Bannink, M

Bontenbal, Marijke

Gool, AR

Seynaeve, Caroline

Undetermined

EUR Research Repository

A B S T R A C TObjective: To obtain practical experience with venlafaxinefor hot flushes in breast cancer patients and incorporatethis in a treatment protocol. Method: Twenty-two women with a history of breast cancer(mean age 49.2 years, range 35-65) were referred forconsideration of treatment with venlafaxine for hot flushes.Patients received extensive information on treatment withvenlafaxine and were advised to self-monitor the frequencyof their hot flushes. Results: Eight women did not start venlafaxine because theyhad no postmenopausal complaints, were lost to follow-up, had too low a frequency of hot flushes, or refusedtreatment. Eventually 14 women started venlafaxine. Twoof them did not tolerate venlafaxine, four reported someeffect but stopped because of side effects, two women hadno effect whatsoever. Six women observed a clear (>50%)reduction in their hot flush frequency that was main-tained at a median follow-up of 13 months.Conclusion: The group of patients referred for treatmentwas more heterogeneous and more patients dropped outbecause of side effects than expected. Extensive patienteducation, patient selection and evaluation of the treatmenteffect (by self-monitoring of hot flush frequency) aremandatory to avoid useless (continuation of) treatment andto prepare patients for side effects. Under these conditions, asubstantial minority of patients benefit from venlafaxine.K E Y W O R D SAntidepressants, breast cancer, hormonal therapy, hot flushes, venlafaxineI N T R O D U C T I O NHot flushes can be very bothersome postmenopausalsymptoms. In this phase of life, about 75% of womenexperience hot flushes.1-3 Most prominent are attacks ofintense feelings of warmth, ascending from the chest to thehead and neck region. A hot flush lasts several minutes andis accompanied by (often heavy and visible) transpirationand reddening of the skin of the head and neck. Hot flushescan also be accompanied by palpitations, dizziness, anxietyand irritability.1Some women have a couple of hot flushes a week, othersexperience dozens a day. Also the intensity of hot flushescan vary considerably. Hot flushes can easily lead toavoidance of social contacts. Nightly hot flushes are especiallytroublesome, resulting in awakening due to profusetranspiration and having to change nightclothes and bedsheets. The consequent interference with sleep easily leadsto daytime fatigue and diminished functioning. In women with breast cancer, menopause can occur as aphysiological phenomenon, but also as a side effect of the(systemic) oncology treatment. Chemotherapy can inducepremature ovarian dysfunction, and in addition, hormonaltreatment with drugs such as tamoxifen and LH-RH-agonists(‘chemical castration’) in hormone-sensitive breast cancercan lead to frequent and annoying hot flushes.4 Bilateraloophorectomy, if performed, equally results in an irreversiblepostmenopausal state.Temporary treatment with oestrogens is the most effectivetreatment for hot flushes. In women without a history ofbreast cancer, oestrogens provide a 50 to 100% reduction inhot flush frequency.1,5 However, in patients with a historyof breast cancer, oestrogens are relatively contraindicated.This is certainly the case for patients with hormone-sensitivetumours, because oestrogens can stimulate the growth ofM A Y  2 0 0 5 ,  V O L .  6 3 ,  N O .  5© 2005 Van Zuiden Communications B.V. All rights reserved.175O R I G I N A L  A R T I C L EClinical experience with venlafaxine in thetreatment of hot flushes in women with a history of breast cancerA.R. van Gool1*, M. Bannink1, M. Bontenbal2, C. Seynaeve2Departments of 1Psychiatry and 2Medical Oncology, Erasmus Medical Centre-Daniel den HoedCancer Centre, Rotterdam, the Netherlands, tel.: +31 (0)10-439 17 52, fax: +31 (0)10-439 10 18, e-mail: a.vangool@erasmusmc.nl, *corresponding author‘microscopic’ tumour cells that might still be present aftersurgery, radiotherapy and/or chemotherapy.6,7 In addition,specifically in hormone-sensitive tumours, hormonalmanipulations aim to knock out the production of oestro-gens or to block the stimulatory effects of oestrogens onthe tumour cell.Until recently, only moderately effective alternatives fortreatment of hot flushes were available for this patientgroup. With clonidine (Catapresan®, Dixarit®), for instance,a drug that affects the central noradrenergic neurotrans-mission and that in higher doses is used for the treatmentof hypertension and migraine, 10 to 20% reduction influshes are found as compared with placebo. This is amodest effect, taking into account the possible side effectsas sedation, sleep disturbance, gastrointestinal symptomsand hypotension.4,8Over the past years, however, favourable results have beenreported with several modern antidepressants in womenwith a history of breast cancer, at first with venlafaxine(Efexor®), later on with fluoxetine (Prozac®) and paroxetine(Seroxat®).9-11 In a randomised, placebo-controlled trial in221 women with either a history of breast cancer or reluc-tance to take hormones because of fear of breast cancer,venlafaxine 75 mg daily resulted in a 61% reduction inthe hot flush scores (number of hot flushes/24 hours xintensity), a response that was twice as high as in theplacebo group.9 A daily dose of 37.5 mg was somewhatless effective, a dose of 150 mg was as effective as 75 mgbut induced more side effects.9 Recently, paroxetine wasalso reported to be effective against hot flushes in healthywomen.12 The effects on hot flushes of these serotonergicdrugs are thought to be mediated by an influence on acomplex interaction of serotonin, noradrenaline, gonado-tropic hormones and sex hormones in the thermoregulatorycentres of the brain.12,13After the publication by Loprinzi et al. in 2000, the oncologystaff of our hospital decided to refer breast cancer patientswith troublesome hot flushes to the psychiatry service inorder to concentrate the experience with venlafaxine for thisindication. At that time, we were unsure of the generalis-ability of the findings. In addition, the psychiatrists werefamiliar with venlafaxine and its side effects. The aim wasto incorporate this clinical experience, finally, in a protocolor checklist. P A T I E N T S  A N D  M E T H O D SFrom January 2001 until July 2003, 22 women (mean age49.2 years, range 35-65, SD 7.8) with a history of breastcancer were referred to the psychiatry department forpossible treatment with venlafaxine for hot flushes. Nostrict referral criteria were established: obviously, patientshad to be burdened significantly by hot flushes.Pretreatment with clonidine was advised. A semistructuredhistory was taken and patient information was givenaccording to table 1. For five days prior to starting venlafax-ine, the patients monitored the frequency of troublesomehot flushes on a registration sheet (for each night, morning,afternoon, and evening). The decision to start venlafaxineVan Gool, et al. Venlafaxine for hot flushes in breast cancer patients.M A Y  2 0 0 5 ,  V O L .  6 3 ,  N O .  5176Table 1Items to be addressed in breast cancer patients when prescribing venlafaxine for hot flushesINFORMATIONNo registration for this indication; few data on long-term efficacyMost frequently occurring side effects: agitation, anxiety, gastric symptoms, constipation, dry mouthMay influence driving ability (warning on package)Side effects manifest first, positive effects on hot flushes laterVenlafaxine only influences hot flushes, not other menopausal complaints as vaginal dryness or osteoporosis, nor does it have a direct positive effect on joint pains, fatigue, concentration difficultiesEffect to be expected is a reduction of 50% or more in hot flush frequency, according to literature data, intensity of flushes can also decrease Explanation of rationale for self-monitoring of hot flush frequency: avoiding unnecessary treatment, enabling evaluation of the effect of therapy and of the ratio of benefits over side effectsINDICATION FOR PSYCHIATRIC REFERRAL, (RELATIVE) CONTRAINDICATIONS FOR VENLAFAXINEPrevious experience (side effects!) with serotonergic antidepressants (fluvoxamine-Fevarin®, fluoxetine-Prozac®, paroxetine-Seroxat®, sertraline-Zoloft®, citalopram-Cipram®)Depressed now? Have you been consistently depressed or down, most of the day, nearly every day, for the past two weeks? In the past two weeks,have you been less interested in most things or less able to enjoy the things you used to enjoy most of the time?History of manic episode(s)? Have you ever had a period of time when you were feeling, ‘up’ or ‘high’ or so full of energy or full of yourself that you got into trouble, or that other people thought you were not your usual self? Do not count times when you were intoxicated by drugs or alcohol. Have you ever been persistently irritable, for several days, so that you had arguments or verbal or physical fights, or shouted at people outside your family? Have you or others noticed that you have been more irritable or overreacted, compared with other people, even in situations that you felt were justified? Anxiety disorder? Easily worried and tense? Sudden attacks of anxiety? Avoidance of places and situations in which you could become anxiousor panicky? Compulsive behaviour as excessive checking or washing hands?was made by the patient and the psychiatrist together; athreshold frequency of hot flushes for starting venlafaxinewas not required. Follow-up visits were arranged after twoto three weeks, four to six weeks and four to six months.Before each follow-up visit, the women monitored thefrequency of troublesome hot flushes for a period of twoto three days. Some of these follow-up appointments tookplace by telephone, e-mail or fax. The starting daily doseof venlafaxine was 75 mg, after two or three weeks, thedose could be increased to 150 mg in case of insufficienteffect. We did not use predetermined criteria for response:the decision to stop or to continue venlafaxine after fourto six weeks (or earlier in case of side effects) was takenafter the patient and psychiatrist had discussed the costsand benefits.R E S U L T SAt the first visit to the psychiatrist (AVG), one woman hadcomplaints which could not be regarded as hot flushesand not even as postmenopausal. She was not prescribedvenlafaxine. Of the remaining 21 patients, the hot flusheswere attributed to the physiological menopause in twowomen, and in 19 to previous or ongoing treatment forbreast cancer. Fourteen women had previously been treatedwith clonidine for hot flushes. For one woman, no reliableself-monitoring could be obtained; she was lost to follow-up.At self-monitoring, the frequencies of hot flushes turnedout to be rather variable. In six cases it was decided not tostart with venlafaxine. In three of these six women, to theirown surprise, the hot flush frequency at self-monitoringwas considerably lower than previously perceived by them.After receiving information, three women declined treat-ment, mainly because of a reluctance to use more drugsthan they were already taking and a reluctance to take a‘psychiatric’ drug. One patient had a depressive syndrome,of mild intensity (score on the Zung self-rating scale fordepression: 49). Problems at work and sleep disturbancebecause of nightly hot flushes (with resulting daytimefatigue and irritability) were thought to be causal factorsin this depression. Eventually, 14 women (mean age 48.5 years, range 42-59,SD 6.0) started venlafaxine. In one of these women thehot flushes were attributed to the physiologicalmenopause, in the other 13 to previous or ongoing treatmentfor breast cancer (hormonal therapy in eight, chemotherapyin one, combination of hormonal and chemotherapy infour). The reported duration of annoying hot flushes wasmore than two years in eight women, between six monthsand two years in four, and less than six months in two.On self-monitoring, ten women recorded between 10 and25 hot flushes per 24 hours, while four women recordedmore than 25. Ten women had been treated with clonidine. One patient insisted on continuing clonidine, and venlafax-ine was added. Two women did not tolerate the startingdose of 75 mg venlafaxine because of severe agitation,anxiety and profound malaise occurring in the hours aftertaking the first dose. In four women, venlafaxine waseffective to some extent (30 to 50% decrease in hot flushfrequency), but they stopped taking venlafaxine becauseof troublesome side effects as constipation, weight gainand sleep disturbance. In two women, venlafaxine had noeffect at all in doses of 75 and 150 mg respectively. Six women took venlafaxine for three months or longer(four women in a daily dose of 75 mg, and two in a doseof 150 mg) and experienced a more than 50% reductionin hot flush frequency without significant side effects. Intwo of them, the hot flushes disappeared completely.Two women reported a definite psychic alteration: in theabove-mentioned depressive patient, the depression wentinto remission; the other woman reported feeling lessirritable and more able to cope emotionally with herdifficulties. In these six women, the effect was maintainedin the long term: dose increase was not necessary duringa median follow-up of 13 months (range: 5-36 months). D I S C U S S I O NThe group of breast cancer patients referred for treatment ofhot flushes was more heterogeneous than expected in termsof the frequency (and in one patient even the presence) ofhot flushes and in terms of subjective burden. After self-monitoring, some women turned out to have far lessflushes than had thought beforehand. Others decidedagainst treatment after receiving information. Presumably,aside from their reluctance to take more or ‘psychiatric’drugs, knowing that a form of treatment would be availableif the symptoms became more intense satisfied thesepatients. Patient selection by giving extensive patientinformation, a standardised history (table 1) and self-monitoring of the hot flush frequency appears to preventunnecessary treatment in majority of patients. Of the treated patients, quite a lot dropped out because ofside effects. Two patients even became severely agitated afterthe first dose. Patient education, in this way, is obviouslyalso useful to prepare patients for annoying or evenfrightening side effects. Furthermore, evaluation of thetreatment effect by means of self-monitoring is mandatoryto avoid useless continuation of treatment. We noticed inseveral patients that clonidine had been prescribed forlonger periods without much evidence of a positive effect.Evaluation of the treatment turned out to also be usefulin enabling the patients to weigh the beneficial effects onthe hot flushes against the side effects and the necessity totake another medication. In a context of extensive patienteducation, standardised history taking and self-monitoring,M A Y  2 0 0 5 ,  V O L .  6 3 ,  N O .  5Van Gool, et al. Venlafaxine for hot flushes in breast cancer patients.177more than one third of patients appear to derive a long-termbenefit from venlafaxine.The number of referrals was unexpectedly low. Accordingto the oncology staff, women were mainly reluctant totake more drugs. In addition, a referral to a psychiatrist,for a possible treatment with a psychotropic drug, couldhave been an obstacle. We realise that the procedure as presented here is relativelylaborious. However, specialised oncology or psychiatrynurses could assist in patient education and self-monitoring.Moreover, as most oncologists will not be confrontedfrequently enough with this problem to build up experience,a standardised history as shown in table 1 could be useful.In addition, it is important to obtain a short psychiatrichistory. For instance, in patients who went through amanic episode earlier in their life antidepressants mightprovoke a recurrent mania. Patients who had previouslybeen treated with a serotonergic antidepressant should beasked about side effects: logically, they could experiencethe same side effects again. It is important to assess thepresence of an ongoing mood or anxiety disorder.Questions on depression and a history of manic episodescan be asked directly or, as shown in table 1, with modulesof the M.I.N.I.14 Screening on depression and anxiety canalso be done with self-report questionnaires as the HospitalDepression and Anxiety Scale.15 If a mood or anxietydisorder is suspected, consulting with a psychiatrist orthe general practitioner is self-evident. Finally, we believe that our clinical experience in breastcancer patients is also relevant for the treatment of hotflushes in general (as part of the physiological menopausein otherwise healthy women), especially since long-termhormone replacement therapy in women with menopausalsymptoms is under debate.16According to the literature, venlafaxine is an effective therapyfor hot flushes in breast cancer patients. Our experienceindicates that matters are more complex and that the bestresults with this drug are obtained with extensive patientinformation, patient selection and repeated evaluation ofthe effects by self-monitoring of hot flush frequency.R E F E R E N C E S1. Stearns V, Ulmmer L, Lopez JF, Smith Y, Isaacs C, Hayes DF. Hot flushes.Lancet 2002;360:1851-61.2. Bachmann GA. Vasomotor flushes in menopausal women. Am J ObstetGynecol 1999;180:312-6.3. Kronenberg F. Hot flashes: epidemiology and physiology. Ann N Y AcadSci 1990;592:52-86.4. Wymenga ANM, Sleijfer DT. Management of hot flushes in breast cancerpatients. Acta Oncologica 2002;41:269-75.5. McLennan A, Lester S, Moore V. Oral estrogen replacement therapy versusplacebo for hot flushes (Cochrane Review). Cochrane Database Syst Rev2001;1:CD002978.6. Barton DL, Loprinzi C, Gostout B. Current management of menopausalsymptoms in cancer patients. Oncology 2002;16:67-72.7. Pritchard KI. Hormone replacement in women with a history of breastcancer. Oncologist 2001;6:353-62.8. Clemons M, Clamp A, Anderson A. Management of the menopause incancer survivors. Cancer Treat Rev 2002;28:321-33.9. Loprinzi CL, Kugler JW, Sloan JA, et al. Venlafaxine in management of hotflashes in survivors of breast cancer: a randomised controlled trial.Lancet 2000;356:2059-63.10. Loprinzi CL, Sloan JA, Perez EA, et al. Phase III evaluation of fluoxetinefor treatment of hot flashes. J Clin Oncol 2002;20:1578-83.11. Weizner MA, Moncello J, Jacobsen PB, Minton S. A pilot trial of paroxe-tine for the treatment of hot flushes and associated symptoms in womenwith breast cancer. J Pain Symptom Manage 2002;23:337-45.12. Stearns V, Beebe KL, Iyengar M, Dube E. Paroxetine controlled release inthe treatment of menopausal hot flashes. A randomized controlled trial.JAMA 2003;289:2827-34.13. Kouriefs C, Georgiou M, Ravi R. Hot flashes and prostate cancer: pathogenesis and treatment. BJU Int 2002;89:379-83.14. Sheehan DV, Lecrubier Y, Sheehan KH, et al. The Mini-InternationalNeuropsychiatric Interview (M.I.N.I.): the development and validation ofa structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psych 1998 ;59(suppl 20):22-33.15. Zigmond AS, Snaith RP. The Hospital Anxiety and Depression Scale.Acta Psych Scand 1983;67:361-70.16. Vandenbroucke JP, van Leeuwen FE, Helmerhorst FM. Borstkanker enhormoongebruik rond de menopauze. Ned Tijdschr Geneeskd2003;147:1829-34.Van Gool, et al. Venlafaxine for hot flushes in breast cancer patients.M A Y  2 0 0 5 ,  V O L .  6 3 ,  N O .  5178

Clinical experience with venlafaxine in the treatment of hot flushes in women with a history of breast cancer

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Clinical experience with venlafaxine in the treatment of hot flushes in women with a history of breast cancer

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