Safety of Alternative Treatments for Menopausal Symptoms After Breast Cancer: a Qualitative Systematic Review

By Antoine, C; Liebens, F; Carly, B; Pastijn, A; Rozenberg, S

Key words: TIBOLONE, ANTIDEPRESSIVE AGENTS, CLONIDINE, GABAPENTIN, PHYTOESTROGENS, VERALIPRIDE, BLACK COHOSH, BREAST CANCER SURVIVORS

ABSTRACT

Aim This qualitative review analyzes systematically the safety of drugs used to alleviate menopausal symptoms, other than hormone replacement therapy, in breast cancer patients.

Methods We searched systematically studies using tibolone, serotonin reuptake inhibitors, clonidine, veralipride, gabapentin, black cohosh and phytoestrogens in breast cancer patients. We selected five studies for which we evaluated the methodology, characteristics of the studied populations, outcomes in terms of mortality and recurrence rates.

Results Four trials were conducted using tibolone in breast cancer patients: one double-blind, randomized trial, one prospective controlled study, and two uncontrolled studies. They considerably lack power to detect any difference in breast cancer recurrence or mortality between the treated and control patients. Similar conclusions have to be drawn from the only controlled retrospective study analyzing the safety of antidepressants and antihistamines. We were unable to find studies reporting the safety of the other drugs in breast cancer patients.

Conclusions There are no valuable data indicating the absence of a harmful effect of drugs used to alleviate climacteric symptoms in breast cancer patients. There is a need for randomized trials to assess the safety of these drugs. In the meantime, patients should be informed about the absence of safety data.

INTRODUCTION

Breast cancer mortality has decreased during the last decades as a consequence of systematicscreening and progress in its treatment1″3. Quality of life has emerged as an important challenge in the management of breast cancer. Many women affected by breast cancer will, following chemotherapy or hormonotherapy, go through menopause and suffer more from climacteric symptoms, and at an earlier age, than other women4’5. Some publications have even reported a five times higher prevalence of menopausal symptoms in breast cancer patients than in the general population6. An exacerbation of the symptoms can certainly be partially explained by the distress linked to the disease. On the other hand, hormone replacement therapy (HRT) is seldom prescribed for fear of increased risk of recurrence even though, in the last decade, the question has been raised as to whether HRT is really contraindicated in these patients7’8. Alternatively, physicians and patients have often tried other medications such as phytoestrogens, black cohosh, inhibitors of serotonin reuptake, clonidine, veralipride, gabapentin or tibolone for symptomatic relief9, even if the efficacy of some of these molecules is not proved and not much studied in breast cancer patients10,11.

Since breast cancer affects an increasing number of women, the search for an effective and safe strategy to alleviate their climacteric symptoms has become essential.

The safety of HRT was recently reviewed12 and this article focuses on the safety of drugs used to alleviate menopausal symptoms, other than HRT, in women with a personal history of breast cancer and systematically and thoroughly evaluates the available data.

MATERIAL AND METHODS

In order to identify all published trials assessing alleviation of menopausal symptoms with alternative treatments in breast cancer patients, we conducted a Medline search using the following key words: gabapentin, antidepressive agents, phytoestrogens, black cohosh, clonidine, veralipride, tibolone, breast cancer, breast neoplasm, breast cancer survivors, menopause, and menopausal symptoms. The references from each identified study and from review articles were then cross-checked for other potentially relevant studies. We also searched other data bases (Cochrane Controlled Trials Register) and abstract books from recent conferences, either on the subjects of menopause or breast cancer.

We established the following inclusion criteria: articles should be written in English or French, studies had to include the safety data of a medication (phytoestrogens, inhibitors of serotonin reuptake, clonidine, veralipride, gabapentin or tibolone) on the recurrence of breast cancer, contralateral breast cancer and survival in women with a past history of invasive breast cancer .

Five articles were found13-17, for which we evaluated the design of the study, the methodology, the characteristics of the studied populations, potential sources of bias, as well as the consequences of treatment on disease evolution.

RESULTS

Tibolone

One uncontrolled, prospective, phase II trial, analyzing the potential anti-cancer activity of tibolone on 14 postmenopausal women with advanced or metastatic breast cancer, who had suffered a recurrence using tamoxifen, was stopped after a median follow-up period of 12 weeks (range 3-24 weeks) because of progressive disease. It should be noted that one patient with progressive disease on Org OD 14 improved on stopping the drug, suggesting that changes in hormonal environment may be relevant for some patients14.

A double-blind, randomized trial was conducted between 1996 and 2000 and involved a limited number of early-stage breast cancer patients (n = 67; in situ or invasive ≤ stage IIb)16. The patients were randomized to tamoxifen 20 mg/day and tibolone or tamoxifen and placebo and followed for 12 months. In this small trial, where there were no differences in age, weight, body mass index, time since menopause, tumor size, nodal invasion and receptor status between the two groups, no recurrence occurred in either group. Dimitrakakis and colleagues17 followed breast cancer patients who had used tamoxifen for 5 years. One month after stopping tamoxifen, they were offered tibolone (n = 52) or not (n = 104). The objectives of the study were to assess the safety and efficacy of tibolone. These patients were followed in an open prospective study with a mean duration of 61 months, during which the authors did not observe a significant difference in recurrences between groups: one systemic and one contralateral breast cancer occurred in the tibolone group, while, in the control group, there were two systemic and three local recurrences. An uncontrolled study involving only 15 breast cancer patients treated with tibolone for a period ranging between 3 months and 5 years has also been reported by Ginsburg and colleagues”. Among them, one patient developed a breast neoplasm in the contralateral breast and another patient metastases. Currently, a randomized trial, the LIBERATE study, is ongoing and involves about 3000 breast cancer patients who were diagnosed within the last 5 years. The end of the trial is scheduled for 2007.

Antihistamines and antidepressants

Weiss and colleagues15 conducted a case-control study which aimed at evaluating the risk of antihistamines and antidepressants on cancer recurrence, using a cohort of 1416 patients who had suffered from breast cancer, colon cancer or melanoma and who were diagnosed between 1988 and 1994. The mean length of follow-up was 2.2 years after the end of the oncological treatment. They matched five control patients to each case, stratified for the type of cancer, its stage and the length of follow-up. There were 95 recurrences and 78 cases of new primitive cancer. Four patients out of 18 who presented a recurrence had used more than eight prescriptions of antihistamines or antidepressants and the multivariate analysis (adjusted for age, sex and exposition to these drugs before the onset of the study) did not suggest an association between the use of antihistamines or antidepressants and cancer recurrence (odds ratio (OR) 0.9; 95% confidence interval (CI) 0.52-1.78). Among patients who developed another primitive cancer, three had received between three and seven prescriptions and two, more than seven prescriptions. Again no association was suggested by multivariate analysis (OR 0.94; 95% CI 0.51-1.77).

We were unable to find studies reporting the safety of clonidine, phytoestrogens, black cohosh, gabapentin or veralipride in breast cancer patients. Only studies about their efficacy on hot flushes are available10,18-21.

DISCUSSION

Very few data are actually available about the safety of drugs, such as tibolone, inhibitors of sertonine reuptake, clonidine, veralipride, gabapentin, black cohosh and phytoestrogens, on breast cancer disease.

Only a few studies assessed the influence of tibolone on breast cancer patients13,14,16,17. While three of these studies seem reassuring13,16,17, they considerably lack power to detect any differences in breast cancer recurrence or mortality. Therefore, we will have to wait till 2007 for the results of the LIBERATE trial which is still ongoing and involves about 3000 breast cancer patients treated with tibolone or placebo.

While the study of Weiss and colleagues15 suggests that there is no association between the use of antidepressants or antihistamines and breast cancer evolution, the data should also be interpreted with great caution: the data are based on prescription collections in cancer patients, not only breast but also colon cancers and melanoma; the design is not optimal; and only a small number of cases were involved in this study. Law\lor and colleagues 2 conducted a systematic review, and found that, in most studies, there was no association between the consumption of antidepressant medication and the breast cancer risk in the overall population. But the authors noted, however, that few trials have assessed this association specifically22. For breast cancer survivors, experimental studies suggested that interactions may exist between serotonin reuptake inhibitors and cytochrome p450 metabolism23,24. Stearns and colleagues24 observed a reduced concentration of active metabolites of tamoxifen when paroxetine was co-administered. This phenomenon varied in relation to the cytochrome p450 genotype.

In conclusion, we currently have, unfortunately, no reassuring data indicating the absence of a harmful effect of drugs commonly used to alleviate climacteric symptoms in breast cancer patients. Pharmacological studies and in vitro data on drugs such as inhibitors of serotonin reuptake suggest the existence of deleterious effect. This is rather alarming when considering the increasing number of breast cancer patients who seek help for their climacteric symptoms and who are currently treated. We believe that there is an urgent need for randomized trials to assess the safety of drugs in these patients. In the meantime, when prescribing drugs, physicians should inform patients about the absence of safety data, and a safety registration data base should be created.

Conflict of interest Nil.

Source of funding C.A. received a grant from Vesalius Fund to conduct this study.

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C. Antoine, F. Lichens, B. Carly, A. Pastijn and S. Rozenberg

Department of Obstetrics and Gynaecology, Free Universities of Brussels, CHU Saint-Pierre, Brussels,

Belgium

Correspondence: Professors. Rozenberg, Department of Obstetrics and Gynaecology, Free Universities of Brussels, CHU Saint-Pierre, Hoogstrasse 322, 1000 Brussels, Belgium

REVIEW

; 2007 International Menopause Society

DOI: 10.1080/13697130601 176734

Received 08-10-06

Revised 21-1 1-06

Accepted 28-1 1-06

Copyright Taylor & Francis Ltd. Feb 2007

(c) 2007 Climacteric. Provided by ProQuest Information and Learning. All rights Reserved.