cacy of venlafaxine, medroxyprogesterone acetate, and
cyproterone acetate for the treatment of vasomotor hot
fl ushes in men taking gonadotropin-releasing hormone
analogues for prostate cancer: a double-blind,
randomised trial

Jacques Irani, Laurent Salomon, Rostand Oba, Philippe Bouchard, Nicolas Mottet Summary
Background Hot fl ushes are the most common complaints reported by men undergoing androgen suppression
Published Online
treatment for prostate cancer. We designed a randomised double-blind trial to compare the effi
cacy of three drugs, December 7, 2009
each of which has proven eff ective for preventing hot fl ushes in previous studies.
See Online/Refl ection and
Methods Men with prostate cancer with an indication for androgen suppression were enrolled in the study at Reaction
106 urology centres in France between April 14, 2004, and April 20, 2007. All patients were treated for 6 months with DOI:10.1016/S1470-
leuprorelin (11·25 mg). At month 6, patients who spontaneously asked for treatment, or those who presented with 2045(09)70349-3
14 hot fl ushes or more during the week before the visit, were randomly assigned to either venlafaxine 75 mg daily, Urology Unit, University
medroxyprogesterone acetate 20 mg daily, or cyproterone acetate 100 mg daily. All patients received two Hospital, Poitiers, France

(Prof J Irani MD); Urology Unit,
indistinguishable pills in the morning and one in the evening from week 1 to week 8, and one indistinguishable pill University Hospital, Créteil,
in the morning from week 9 to week 10, to comply with the double-blind design. Random assignment with a block France (Prof L Salomon MD);
size of three was done centrally, by fax, and each patient was given a randomisation number. The allocation sequence Medical Department, Takeda
was stratifi ed by centre. Assessment was done at inclusion, at randomisation, and then at 4 weeks, 8 weeks, and Laboratories, Puteaux, France

(R Oba MSc); Endocrinology
12 weeks after randomisation. Participants completed a daily hot-fl ush diary for 1 week, and a quality of life Unit, Saint Antoine University
questionnaire before each visit throughout the study. The primary outcome was the change in median daily hot-fl ush Hospital, Paris, France
score between randomisation and 1 month. All patients who received at least one study treatment dose were included (Prof P Bouchard MD); and
in the effi

cacy analysis. This trial is registered with, number NCT01011751.
Urology Unit, Clinique
Mutualiste, Saint Etienne,
(N Mottet MD)
Findings Of the 919 men initially enrolled, 311 were randomly assigned to one of the study treatments at 6 months: Correspondence to:
102 to venlafaxine, 101 to cyproterone, and 108 to medroxyprogesterone. 309 patients were included in the effi
cacy Prof Jacques Irani, Urology Unit,
analysis, since two were excluded for protocol deviations (one in the cyproterone and one in the medroxyprogesterone University Hospital, 2 rue de la
group; both were excluded because they were already undergoing treatment with serotonin reuptake inhibitor Miletrie, 86 000 Poitiers, France
[email protected]
antidepressants at randomisation). The change in median daily hot-fl ush score between randomisation and 1 month
was –47·2% (IQR –74·3 to –2·5) in the venlafaxine group, –94·5% (–100·0 to –74·5) in the cyproterone group, and
–83·7% (–98·9 to –64·3) in the medroxyprogesterone group. The decrease from baseline was signifi cant for all three
groups (p<0·0001). Pairwise comparison of treatment groups adjusted by the Bonferroni method confi rmed that the
decreases in hot-fl ush score were signifi cantly larger in the cyproterone and medroxyprogesterone groups than in
the venlafaxine group, regardless of the interval considered (p<0·0001 in all cases). There was no signifi cant diff erence
between the cyproterone and medroxyprogesterone groups (p>0·2 in all cases). Serious side-eff ects occurred in four,
seven, and fi ve patients in the venlafaxine, cyproterone, and medroxyprogesterone groups, respectively, of which
none, one (dyspnoea), and one (urticaria) were considered related to the drug, respectively.

Interpretation After 6 months of treatment with leuprorelin, venlafaxine, cyproterone, and medroxyprogesterone
proved to be eff ective in reducing hot fl ushes. However, the hormonal treatments cyproterone and medroxyprogesterone
were signifi cantly more eff ective than venlafaxine. As cyproterone is a recognised treatment in prostate cancer, and its
use could interfere with hormonal therapy, medroxyprogesterone could be considered to be the standard treatment
for hot fl ushes in men undergoing androgen suppression for prostate cancer.

Funding Takeda Laboratories, Puteaux, France.
using gonadotropin-releasing hormone (GnRH) Androgen suppression is the most common treatment analogues.1 Leuprorelin, like most GnRH analogues, is for advanced prostate cancer, and can be achieved administered subcutaneously two to four times a year surgically or, as is most common in the west, by blockade depending on the injected dose, and this schedule is Published online December 7, 2009 DOI:10.1016/S1470-2045(09)70338-9
associated with a good tolerance of the treatment. fl ushes, more than half report a signifi cant eff ect on their However, side-eff ects related to androgen depletion are quality of life.4,5inevitable, the most frequent of which are erectile Most treatments for hot fl ushes have been assessed in dysfunction and the occurrence of hot fl ushes.
postmenopausal women being treated for breast cancer. Hot fl ushes are characterised by a subjective sensation Apart from non-medical treatments, the effi of a rise in temperature in the face and trunk and by the has not been shown in prospective trials,6–8 the currently occurrence of a cutaneous vasodilatation predominantly available therapeutic options can be divided into hormonal on the face, throat, and extremities, usually followed by and non-hormonal treatments. Low-dose oestrogens have profuse sweating. Hot fl ushes fi rst occur a few months proven to be eff ective in women, but side-eff ects such as after the onset of GnRH agonist treatment, and each raised frequency of cardiovascular events and potential episode usually lasts less than 5 min. The patho- prostate tumour growth or gynaecomastia are highly physiological mechanism of hot fl ushes is now well undesirable in men.9 Hormonal treatment can also be defi ned: the steep decline in the serum level of sexual achieved with steroidal anti-androgens.10,11 Cyproterone hormones, following treatment with a GnRH agonist, acetate is probably the steroidal anti-androgen used most leads to the release of hypothalamic catecholamine, widely in Europe, with a reasonable effi particularly norepinephrine, that fl ood the thermo- profi le. Progestagens, such as megestrol acetate or regulation centre located in the upper hypothalamus. medroxyprogesterone, have also been shown to be eff ective This results in an abnormal and poorly regulated in men treated for prostate cancer.7,12 Amongst peripheral vasodilatation and the occurrence of hot non-hormonal treatments, the most commonly used are fl ushes followed by perspiration.2 selective serotonin-re-uptake inhibitor antidepressants Up to 80% of patients undergoing treatment with such as venlafaxine, which although mainly investigated GnRH analogues report hot fl ushes, and up to 27% in women13 has also been investigated in men.14–16report hot fl ushes as being the most troublesome side- To our knowledge, head-to-head comparisons between eff ect of treatment.3 Among patients who suff er from hot treatments have not been made in men treated with Figure 1: Trial profi le
*10 disease progression; 11 adverse events; 8 deaths; 24 cases of non-compliance; 26 refusals to continue; 4 other. Published online December 7, 2009 DOI:10.1016/S1470-2045(09)70338-9
androgen-suppression therapy for prostate cancer. We Venlafaxine
therefore designed a multicentre, randomised, double- group(N=102)
group (N=100)
group (N=107)
cyproterone acetate, and medroxyprogesterone acetate, for the treatment of hot fl ushes in patients with prostate cancer who were being treated with GnRH analogues.
Patients were enrolled from 106 urology centres in France between April 14, 2004, and April 20, 2007. Eligible patients Total number of hot fl ushes in the week had to have histologically confi rmed prostatic adeno- preceding randomisation visit (mean [SD]) carcinoma with localised or locally advanced disease, a Karnofsky index score of 70% or more, and could not have received any hormonal therapy. The inclusion criteria were extended to patients with metastatic disease following an amendment soon after the beginning of the study. Patients treated with drugs related to the study Table 1: Characteristics at randomisation according to treatment group
medications (such as selective serotonin-re-uptake inhibitors and steroid hormones) or that were potentially eff ective for the treatment of hot fl ushes (clonidine, each visit, patients had to complete daily self-evaluation gabapentine, veralipride, or β-alanine) were not included questionnaires—the Mayo Clinic hot-fl ush diary,17 in the study. Other exclusion criteria were contraindications which is a validated symptom-measuring tool used to to any of the study drugs (mainly corticosteroids and assess the frequency and severity grade of hot fl ushes. monoamine oxidase inhibitors), diabetes, severe kidney, Based on the defi nitions we provided them, patients liver, and cardiovascular disease, and psychiatric had to categorise the severity of their hot fl ushes as progressive disease. A history of thromboembolism was mild (less than 3 min, light physical symptoms, no also a criterion for exclusion. The trial was approved by emotional symptoms and no action needed), moderate the ethics committee of the coordinating centre, and (up to 5 min, moderate physical symptoms, mild regulatory bodies in all participating centres. All patients anxiety, some irritability and loss of concentration, need provided written informed consent before inclusion.
to use a fan, loosen clothing, and remove bedding), severe (up to 10 min, physical symptoms described as Procedures
feeling hotter or very hot, heavy perspiration, dizziness, This study was designed as a prospective, randomised, nausea, shortness of breath, weakness, and extreme double-blind trial, with the main objective of comparing discomfort; moderate anxiety and irritability; need to the effi cacy of venlafaxine, medroxyprogesterone acetate, loosen clothing, change clothing, and change bedding), or and cyproterone acetate for the prevention of vasomotor very severe (up to 30 min, very signifi cant physical and hot fl ushes in men with prostate cancer treated with GnRH emotional symptoms and the need to change clothing, analogues. All included patients received a quarterly bedding, towel off , take a shower, and take rest). Patients 11·25 mg depot of leuprorelin, administered subcutan- were asked to make a daily record of the number of hot eously. Flutamide 750 mg daily was given orally during the fl ushes and their severity (mild=1; moderate=2; severe=3; fi rst month of treatment to prevent testosterone fl are-up. and very severe=4). A daily score was calculated by After 6 months, patients who experienced 14 or more hot multiplying the number of hot fl ushes by the average fl ushes in the week before the visit, or those who severity. The “daily hot fl ush score” represented the mean experienced discomfort from hot fl ushes suffi cient for value of these scores during the week preceding the visit.
them to spontaneously request treatment, were randomly Additionally, participants completed the self-administered assigned to receive either venlafaxine delayed release European Organisation for Research and Treatment of 75 mg/day, medroxyprogesterone 20 mg/day, or cypro- terone acetate 100 mg/day, in addition to their third (version 3) on each visit, and informed the investigator leuprorelin injection. All patients received two indistin- about their compliance with the treatment and their guish able pills in the morning and one in the evening from week 1 to week 8, and then one pill in the morning and (poor, average, good). The quality-of-life questionnaire one in the evening from week 9 to week 10, to take account QLQ-C30 includes 30 questions covering fi ve functional of the gradual discontinuation of venlafaxine, which was scales (physical, role, emotional, cognitive, and social); given at half-dose (37·5 mg/day) in weeks 9 and 10.
three symptom scales (fatigue, pain, and nausea and Patients had follow-up visits 4 weeks, 8 weeks, and vomiting); and a global health and quality-of-life scale. Six 12 weeks after randomisation. During the week before single-item symptom measures cover dyspnoea, sleep Published online December 7, 2009 DOI:10.1016/S1470-2045(09)70338-9
in median hot fl ush score after 4 weeks of treatment could be detected with an α risk of 5% and a β risk of 20%. We estimated that 14% of the study population would not yield evaluable data, and therefore decided to randomly assign 117 patients to each group (351 in total). All patients who received at least one study treatment data were compared using Fisher’s exact test or, when not applicable, χ² test. Quantitative data were compared by a Kruskall–Wallis test. Analysis of covariance was used when comparing the change in hot-fl ush score between randomisation and another time period. In case of a signifi cant diff erence between the three treatment groups, all pairwise diff erences were tested using the student’s test or, when applicable, the Wilcoxon test with level of signifi cance adjustment using the Bonferroni method (αĽ=α/3). This statistical procedure included the QLQ-C30 scores. Because of the numerous comparisons Figure 2: Median daily hot fl ush score according to randomisation group
involved in the QLQ-C30 analysis and the subsequent α risk, only signifi cant diff erences noted for at at least two timepoint comparisons were considered. Tests were disturbance, appetite loss, constipation, diarrhoea, and bilateral, and considered as signifi cant at the level of fi nancial impact. All scales are scored from 0 to 100. High α=0·05. Statistical analyses were done with SAS 8.2 and scores for a functional scale represent high or healthy AdClin 3.1.1. This trial is registered with AFSSAPS levels of functioning, and similarly for global health or French National Registry, number F-LEU-100/ 03.11.21, quality of life. High scores for a symptom scale or item and number NCT01011751.
represent a high severity of symptom or problem.18 The primary endpoint was the change in median daily Role of the funding source
hot fl ush score after 4 weeks of treatment (between The study sponsor was involved in study design and data randomisation and 1 month) according to the hot-fl ush collection. An advisory board had overall scientifi c diary. Secondary endpoints included frequency of hot responsibility for study and protocol design, and advised fl ushes at each visit and relative score changes, percentage the sponsor as to the conduct of the trial. After the end of of patients with a decrease in hot fl ushes (complete or the trial, the board received all data analyses they more than 50%), eff ect of the treatment on quality of life, requested. The sponsor had no role in the data analysis, interpretation, or writing of the report. JI had full access to the raw data and had fi nal responsibility for the Randomisation and masking
decision to submit the manuscript for publication.
An independent contract research organisation
(CREAPHARM, Saint-Médard-en-Jalles, France) gener-
ated the randomisation list using a randomisation table, 919 men were enrolled in the study, with 311 (33·8%) and assigned the patients to the trial groups. Random reporting hot fl ushes requiring treatment 6 months after assignment with a block size of three was done centrally, androgen suppression. The ratio of randomised/included which was communicated to investigators by fax, and patients was lower than planned at the beginning of the each patient was given a randomisation number. The study, and despite amendments to increase the number allocation sequence was stratifi ed by centre. Participants, of investigators, the number of inclusions, and the investigators, sponsor personnel, and outcome assessors duration of the study, we could not reach the primary goal were blinded to treatment assignment, since the pills of 351 patients taking into account a 14% dropout rate.
used for each of the three study treatments were From Oct 19, 2004, to Sept 14, 2007, 311 patients were randomly assigned to either the venlafaxine group (n=102), the cyproterone group (n=101), or the medroxyprogesterone Statistical analysis
group (n=108; fi gure 1). Two patients were excluded for cacy data from previous reports were only available for protocol deviations (one in the cyproterone group and one medroxyprogesterone acetate and venlafaxine. We used in the medroxyprogesterone group, both because they successive iterations based on the values selected for the were already taking serotonin re-uptake inhibitor averages, standard deviations, and α and β risks, to antidepressants at randomisation); thus 309 patients calculate that 92 patients per treatment group—276 in received at least one study treatment dose and were total—were needed to ensure a diff erence between groups cacy analysis. The fi nal study visit was Published online December 7, 2009 DOI:10.1016/S1470-2045(09)70338-9
Venlafaxine group
Cyproterone group
Medroxyprogesterone group
Median relative change from randomisation to 1 month (IQR) Median relative change from 4 weeks to 8 weeks (IQR) Median relative change from randomisation to 8 weeks (IQR) Median relative change from randomisation to last available score (IQR) Relative changes are signifi cant for the three drugs at all time intervals (p<0·0001) except for venlafaxine between 1 month and 2 months (p=0·4; signed rank Wilcoxon test).
Table 2: Relative median daily hot-fl ush score changes according to the hot-fl ush diary
Cyproterone group vs
Cyproterone group vs
Medroxyprogesterone group vs
medroxyprogesterone group
venlafaxine group
venlafaxine group
Randomisation to 4 weeks
–44·3 (–61·4 to –27·2, <0·0001) –44·2 (–59·3 to –29·1, <0·0001) 4 weeks–8 weeks
14·8 (–56·5 to 86·1, 0·6676) –83·2 (–204·2 to 37·8, 0·0122) Randomisation: last available score
–52·4 (–70·3 to –34·5, <0·0001) –52·2 (–69·8 to –34·6, <0·0001) p value adjusted by Bonferroni method of two-by-two comparisons of treatment groups (covariance analysis).
Table 3: Daily mean hot-fl ush score relative changes according to the hot fl ush diary
done on Dec 6, 2007. 264 patients (88 in the venlafaxine The changes in median hot-fl ush score from randomisation group, 81 in the cyproterone group, and 95 in the to 4 weeks; 4 weeks to 8 weeks; randomisation to 8 weeks, medroxyprogesterone group) attended all three scheduled and randomisation to the last available score are shown in follow-up visits and had no missing data (fi gure 1). table 2. Pairwise comparison of treatment groups adjusted At randomisation, 62 (20·1%) patients described their by the Bonferroni method confi rmed that the decreases in hot fl ushes as mild, 134 (43·4%) described them as hot-fl ush scores were signifi cantly larger in the cyproterone moderate, and 113 (36·6%) described them as severe. and medroxyprogesterone groups than in the venlafaxine The median (mean) weekly number of hot fl ushes and group, regardless of the time interval looked at. There was daily hot-fl ush score in the week preceding the no signifi cant diff erence between the cyproterone and randomisation visit was 33·0 (44·4) and 7·6 (10·5), medroxyprogesterone groups (table 3). Overall, after respectively. The three treatment groups were comparable 4 weeks of treatment, 219 patients (70·9%) had an in size, and well matched in terms of age, body-mass improvement of at least 50% in their hot-fl ush scores, and index, blood pressure, Karnofsky index score, and the 70 patients (22·7%) reported a complete absence of hot proportion of mild, moderate, or severe hot fl ushes fl ushes (table 4). Improvements for both criteria were (table 1). However, there were a higher number of hot signifi cantly lower in the venlafaxine group than in the fl ushes and a higher median hot-fl ush score in the other two groups (p=0·0006; table 4). medroxyprogesterone acetate group in the week leading QLQ-C30 questionnaires were not evaluable for fi ve, 20, up to the randomisation visit (table 1). 40, and 53 patients at randomisation, 4 weeks, 8 weeks, At 4 weeks, the median weekly number of hot fl ushes for and 12 weeks, respectively. Functional domains were the study group was 9·0 (mean 15·7), with 21·0 (26·6), 4·0 scored high at all visits (median 83·3 [mean 85] out of (1·8), and 7·5 (12·7) for the venlafaxine, cyproterone, and 100). The following functional and symptom scales were medroxyprogesterone groups respectively. The median not signifi cantly diff erent between any of the follow-up daily hot-fl ush score was 1·6 (mean 3·6) for the whole visits and randomisation: physical; role; cognitive and tudy group, 4·0 (6·5)for the venlafaxine group, 0·9 (1·8) social functioning; fatigue; pain; nausea and vomiting; for the cyproterone group, and 1·3 (2·7) for the global health status; insomnia; appetite loss; constipation; medroxyprogesterone group (fi gure 2). The decrease in diarrhoea; and fi nancial diffi median daily hot-fl ush score between randomisation and emotional functional scale was signifi cantly better in the 4 weeks was signifi cant for all three groups (p<0·0001). venlafaxine group compared with the two other treatment Published online December 7, 2009 DOI:10.1016/S1470-2045(09)70338-9
thrombosis, hypertension), investigations abnormalities Venlafaxine
Cyproterone group
Medroxyprogesterone Total
(abnormal blood glucose, increased blood pressure, group (N=102)
group (N=107)
increased weight), and nervous system disorders (balance confusional state, sleep disorder). Other adverse events included infections, neoplasms, psychiatric disorders, respiratory disorders, and breast tenderness (table 5). Table 4: Improvement in daily hot-fl ush score after 4 weeks
There were 75 adverse events in 100 patients in the cyproterone group, 66 in 102 patients in the venlafaxine group, and 60 in 107 patients in the medroxyprogesterone group. Cyproterone led to a higher number of vascular Medroxyprogesterone groupVenlafaxine group adverse events than did the other treatments, but this was not statistically signifi cant (table 5). The number of patients who presented with adverse events related to study drug or which led to treatment discontinuation between randomisation and 12 weeks was comparable (table 5). 16 patients presented with serious adverse events, two of which were related to the study drugs: one case of dyspnoea caused by cyproterone acetate and one case of urticaria caused by medroxyprogesterone acetate.
Our study shows that men with signifi cant hot fl ushes during androgen suppression responded better to cyproterone acetate and medroxyprogesterone acetate than to venlafaxine within the 12-week study period.
Androgen suppression using GnRH analogues is Figure 3: Mean emotional functioning scores
Among the EORTC QLQ-C30 domains, the emotional functional scale score (0–100) changes were signifi cantly
widely prescribed in prostate-cancer treatment.1 Hot diff erent between the three treatment groups between randomisation and 4 weeks (p=0·0147) and between fl ushes are the most common side-eff ect of this treatment, randomisation and 8 weeks (p=0·0047). Venlafaxine achieved the highest scores at 4 weeks and 8 weeks. and can be very uncomfortable for patients.3 However, The blue, red and green dotted lines represent the linear tendency between randomisation and 12 weeks for hot fl ushes do not always occur, and when they do their venlafaxine, cyproterone, and medroxyprogesterone groups, respectively.
eff ect is not always considered by the patient as worthy of groups between randomisation and 4 weeks and between treatment. In our study, after 6 months of androgen-randomisation and 8 weeks (fi gure 3). The dyspnoea suppression treatment with leuprorelin, 311 patients single-item symptom score was also signifi cantly diff erent were randomised either because of the frequency of their between randomisation and 4 weeks (p=0·0353) and hot fl ushes or their level of discomfort, whereas between randomisation and 8 weeks (p=0·0126), with the 386 patients did not meet the randomisation criteria best scores being achieved in the venlafaxine group.
(fi gure 1). The proportion of patients entering the study cacy was rated as good in 171 was much lower than the 65% expected on the basis of (57·0%) of 300 patients at 4 weeks, 171 (61·5%) of previous reports. It became apparent during the study 278 patients at 8 weeks, and 151 (57·0%) of 265 patients at that a signifi cant number of patients with hot fl ushes do 12 weeks. Cyproterone acetate and medroxyprogesterone not seek treatment: only 204 patients among the acetate were considered to have good effi cacy at all visits, 919 enrolled (22·2%) spontaneously asked for treatment. with 60·0–84·1% patients rating treatment effi cacy as In our view, this justifi es the recommendation not to good. Signifi cantly fewer patients in the venlafaxine group systematically prevent hot fl ushes in all patients on cacy as good (28·4–33·7%; p<0·0001).
initiation of an androgen-suppressing treatment.
Compliance was good in all treatment groups (291 of Diff erent treatments have been assessed for the 303 patients; >96%). Six deaths were reported during the treatment of hot fl ushes, including complementary study, three during the fi rst 6 months, and three between or alternative treatments,6 acupuncture,8 clonidine,19 randomisation and 12 weeks. None of the deaths were gabapentine,13 selective serotonin re-uptake inhibitors, and considered to be related to study treatments. During the hormonal treatments. Many have been assessed hot-fl ush treatment period, 201 adverse events occurred individually against a placebo in randomised trials, mostly (table 5). The most frequent adverse events related to in postmenopausal women or women being treated for study drug were gastrointestinal disorders (abdominal breast cancer. Fewer trials have been done in men who are pain, constipation, diarrhoea, and nausea), general undergoing hormonal therapy for prostate cancer. We disorders (asthenia, face oedema, feeling cold, sense of designed this study to assess the drugs with the most oppression), vascular disorders (deep and superfi cial vein convincing previous evidence of good response rates and Published online December 7, 2009 DOI:10.1016/S1470-2045(09)70338-9
Venlafaxine group
group (N=100)
group (N=107)
Total number of adverse events related to study drugs Patients with one or more serious adverse event Patients with one or more adverse event related to study drug Patients with one or more serious adverse event related to study drug Patients with one or more vascular disorders related to study drug (n) Patients with one or more adverse event leading to discontinuation All data are n (%) unless stated otherwise. *There is no signifi cant diff erence between the three treatment groups.
Table 5: Adverse events in the 3 months after randomisation by treatment group*
tolerance,7,9 and our study confi rmed the fi ndings of and 4 weeks and between randomisation and 8 weeks previous studies, since all three drugs induced a signifi cant (fi gure 3). This could be seen as a positive side-eff ect of improvement in hot fl ushes compared with baseline venlafaxine caused by its antidepressant properties.
(randomisation). Progestagens proved their eff ectiveness An intra-patient improvement in hot-fl ush frequency and satisfactory tolerance.20,21 We used medroxyprogesterone and intensity is not enough to draw a defi nite conclusion acetate rather than megestrol acetate, since no low-dose about drug effi cacy, owing to possible confounding by the formulation of megestrol acetate is available in France; the placebo eff ect.9,18 Most of the phase 3 studies of the three only marketed form consists of strongly dosed tablets study drugs to date have been placebo-controlled, but (160 mg). The dose of 20 mg/day of medroxyprogesterone there are very few data on direct comparisons between acetate seemed to have a good benefi t/risk profi le, since drugs with an established effi the response rates seem independent of the dose according cacy and tolerance of the three drugs head to head, cacy of cyproterone acetate with the aim of producing directly comparable data to in treating hot fl ushes was shown many years ago.10,24 help guide therapeutic choices, since there are no clear However, this steroidal anti-androgen has mainly been recommendations in this fi eld. We also chose not to used as a treatment for prostate cancer. We decided to use include a placebo group, since we considered that enough the dose of 100 mg/day, owing to the lack of previous data data were available for the study drugs versus placebo.
assessing doses lower than 100 mg/day for hot-fl ush We found that the hormonal treatments (cyproterone treatment. The use of antidepressants such as venlafaxine acetate and medroxyprogesterone acetate) were better at to treat hot fl ushes is a recent development. The venlafaxine reducing hot fl ushes and are more eff ective than dose we used in our study was 75 mg/day, after previous venlafaxine, with little diff erence in tolerance between the studies showed that higher doses gave the same response treatments. Our results confi rm those of the North with a less satisfactory tolerance.25 It is possible that starting Central Cancer Treatment Group Trial N99C7, in which at 75 mg/day rather than at a lower dose could have led to depomedroxy progesterone acetate was shown to be better more cases of early drug discontinuation; however, overall at controlling hot fl ushes than venlafaxine in menopausal compliance was good in all treatment groups (>96%). The women.26 We believe that the randomised, double-blind number of patients who presented with adverse events design of our study enables us to conclude with reasonable between randomisation and 12 weeks that led to confi dence that cyproterone acetate and medroxy- discontinuation were comparable in the three treatment progesterone acetate are more eff ective than venlafaxine groups (table 5). The functional and symptom scales at 12 weeks for treating hot fl ushes in men who are treated assessed by the QLQ C-30 were not signifi cantly diff erent with GnRH analogues for prostate cancer. There was no between visits and compared with randomisation except signifi cant diff erence between cyproterone acetate and for the emotional functional scale, which was signifi cantly medroxyprogesterone acetate, although there was an improved in the venlafaxine group between randomisation imbalance in the number of patients spontaneously Published online December 7, 2009 DOI:10.1016/S1470-2045(09)70338-9
asking for hot-fl ush treatment before randomisation and 7 Loprinzi CL, Barton DL, Sloan JA, et al. Mayo Clinic and North in the total number of hot fl ushes in the week preceding Central Cancer Treatment Group hot fl ash studies: a 20-year
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for decades to treat prostate cancer, either alone or in 14 Quella SK, Loprinzi CL, Sloan J, et al. Pilot evaluation of venlafaxine for the treatment of hot fl ushes in men undergoing combination with androgen suppression. Patients treated androgen ablation therapy for prostate cancer. J Urol 1999; with a combination of GnRH analogues and cyproterone 162: 98–102.
acetate or medroxyprogesterone acetate should be aware 15 Loprinzi CL, Barton DL, Carpenter LA, et al. Pilot evaluation of paroxetine for treating hot fl ushes in men. Mayo Clin Proc 2004; of the potential for withdrawal syndrome, and consider 79: 1247–51.
stopping cyproterone acetate or medroxyprogesterone 16 Naoe M, Ogawa Y, Shichijo T, Fuji K, Fukagai T, Yoshida H. Pilot acetate as a fi rst step when prostate-specifi c antigen evaluation of selective serotonin reuptake inhibitor antidepressants in hot fl ash patients under androgen-deprivation therapy for prostate cancer. Prostate Cancer Prostatic Dis 2006; 9: 275–78.
17 Aaronson NK, Ahmedzai S, Bergman B, et al. The European JI, PB, and NM designed the study. JI and RO collected the data. JI, LS, Organization for Research and Treatment of Cancer QLQ-C30: PB, and NM were involved in the analysis and interpretation of the data. a quality-of-life instrument for use in international clinical trials in
oncology. J Natl Cancer Inst 1993; 85: 365–76.
All authors critically revised the manuscript and gave their fi nal approval for its publication.
18 Sloan JA, Loprinzi CL, Novotny PJ, Barton DL, Lavasseur BI, Windschitl H. Methodologic lessons learned from hot fl ash studies. Confl icts of interest
J Clin Oncol 2001; 19: 4280–90.
JI has received honoraria for the study advisory board and for postgraduate 19 Buijs C, Mom CH, Willemse PH, et al. Venlafaxine versus education lectures from Takeda, Ipsen, and Astellas. PB has received clonidine for the treatment of hot fl ushes in breast cancer patients: research grants and honoraria for consultancies from Schering Plough, a double-blind, randomized cross-over study. Breast Cancer Res Treat PregLem, Wyeth, HRA Pharma, and Pierre Fabre Research. RO is an 2009; 115: 573–80.
employee of Takeda. NM has received research grants from Takeda and 20 Loprinzi CL, Michalak JC, Quella SK, et al. Megestrol acetate for the Caprion, and has served on advisory boards for Takeda, Caprion, and prevention of hot fl ushes. N Engl J Med 1994; 331: 347–52.
Thallion. He received honoraria for postgraduate education lectures from 21 Quella SK, Loprinzi CL, Sloan JA, et al. Long term use of megestrol Takeda, Ipsen, and Astellas. LS declared no confl icts of interest.
acetate by cancer survivors for the treatment of hot fl ushes.
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22 Charig CR, Rundle JS. Long-term side eff ect of orchiectomy in We thank Stéphanie Chretin and Françoise Bugnard for assistance in the treatment of prostatic carcinoma. Urology 1989; 33: 175–78.
statistical analysis and interpretation of the data.
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3 Sharifi N, Gulley JL, Dahut WL. Androgen deprivation therapy for 25 Loprinzi CL, Kugler JW, Sloan JA, et al. Venlafaxine in management prostate cancer. JAMA 2005; 294: 238–44.
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Moyad MA. Complementary/alternative therapies for reducing hot 28 Sella A, Flex D, Sulkes A, Baniel J. Antiandrogen withdrawal fl ushes in prostate cancer patients: reevaluating the existing indirect syndrome with cyproterone acetate. Urology 1998; 52: 1091–93.
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Urology 2002; 59 (suppl 1): 20–33. Published online December 7, 2009 DOI:10.1016/S1470-2045(09)70338-9



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