Cimicifuga racemosa for the treatment of hot flushes in women surviving breast cancer

Abstract

Objectives: To examine the effect of Cimicifuga racemosa (CR BNO 1055) on hot flushes caused by tamoxifen adjuvant therapy in young premenopausal breast cancer survivors. This treatment presents an off-label use of CR BNO 1055. Methods: Between May 1999 and December 2001, we accrued 136 breast cancer survivors aged 35–52 years. After treatment with segmental or total mastectomy, radiation therapy and adjuvant chemotherapy, participants were in open-label randomly assigned (1–2) to receive tamoxifen 20 mg per day orally (usual-care group; n=46) or tamoxifen (same dose and posology) plus CR BNO 1055 (Menofem®/Klimadynon®, corresponding to 20 mg of herbal drug; intervention group n=90). Duration of treatment was 5 years for tamoxifen, according to international standards for adjuvant therapies, and 12 months for CR BNO 1055. Follow-up included clinical assessment every 2 months; the primary endpoint was to record the number and intensity of hot flushes. Results: Comparing patients assigned to usual-care group with those assigned to intervention group, the number and severity of hot flushes were reduced after intervention. Almost half of the patients of the intervention group were free of hot flushes, while severe hot flushes were reported by 24.4% of patients of intervention group and 73.9% of the usual-care group (P<0.01). Conclusions: Hot flushes were the most frequent adverse reaction to tamoxifen adjuvant therapy in breast cancer survivors. The combined administration of tamoxifen plus CR BNO 1055 for a period of 12 months allowed satisfactory reduction in the number and severity of hot flushes.

Introduction

Aging ovaries stop secreting estradiol when menopause occurs; by then, estrone (less active estrogen) replaces estradiol. The lack of physiological feedback of estradiol production increases serum levels of both, follicle stimulating hormone (FSH) and luteinizing hormone (LH). During this time period, the quality of life is reduced in most women due to vasomotor episodes [1].

Frequent hot flushes are associated with psychosomatic complaints such as tenseness, tiredness, irritability, headache, muscle and joint pains and depression. Vasomotor complaints vary widely in both, severity and duration. Severe vasomotor complaints in menstruating women cause larger decrease in wellbeing than in non-menstruating women. As a consequence of decreased levels of estrogen, bone turnover increases and bone resorption prevails over bone formation [2]. Menopause is also linked to cardiovascular health and to reduction in cognitive function [3], [4].

Of primary importance in the treatment of postmenopausal women are the prevention of bone loss and the amelioration of vasomotor systems, which have established benefits of replacement therapy. Since 1980, hormone replacement therapy (HRT) that includes both an estrogen and a progestin has been seen as a specific treatment for symptoms in the short-term and preventive therapy in the long-term.

Recent data from a randomized, blinded and controlled clinical trial indicate that HRT for up to more than 5 years is not beneficial overall and that there is early harm for stroke and venous thromboembolism, and increasing harm for breast cancer with increasing duration of treatment [5]. Moreover, the comparison of HRT with placebo in older women with coronary disease reveals increased rates of venous thromboembolism and biliary tract surgery without favorable trends in overall rate of cardiovascular disease [6]. These contradictory evidences indicate that HRT should be applied when beneficial clinical outcomes outweigh harmful ones.

As would be expected, the issues of HRT become even more complicated when its use is considered for women with a known history a breast cancer. This population of postmenopausal breast cancer survivors is rising. In addition, the increasing use of adjuvant chemotherapy for patients whose axillary lymph nodes are negative or positive for disease results in an additional population of younger patients who are rendered prematurely menopausal [7]. It has been demonstrated that ovarian ablation may be associated with a 15–25% reduction in rates of breast cancer recurrence and of mortality [8]. This has led to speculation that the ovarian failure induced by chemotherapy may contribute to the survival benefit derived from adjuvant therapy. The evidence that estrogens have an adverse effect on breast cancer risk is based on the in vitro effects of estrogens on breast cancer cell lines and the recent epidemiological data suggesting that long-term use of HRT may increase the risk of developing breast cancer [5].

Due to the uncertainty of this situation, most clinicians chose to use alternative therapeutic routes; moreover, women with a previous diagnosis of breast cancer are averse to accept much increased risk of recurrence in order to take HRT [9].

The selective estrogen receptors modulators (SERMs) are a new class of pharmacological agents now available to women who cannot tolerate or are unwilling to use conventional HRT. SERMs were formerly referred to as anti-estrogens, a description that is now known to be inappropriate. The term SERM has been coined to describe compounds that, in contrast to pure estrogen agonists or antagonists, have a mixed and selective pattern of estrogen agonist–antagonist activity, which largely depends on the tissue targeted [10].

The pharmacological goal of these drugs is to produce estrogenic actions in those tissues, where these actions are beneficial (bone, brain, liver) and to have either no activity or antagonistic activity in tissues such as breast and endometrium, where estrogenic actions (cellular proliferation) might be deleterious. The most actively studied SERMs commonly are tamoxifen and raloxifen. Tamoxifen is currently approved as an adjuvant for the treatment of breast cancer (node-negative or node-positive) in women after total or segmental mastectomy and breast irradiation, in the treatment of women with advanced or metastatic breast cancer, and as a preventive agent for women at high risk for breast cancer. The NSABP P-1 trial has shown that 20 mg per day of tamoxifen reduced the risk of invasive breast cancer by 49% (69 months of follow-up). The decreased risk occurred in women of all age groups with ER-positive breast cancer; it had no effect on ER-negative tumors. However, women aged 50 or older, receiving tamoxifen, had more than a twofold increased risk of early stage endometrial cancer; women younger than 50 had no increased incidence of adverse events, including endometrial cancer [11]. Moreover, NSABP P-1 study shows that the use of tamoxifen is associated with an increase in specific vasomotor and gynecological symptoms [12].

Hot flushes are a well-known side effect which occur in pre- and postmenopausal breast cancer patients treated with tamoxifen. Severe hot flushes are more frequent in menstruating women with a greater impact on quality of life; the majority of them cannot use conventional HRT for the control of the menopausal symptoms. Medications other than estrogens have to be used to control such symptoms among breast cancer survivors.

Preparations with extracts of Cimicifuga racemosa were originally used for menstrual and climacteric conditions. In recent years, C. racemosa has increasingly been recommended for use in the treatment of the physical and psychological symptoms of menopause [13], [14]. The exact mechanism by which these preparations elicit their effects on menopausal symptoms has not been elucidated. While some have proposed that its effectiveness is mediated by an inhibitory effect on the hypothalamus or an effect on neurotransmitters [15], others have suggested that it has a direct estrogenic effect with the hypothesis that C. racemosa contains phytoestrogens, estrogen-like compounds found in plants [16]. To date, no known phytoestrogens have been identified in C. racemosa. An estrogenic activity is supported by some preclinical and clinical trials and not by others. The results of preclinical research appear to indicate that CR BNO 1055 contains phyto-SERMs (Jarry et al., Seidlovà-Wuttke et al. and Wuttke et al., this volume).

Of theoretical importance in this controversy is the safety of C. racemosa in women with estrogen-sensitive conditions such as breast cancer. On this respect, the manufacturer of CR BNO 1055 states that the preparation should not be given to patients who have or have had a history of estrogen-dependent tumors. We conducted an open randomized clinical trial to assess the efficacy and side effects of CR BNO 1055 in controlling hot flushes among breast cancer survivors under tamoxifen adjuvant therapy. This is an off-label use of the preparation. The combination therapy tamoxifen–CR BNO 1055 invites for theoretical speculations: it is known that CR BNO 1055 does not bind to ERα or ERβ-recombined proteins. It does bind, however, to cytosolic estrogen-binding proteins of human and porcine origin. Therefore, the possibility exists that other, possibly not yet identified, ERs exist (Jarry et al., this volume).