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Phase III Evaluation of Fluoxetine for Treatment of Hot Flashes

Mayo Clinic and Foundation, Rochester, MN; Mayo Clinic and Foundation, Jacksonville, FL; McAuley Cancer Care Center, Ann Arbor, MI; Creighton Cancer Center, Omaha, NE; and Mayo Clinic and Foundation, Scottsdale, AZ.

Address reprint requests to Charles L. Loprinzi, MD, Division of Medical Oncology, Mayo Clinic, 200 First St SW, Rochester, MN 55905; email: cloprinzi{at}mayo.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: Hot flashes can be a prominent problem in women with a history of breast cancer. Given concerns regarding the use of hormonal therapies in such patients, other nonhormonal means for treating hot flashes are required. Based on anecdotal information regarding the efficacy of fluoxetine and other newer antidepressants for treating hot flashes, the present trial was developed.

PATIENTS AND METHODS: This trial used a double-blinded, randomized, two-period (4 weeks per period), cross-over methodology to study the efficacy of fluoxetine (20 mg/d) for treating hot flashes in women with a history of breast cancer or a concern regarding the use of estrogen (because of breast cancer risk). Eligible patients had to have reported that they averaged at least 14 hot flashes per week; they could have received tamoxifen or raloxifene as long as they were on a stable dose. The major outcome measure was a bivariate construct representing hot flash frequency and hot flash score, analyzed by a classic sums and differences cross-over analysis.

RESULTS: Eighty-one randomized women began protocol therapy. By the end of the first treatment period, hot flash scores (frequency x average severity) decreased 50% in the fluoxetine arm versus 36% in the placebo arm. Cross-over analysis demonstrated a significantly greater marked hot flash score improvement with fluoxetine than placebo (P = .02). The results were not adjusted for potential confounding influences, including age and tamoxifen use. The fluoxetine was well tolerated.

CONCLUSION: This dose of fluoxetine resulted in a modest improvement in hot flashes.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
HOT FLASHES ARE A major clinical problem for many women as they enter menopause and also for men who have undergone androgen deprivation therapy for prostate cancer. Because estrogen and androgens are often contraindicated in patients with cancer, other methods for alleviating this prominent clinical problem are required.

Pursuant to this problem, our group became interested in finding other means for alleviating hot flashes in the late 1980s. Initial work evaluated clonidine, demonstrating that this drug does decrease hot flashes to a moderate degree but also carries with it a number of toxicities.¹ Next, the progestational drug, megestrol acetate, demonstrated an 80% reduction of hot flashes compared with a 20% reduction with a placebo.²

Related to our interest in providing new therapies for hot flashes, in late 1992, we were approached with a clinical story of a patient who had a dramatic improvement in her hot flashes with the use of fluoxetine (Prozac; Eli Lilly and Company, Indianapolis, IN). This led to discussions with psychiatric colleagues and other colleagues as to whether there was any known evidence of fluoxetine acting on hot flashes. These discussions did not produce any leads. Therefore, the idea was documented and shelved.

Subsequently, information became available that another of the newer antidepressants, venlafaxine, seemed to alleviate hot flashes. Pilot experience with this drug revealed promising results.³ Pursuant to this, this current placebo-controlled, double-blind, cross-over clinical trial was developed to formally assess the efficacy of fluoxetine for the treatment of hot flashes.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patients considered for this study were women with a history of breast cancer or a perceived increased risk of breast cancer. All patients were without current evidence of malignant disease. They must have had a history of bothersome hot flashes (at least 14 per week) that were of sufficient severity for the patient to desire therapeutic intervention. The hot flashes must have been present for at least 1 month before study entry. There was no requirement that a patient had to fulfill any certain menopausal status criteria. Patients were not allowed to be receiving antineoplastic chemotherapy, androgens, estrogens, progestational drugs, or coumadin. Concomitant therapy with tamoxifen or raloxifene was allowed as long as the patient had been on such therapy for at least 1 month and was planning to continue on such therapy for the duration of the study. Previous use of fluoxetine was not allowed, nor was the use of any other antidepressants for 2 years before study entry. Patients were not allowed to be receiving any other substances for the treatment of hot flashes, nor was such allowed during the study period.

After eligibility determination, patients were stratified on the basis of age ( 49 v 50 years), current use of tamoxifen (or not), duration of their hot flash symptoms (< 9 months v 9 months), and their average estimated frequency of hot flashes (two to three, four to nine, or 10 hot flashes per day) using a dynamic allocation procedure that balances the marginal distributions.^4,5 All patients were required to give written informed consent as dictated by federal guidelines (and approved by an institutional review board). After randomization, patients were asked to complete a daily hot flash diary for 1 week without the use of any study medication. Then they received 4 weeks of therapy with fluoxetine (20 mg/d orally) versus an identical-appearing placebo. For the next 4 weeks, patients were crossed over to the alternative treatment arm. All treatment arms were double blind.

Patients were asked to complete a daily hot flash diary for all 9 weeks of the study. In addition to requesting information about hot flashes on a daily basis, these questionnaires also asked about toxicity (by both a checklist and an open-ended question) on a weekly basis. These hot flash diary forms have been validated in previous trials, as outlined in another article.⁶ In addition, patients completed the Beck Depression Inventory (BDI) and a uniscale global quality-of-life (QOL) instrument when they entered the study and at the completion of each of the 4-week treatment periods.^7,8 Patients were also contacted by a study nurse at each of these times to address questions and to assure compliance to the study medications and diaries. At the completion of the 9-week study period, patients were asked which study period they felt was best with regard to resolution of their hot flashes.

Statistical Considerations
Analysis methods for the data in the present study were similar to those used for previous North Central Cancer Treatment Group two-period, two-treatment, placebo-controlled, cross-over trials. Analytic procedures used on these studies have been compiled into a specialized computer algorithm by the Mayo Clinic Cancer Center Statistics Unit for use in cross-over studies.⁹ These routines have recently been augmented by inclusion of a Bayesian modeling approach involving Markov Chain Monte Carlo procedures and Gibbs sampling.¹¹ For the sake of brevity, only some of the pertinent results from this series of algorithms will be presented. Results for all approaches were consistent for this study in terms of the overall conclusion regarding the efficacy of fluoxetine in reducing hot flash activity.

The primary end point for this study was a bivariate construct representing hot flash frequency (the number of hot flashes reported per day) and a hot flash score. The hot flash score was calculated by scoring each individual hot flash (ie, one point for a mild hot flash, two points for a moderate hot flash, three points for a severe hot flash, and four points for a very severe hot flash) and then multiplying the average score for a day times the hot flash frequency for that day.

The average values for the hot flash score and the hot flash frequency were calculated for each treatment period for input into a classical cross-over sums and differences analysis.¹² Two-sample t tests, or the Wilcoxon rank sum test, were used depending on the measurement level and normality of the data. The sums and differences approach was supplemented by an approach using the intrapatient difference of hot flash activity between the two periods as a dependent variable in a linear model.¹³ The analyses were run using data from all 4 weeks in each treatment period, using only the last week in each period to assess the sensitivity of the results relative to the achievement of a steady-state level of hot flash activity by the fourth week of each treatment period. All treatment comparisons were made using two-sided testing and a 5% type I error rate.

Secondary end points included the incidence of each toxicity reported in each treatment period. The analyses of these variables were the same as that for the primary end point. Another end point included the proportion of patients who reported a preference for fluoxetine or placebo. These data were analyzed using a simple ² test. Linear models and logistic regression models were used to verify that the results for the primary analysis were consistent in the presence of concomitant potentially confounding variables (age, tamoxifen use, and so on). Missing data were handled in a number of ways as a sensitivity analysis of the robustness of results relative to the missing data.¹³ First, only complete cases were used in the analysis (patients completing all 8 weeks of treatment). Subsequently, analyses using all available data were run. Finally, a series of analyses using various imputation methods (average value carried forward, last value carried forward, and minimum or maximum value carried forward) was carried out to assess the impact of missing data on the results. The amount of missing data in this study was small, and the results were consistent across the various approaches.

Data from previous studies produced an estimate for the SD of the differences in hot flash frequency and score between baseline and the end of the first treatment period (two hot flashes and 5 score units per patient per day). Forty patients per group provides an 80% power to detect the differences in average hot flash activity (SD, 0.65) via a standard two-sample t test using a two-sided type I error rate of 5%, which is a moderate effect size.¹⁴ Hence, we had 80% power to detect an average shift of 1.3 hot flashes per day or a score of 3 units per day. Power for the cross-over design linear model approach was greater than these specifications because each patient served as her own control. In essence, each power specification effect size above could be divided by the square root of 2 (1.414) to get the appropriate effect sizes for the linear model hypothesis testing.¹⁴ In addition, toxicity incidence comparisons via standard ² testing had 80% power to detect a difference of 28% between the fluoxetine and placebo groups.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Between July 1998 and May 2000, a total of 87 women were entered onto this clinical trial. Six patients canceled study participation before taking any study medication. Of the 81 remaining patients, 72 provided baseline hot flash data, whereas nine patients (five placebo and four fluoxetine) did not provide these data. Of these 72 patients, 68 (84% of the 81 patients who entered onto the study and started the protocol drug therapy) provided data for the first 5-week study period (baseline week plus 4 weeks of their initial randomized study medication), whereas four (one placebo and three fluoxetine) did not. Two additional patients dropped out during the second (cross-over) 4-week period and did not provide cross-over data. One of these patients initially was on fluoxetine and refused cross-over; the other patient (on placebo initially) stopped protocol participation because her husband was quite ill.

Table 1 lists the baseline characteristics of patients in the two treatment sequences, demonstrating a balance among the important demographic factors. Table 2 lists the baseline hot flash activity data. Changes in hot flash scores throughout the study are illustrated in Fig 1. Table 3 lists the distribution of patients whose hot flash activity decreased by varying amounts over the first treatment period. Eleven percent of patients reported that hot flash scores dropped at least 75% while receiving placebo compared with 24% while receiving fluoxetine. However, more patients on fluoxetine had an increase in their hot flashes greater than baseline (23% v 27%). Similar results were reported for hot flash frequencies. Median hot flash frequency dropped by 3.4 hot flashes per day (42%) for patients while receiving fluoxetine and by 2.5 hot flashes per day (31%) while patients were receiving placebo in the first treatment period, respectively (P = .54). Hot flash scores decreased by a median of 4.7 units per day (36%) for those on placebo in the first treatment period and by 6.4 units per day (50%) while receiving fluoxetine (P = .35). Subsequent analysis of the cross-over data indicated that patients reported median improved reductions of 1.5 hot flashes per day (19%) and 3.1 score units per day (24%) on fluoxetine compared with that seen with the placebo (P = .01 and .02, respectively). Cross-over analyses also demonstrated that mean hot flash severity values were improved on the fluoxetine versus placebo periods (0.1 units, P = .055). A subsequent linear model analysis validated the superiority of fluoxetine over placebo, even when adjusted for potential confounding influences of baseline depression score, shift in depression score, tamoxifen use, age, and so on. Results from a further alternative Bayesian model were consistent with these findings.

View larger version (14K): [in this window] [in a new window]   Fig 1. Mean hot flash score changes from baseline for the two study arms.

When asked, after the 9 weeks and while still blinded to the study arm, which treatment period was more efficacious, 21 patients (47%) thought the fluoxetine period was superior, 10 (22%) thought the placebo period was superior, and 14 (31%) could not tell (P = .14).

Over half (54%) of the patients reported depressive symptoms of at least mild severity at baseline, as categorized by the BDI, compared with only 30% of patients after the first treatment period and 21% after the second treatment period. BDI changes from baseline scores are illustrated in Fig 2, showing a trend for lower scores (ie, fewer depressive symptoms) reported by patients while on fluoxetine (cross-over P value of .08). After the first treatment period, 39% of the patients receiving placebo and 32% of the patients receiving fluoxetine reported BDI scores consistent with at least mild depression (P = .55). After the second treatment period, 26% of patients on placebo and 18% of patients on fluoxetine reported BDI scores consistent with at least mild depression (P = .42).

View larger version (14K): [in this window] [in a new window]   Fig 2. Mean BDI changes from baseline for the two study arms.

Overall baseline QOL, as recorded by a single-item global score, averaged 91 on a 0- to 100-point scale. When patients were asked the degree to which hot flashes affected their baseline QOL, the average was 29 on the same point scale (zero = no affect and 100 = as bad an effect as possible). After 5 weeks of treatment, fluoxetine and placebo groups differed by only one point on the global QOL score (P = .51) and eight points on the degree of hot flash effect on QOL (P = .54), with the fluoxetine group showing the greater, albeit modest, improvement in both variables. After cross-over, global QOL and hot flash-related QOL showed a relative improvement trend for fluoxetine over placebo by 4 and 3 points, respectively (P = .07 and .23, respectively).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
The results from this study support our prestudy hypothesis that fluoxetine does reduce hot flashes. However, the size of the effect seems modest. The information from this trial compliments data derived from other trials that were initiated to examine the utility of newer antidepressants for alleviating hot flashes. To date, the most extensively studied of these drugs is venlafaxine. A pilot trial reported an approximate 50% reduction in hot flashes in both women with breast cancer and men receiving androgen deprivation therapy for prostate cancer.³ A subsequent four-arm, dose-seeking, placebo-controlled clinical trial was performed.¹⁵ This trial revealed that a 75-mg/d dose of venlafaxine seemed optimal for treating hot flashes, leading to a hot flash score reduction of approximately 60% from baseline compared with a 27% reduction seen with a matched placebo. It is not clear how an optional dose of fluoxetine would compare with the optional dose of venlafaxine because a dose-seeking trial of fluoxetine has not been performed. Interestingly, the 75-mg/d dose of venlafaxine seemed to be better than both smaller and larger doses of fluoxetine for efficacy and toxicity issues.¹⁵

Data regarding the exact menopausal status in individual patients were not collected on this clinical trial because it was assumed that the women were acting postmenopausal because they were having hot flashes. Whereas it could be hypothesized that the menopausal status of patients might have modified the interpretation of the study results, we are unaware of any available data to confirm or deny this contention. In fact, because we did not note any influence of patient age on the efficacy of fluoxetine, it could be argued that the actual menopausal status of our patients did not influence our study results.

Similar to past experiences with other anti–hot flash drugs,^2,6,15 we did not see any differential effects on the basis of whether patients were receiving tamoxifen or not. Raloxifene was not clinically available when we initiated this clinical trial, so we did not stratify for this. When it became available, we modified the protocol to allow such patients to enter this study as long as they were on a stable dose of raloxifene for at least 4 weeks and planned to continue it during the 9-week study period. Although we did not specifically collect information on whether patients on this trial were receiving raloxifene, based on clinical practice at the time of this study, it is estimated that less than 5% to 10% of patients on this trial were receiving raloxifene. It is extremely unlikely that raloxifene use would bias study results because: (1) the randomization process should have allocated raloxifene users relatively equally to the two study arms, (2) the main analysis was done with patients crossing over to the alternative substance (fluoxetine v placebo), (3) the effect of raloxifene for causing hot flashes seems to be less than that seen with tamoxifen, and (4) similar results were seen in this trial in women who were, versus were not, taking tamoxifen.

A pilot trial of paroxetine, another of the newer antidepressants, has also reported reductions in hot flashes.¹⁶ A placebo-controlled, dose-seeking trial is currently underway to further evaluate this drug for treating hot flashes. In addition, a placebo-controlled trial is being conducted for sertraline. There are anecdotal reports suggesting that several of the newer antidepressants may also reduce hot flashes. A number of trials are ongoing to further evaluate these drugs.

One might ask whether 4 weeks of time is a reasonable period to observe patients for hot flashes. In response, this 4-week period was chosen approximately a decade ago, and it has been used in a series of clinical trials evaluating medications for alleviating hot flashes in patients with breast cancer.^1-3,9,15,16 Our experience with the related medication, venlafaxine, illustrated that the effect on hot flashes occurred over the first week or two after initiation of this drug.¹⁵ Figure 1 also illustrates that the reduction in hot flashes seems to plateau after 3 weeks of therapy. Thus, we have no evidence that a longer duration of fluoxetine would likely cause a further reduction in hot flashes.

The mechanism of action of these newer antidepressants is not clear. It does not seem that these drugs are acting through hormonal (eg, estrogen, progesterone, or androgen) pathways. Presumably, the effects are central and are related to alterations of dopamine, serotonin, or norepinephrine pathways. Further delineation regarding which of the antidepressants help hot flashes may help sort out which of these pathways is most likely to be related their causation and resolution.

Usually when a scientific question is answered, the door is opened for multiple additional questions. In this situation, we have now provided an answer for the question of whether the newer antidepressants can decrease hot flashes. That answer is definitely yes. The resultant questions are many, some of which are: How will these different antidepressants compare with each other? How well will the best of these antidepressants compare with the use of either estrogen or progesterone for alleviating hot flashes? Is there cross-resistance to the hot flash reduction seen with these different antidepressants (eg, will one antidepressant work when another has not worked)? Is there cross-resistance between estrogen or progesterone therapy versus these antidepressants? What is the duration of benefit for these patients? It is hoped that answers to these questions will become more apparent in the near future as ongoing and future studies come to fruition.

To conclude, it is now apparent that the newer classes of antidepressants can inhibit hot flashes in patients. This provides a realistic alternative therapy for patients who do not wish to receive hormones for fear of cancer issues or other reasons. The use of these drugs is already becoming a part of standard clinical practice at many sites. Watch for more as this field develops.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
1. Goldberg RM, Loprinzi CL, O’Fallon JR, et al: Transdermal clonidine for ameliorating tamoxifen-induced hot flashes. J Clin Oncol 12: 155-158, 1994[Abstract]

2. Loprinzi CL, Michalak JC, Quella SK, et al: Megestrol acetate for the prevention of hot flashes. N Engl J Med 331: 347-352, 1994[Abstract/Free Full Text]

3. 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 16: 2377-2381, 1998[Abstract]

4. Pocock SJ, Simon R: Sequential treatment assignment with balancing for prognostic factors in the controlled clinical. Biometrics 31: 103-115, 1975[CrossRef][Medline]

5. Therneau TM: How many stratification factors are "too many" to use in a randomization plan? Control Clin Trials 14: 98-108, 1993[CrossRef][Medline]

6. Sloan JA, Loprinzi CL, Novotny PJ, et al: Methodologic lessons learned from hot flash studies. J Clin Oncol 19: 4280-4290, 2001[Abstract/Free Full Text]

7. Beck AT, Steer RA, Garbin MG: Psychometric properties of the Beck Depression Inventory: Twenty-five years of evaluation. Clin Psychol Rev 8: 77-100, 1988

8. Williamson HA, Williamson MT: The Beck Depression Inventory: Normative data and problems with generalizability. Fam Med 21: 58-60, 1989[Medline]

9. Barton DL, Loprinzi CL, Quella SK, et al: Prospective evaluation of vitamin E for hot flashes in breast cancer survivors. J Clin Oncol 16: 495-500, 1998[Abstract]

10. Sloan JA, Novotny P, Loprinzi CL, et al: Graphical and analytical tools for two-period crossover clinical trials. Proc SUGI 22: 1312-1317, 1997

11. Mandrekar J, Sargent DJ, Novotny PJ, et al: A general Gibbs sampling algorithm for analyzing linear models using the SAS system. Proc SUGI 23: 1312-1318, 1998

12. Senn S: Cross-Over Trials in Clinical Research. New York, NY, John Wiley & Sons Ltd, 1993

13. Troxel AB, Fairclough DL, Curran D, et al: Statistical analysis of quality of life with missing data in cancer clinical trials. Stat Med 17: 653-666, 1998[CrossRef][Medline]

14. Cohen J: Statistical Power Analysis for the Behavioral Sciences. Hillsdale, NJ, Lawrence Erlbaum Assoc, 1988

15. Loprinzi CL, Kugler JW, Sloan JA, et al: Venlafaxine in management of hot flashes in survivors of breast cancer: A randomised controlled trial. Lancet 356: 2059-2063, 2000[CrossRef][Medline]

16. Stearns V, Isaacs C, Rowland J, et al: A pilot trial assessing the efficacy of paroxetine hydrochloride (Paxil) in controlling hot flashes in breast cancer survivors. Ann Oncol 11: 17-22, 2000[Abstract/Free Full Text]

Submitted March 6, 2001; accepted November 29, 2001.

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