Centre Oscar Lambret, Lille, France
* Correspondence to: Dr J. Bonneterre, Département de Senologie, Centre Oscar Lambret, 3 Rue Frédéric Combemale, 59020 Lille Cedex, France. Tel: +33-3-20-29-55-50; Fax: +33-3-20-29-55-80; Email: j-bonneterre{at}o-lambret.fr
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Abstract |
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Patients and methods:: Retrospectively, we reviewed data from 130 premenopausal patients with localized hormone-sensitive breast cancer. These patients were treated between 1985 and 1995 at the same institution. They all underwent a loco-regional treatment and adjuvant chemotherapy. Early CIA was defined as an amenorrhea arising during the first year following the beginning of chemotherapy. Predictors of early CIA were examined. The survival analyses were done using the KaplanMeier method and Cox analysis.
Results:: Median follow-up was 9 years. Mean age was 42.9 ± 5 years. Ninety-two per cent of patients had histologically-proven positive axillary nodes. Adjuvant chemotherapy contained no anthracycline in 63%. Early CIA occurred during or after adjuvant chemotherapy in 57% of the patients. It was definitive in 91%. In our study, age was the only CIA predictor in univariate analysis. Women who experienced early CIA tend to have a longer disease-free survival, but the difference was not significant. This trend was lost in multivariate analysis, most probably due to the small sample size. The overall survival was not different.
Conclusion:: Although not statistically significant, our results on a very selected population of patients suggest that a chemotherapy-induced amenorrhea might have its own therapeutic effect besides the cytotoxic action of chemotherapy.
Key words: amenorrhea, adjuvant chemotherapy, breast cancer
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Introduction |
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The aim of this study was to analyze the influence of early CIA on disease-free and overall survival in a targeted population. Premenopausal women treated with adjuvant chemotherapy for a receptor-positive breast cancer are considered. We studied the early CIA rather than late CIA, which was more likely to be a physiological amenorrhea rather than a chemotherapy-induced amenorrhea [8].
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Patients and methods |
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Definitions
Premenopausal status was clinically defined by regular menstruation at initial diagnosis. For the early CIA, we used the Bines' definition [3]. Early CIA was
6 months without menstrual periods and within 1 year after starting chemotherapy, in a patient who was premenopausal at diagnosis. Temporary CIA was the reappearance of regular menstruation after CIA had occurred.
Disease-free survival (DFS) was defined as the length of time from the date of the diagnosis to relapse (including ipsilateral breast recurrence), the appearance of a secondary primary cancer (ipsi or controlateral), or death. Overall survival (OS) was defined as the time between the diagnosis and the last follow-up or death.
Patients
All patients were premenopausal and presented a localized hormonosensitive breast cancer. Of the 242 patients, 112 were excluded for different reasons: (i) lack of information on the menstrual periods; (ii) previous history of bilateral oophorectomy or hysterectomy; (iii) adjuvant hormonotherapy as ovarian suppression (medical, surgical or by radiotherapy) or antioestrogen (tamoxifen); and (iv) non-specific breast cancer death, for example, one patient died of a sepsis during an aplasia. Finally, 130 patients were assessable.
Treatment
Surgery of the breast cancer was either a total mastectomy or a breast conserving procedure. An axillary lymph node dissection was always done. A loco-regional radiotherapy was delivered after surgery to all patients according to the protocol used at the center. The different protocols of adjuvant chemotherapy used were CMF-type (combination chemotherapy with cyclophosphamide, methotrexate and fluorouracil), FEC-type (50 or 100 mg/m2 epirubicin) and others [epirubicin-navelbine and peri-operative FAC (5-fluorouracil, doxorubicin, cyclophosphamide)] (Table 1). All patients received six cycles of chemotherapy except for peri-operative FAC with only one cycle. The patients never received adjuvant hormonotherapy.
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Results |
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Univariate predictors of CIA
CIA occurred in 74 out of 130 (57%) patients. Most often, it happened during chemotherapy and was definitive in 91% of cases (Table 1). In univariate analysis, the incidence of CIA was significantly higher when women were older (Table 2). The mean age in the CIA group was 46.0 ± 4 years and in the no CIA group 38.8 ± 5 years (P <105). This result was well represented in the age distribution of patients shown in Figure 1. Among women who experienced a CIA, the temporary CIA was more frequent in younger patients (Figure 2) and occurred earlier (Figure 3). However, this difference was not statistically significant due to the small number of patients with temporary CIA (Table 1).
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Disease-free and overall survival analysis
Half of the patients had a relapse, which was usually metastatic. Fifty-one patients died of breast cancer (Table 1). Relapse site and treatment were not statistically different between the CIA and no CIA groups. Nevertheless, the hepatic metastasis rate was higher in the no CIA group (34.4% versus 59.2%, P=0.10).
The KaplanMeier curves for DFS and OS according to CIA are shown in Figures 4 and 5. DFS was longer when a CIA occurred. However, the difference was not significant (P=0.11), even if the study is carried out for patients over and under 40 years (data not shown). Median DFS was 11.1 years in the presence of CIA and 7.2 years in its absence. OS curves, according to CIA status, were not different (P=0.26). Median OS was 13.3 years and 11.4 years in the presence and in the absence of CIA, respectively.
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Discussion |
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Adjuvant chemotherapy, which improves survival in premenopausal women, provides a small hormonal effect by a chemo-induced castration and this effect was observed even if the CIA was temporary. A prospective study to confirm the results is no longer possible since premenopausal patients with hormonal receptor-positive tumors systematically receive adjuvant hormonotherapy.
In our experience, the only predictive factor of CIA is age. According to the literature many predictive factors can be added. For example, the chemotherapy regimen has an important effect on CIA incidence [3]. Furthermore, alkylating agents are more commonly associated with ovarian damages. The importance of ovarian damage can influence the duration of CIA. In our study, CIA incidence was 57%. It was 62% and 50% in the subgroups with CMF-type and FEC regimen, respectively. These data are consistent with the literature. Classical CMF regimens are associated with a 69% amenorrhea rate in a matched population [3
]. Furthermore, cyclophosphamide cumulative dose and dose-density influence the CIA incidence. With anthracycline-based regimens, the CIA rate ranges from 33% to 59% [5
]. Amenorrhea associated with taxanes is less well understood. Data from the BCIRG 01 trial comparing TAC and FAC in early-stage breast cancer show 51.4% and 32.8% CIA incidence, respectively [23
]. In a recent publication, Di Cosimo found a relation between the incidence of CIA and the timing of treatment by menstrual cycle phase in women with early breast cancer treated with adjuvant chemotherapy [24
].
Other methods induce castration: oophorectomy, radiotherapy and LHRH analogs. Many questions remain unanswered about the effectiveness of castration according to its duration in premenopausal women with endocrine-responsive tumors. Several data suggest little, if any, additional benefit from definitive castration (whatever the modalities) following adjuvant chemotherapy, suggesting that CIA would have a similar effect to castration. Oxford overviews have shown that adjuvant ovarian castration adds little compared to the effects of chemotherapy alone [25, 26
]. The Davidson study compared CAF alone (CAF) versus CAF plus goserelin, LHRH analog, (CAFZ) versus CAF plus goserelin plus tamoxifen (CAFZT) [27
]. The CAFZ arm produced a significantly better DFS and OS, whereas the addition of goserelin alone showed only marginal benefit. Unfortunately, this interesting study is not conclusive because of the lack of a CAF plus tamoxifen arm.
The role of castration instead of chemotherapy remains unclear [28]. Indeed, most trials that compared adjuvant ovarian ablation and adjuvant chemotherapy, used CMF regimens and not an anthracycline-based regimen except one, FAGS 06 [34
]; chemotherapy regimen was often suboptimal, intravenous CMF rather than classical CMF, or FEC50 rather than FEC100. Currently, three clinical trials have been proposed by the International Breast Cancer Study Group (IBCSG) to investigate the relative role of hormonotherapy, including temporary or definitive ovarian suppression, and chemotherapy in premenopausal patients with hormonal receptor-positive early breast cancer. These studies, SOFT, TEXT and PERCHE, are summarized in Table 4.
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In conclusion, early chemotherapy-induced amenorrhea is likely to have an influence on DFS in premenopausal women with endocrine-responsive breast cancer. The most important predictors of CIA are age and the chemotherapy regimen. Older women are at greater risk of CIA. With CMF and FEC regimen, the CIA incidence is between 50% and 70%. The hormonal effect of chemotherapy contributes to the cytotoxic mechanism of action. Studies on the adverse effects of these treatments should help to determine the optimal adjuvant treatment.
Received for publication December 15, 2004. Revision received March 2, 2005. Accepted for publication March 3, 2005.
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