evaluation of the SSRI venlafaxine hydrochloride in breast cancer survivors and in men on androgenblockade [20]. These results are markedly similar to our observations. The authors reported that 55% of the subjects included in the study had a greater than 50% reduction in hot flash frequency and 58% had a greater than 50% reduction in hot flash severity scores. However, both studies are pilot trials, and are limited by small sample size and lack of a concomitant placebo arm. This pilot trial cannot answer questions related to the optimal dose of treatment. For example, many of the study participants noted an almost immediate reduction in the frequency and severity of their hot flashes. It is therefore possible that a dose of paroxetine 10 mg daily might be sufficient in alleviating hot flashes. Also, it is possible that women who did not respond to the standard antidepressant dose of 20 mg might benefit from an increased paroxetine dose. The pilot study was not sufficiently powered to detect differences in benefit between various subgroups, such as women who suffered long versus short duration of hot flashes, younger or older women. Moreover, the pilot study does not have sufficient power to detect differences in improvement of hot flashes in women who are on Tamoxifen therapy versus these who were not, or in women who underwent natural menopause as compared to chemotherapy-induced menopause. Finally, optimal duration of treatment was also not established. Many women who suffer severe hot flashes immediately following menopause might experience an improvement over time without therapy. Of interest in this study is the large number of women who continued medication at the end of the study. In summary, the data from this pilot trial strongly suggest that paroxetine hydrochloride is an effective therapy for hot flashes in breast cancer survivors. We are now conducting a prospective randomized clinical trial to determine the effectiveness of paroxetine hydrochloride in reducing hot flashes as compared to placebo.
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Acknowledgements The trial was supported in part and Paroxetine hydrochloride (Paxil®) tablets were provided by SmithKline Beecham Pharmaceuticals. The authors wish to thank Dr C. Loprinzi for his advice and assistance. We thank the following investigators for enrolling their patients in the trial: Drs S. Baidas, C. Berg, P. Cohen, W. Dahut, E. Early, E. Gelmann, R. Kurstin, M. Lippman, T. Tsangaris, Ms A. Galassi and Mr R. Shrout. The authors would also like to thank the Fashion Footwear Association of New York/Shoes on Sale for their generous support of the study.
References 1. Ganz PA, Rowland JH, Desmond K et al Life after breast cancer: Understanding women's health-related quality of life and sexual functioning. J Clin Oncol 1998; 16: 501-14. 2. Kronenberg F. Hot flashes: Phenomenology, quality of life, and search for treatment options. Exp Gerontol 1994; 29: 319-36. 3. Halbreich U. Role of estrogen in postmenopausal depression. Neurology 1997; 48: S16-9. 4. Hormone replacement therapy. Clinical synthesis panel on HRT [published erratum appears in Lancet 1999; 354 (9181): 870]. Lancet 1999; 354: 152-5. 5. Chlebowski RT, McTiernan A. Elements of informed consent for hormone replacement therapy in patients with diagnosed breast cancer. J Clin Oncol 1999; 17: 130-42 6. Loprinzi CL, Michalak JC, Quella SK et al. Megestrol acetate for the prevention of hot flashes. N Engl J Med 1994; 331: 34752. 7. Lebherz TB, French L. Nonhormonal treatment of the menopausal syndrome A double-blind evaluation of an autonomic system stabilizer. Obstet Gynecol 1969; 33: 795-9. 8. Goldberg RM, Loprinzi CL, O'Fallon JR et al. Transdermal clonidine for ameliorating Tamoxifen-induced hot flashes (published erratum appears in J Clin Oncol 1996; 14 (8): 2411). J Clin Oncol 1994; 12: 155-8. 9. Barton DL, Loprinzi CL, Quella SK et al. Prospective evaluation of vitamin E for hot flashes in breast cancer survivors. J Clin Oncol 1998; 16: 495-500. 10. Albertazzi P, Pansini F, Bonaccorsi G et al. The effect of dietary soy supplementation on hot flushes. Obstet Gynecol 1998; 91: 6-11. 11. Day R, Ganz PA, Costantino JP et al. Health related quality of life and Tamoxifen in breast cancer prevention: A report from the national surgical adjuvant breast and bowel project P-l study. J Clin Oncol 1999; 17: 2659-69. 12. Radloff LS. The CES-D scale: A self-report depression scale for research in the general population. Appl Psychol Measurment 1977; 1: 385-401. 13. In Stewart AL, Ware JE (eds): Measuring Functioning and WellBeing: The Medical Outcomes Study Approach. Durham, NC: Duke University Press 1992. 14. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand 1983; 67: 361-70. 15. Froberg DG, Kane RL. Methodology for measuring health-state preferences. I: Measurement strategies. J Clin Epidemiol 1989; 42: 345-54. 16. Kind P. The EuroQOL instrument: An index of health-related quality of life. In Spilker B (ed): Quality of Life and Pharmacoeconomics in Clinical Trials. Philadelphia, PA: Lippincott-Raven 1996.
22 17. Shaver JL. Beyond hormonal therapies in menopause. Exp Gerontol 1994; 29: 469-76. 18. Gonzales GF, Carrillo C. Blood serotonin levels in postmenopausal women: Effects of age and serum oestradiol levels. Maturitas 1993; 17: 23-9. 19. Young RL, Kumar NS, Goldzieher JW. Management of menopause when estrogen cannot be used. Drugs 1990; 40: 220-30. 20. Loprinzi CL, Pisansky TM, Fonseca R et al. Pilot evaluation of venlafaxine hydrochloride for the therapy of hot flashes in cancer survivors. J Clin Oncol 1998; 16: 2377-81.
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Received 6 September 1999; accepted 10 November 1999. Correspondence to: D. F. Hayes, MD Research Building, Room E504 Georgetown University 3970 Reservoir Rd., N.W. Washington, DC 20007 USA E-mail: [email protected]