Chemotherapy-induced Amenorrhea Research Articles

The Clinical Outcome of Chemotherapy-Induced Amenorrhea in Premenopausal Young Patients with Breast Cancer with Long-Term Follow-up

The Clinical Outcome of Chemotherapy-Induced Amenorrhea in Premenopausal Young Patients with Breast Cancer with Long-Term Follow-up

The Clinical Outcome of Chemotherapy-Induced Amenorrhea in Premenopausal Young Patients with Breast Cancer with Long-Term Follow-up

We investigated the factors that predict chemotherapy-induced amenorrhea (CIA) and the prognostic significance of CIA after long-term follow-up. We reviewed data from 241 premenopausal patients with breast cancer who underwent adjuvant CMF or FAC chemotherapy after breast cancer surgery between January 1995 and December 2000. The median follow-up duration was 109.8 (range, 16.6-193.1) months. The age of CIA patients was older than non-CIA patients (median, 44 (range, 28-53) years and 36 (range, 25-49) years, respectively; P < 0.001). The addition of tamoxifen to the chemotherapy increased the incidence of CIA from 48% to 63.6% (P = 0.015). The 10-year disease-free survival (DFS) rate was higher in the CIA group compared with the non-CIA group in hormonal receptor-positive patients (78.4% vs. 67%, respectively; P = 0.022), and the 10-year overall survival (OS) rate also was higher in the CIA group compared with the non-CIA group (90.8% vs. 79.7%, respectively; P = 0.041). The most important predictors of CIA are age and the addition of tamoxifen to the chemotherapy. CIA is likely to have an influence on DFS and OS in premenopausal patients with breast cancer with a positive hormone receptor, and it might be used as a surrogate marker for effective chemotherapy in these young Asian patients.

Incidence of chemotherapy-induced amenorrhea associated with epirubicin, docetaxel and navelbine in younger breast cancer patients

BackgroundThe rates of chemotherapy-induced amenorrhea (CIA) associated with docetaxel-based regimens reported by previous studies are discordant. For navelbine-based chemotherapies, rates of CIA have seldom been reported.MethodsOf 170 premenopausal patients recruited between January 2003 and September 2008, 78 were treated with fluorouracil plus epirubicin and cyclophosphamide (FEC), 66 were treated with docetaxel plus epirubicin (TE), and 26 were treated with navelbine plus epirubicin (NE). Patient follow-up was carried up every 3-4 months during the first year, then every 9-12 months during subsequent years.ResultsIn univariate analysis, the rates of CIA were 44.87% for the FEC regimen, 30.30% for the TE regimen and 23.08% for the NE regimen (P = 0.068). Significant differences in the rates of CIA were not found between the FEC and TE treatment groups (P > 0.05), but were found between the FEC and NE treatment groups (P < 0.05). Furthermore, no significant differences were found between the TE and NE regimens (P > 0.05). Tamoxifen use was a significant predictor for CIA (P = 0.001), and age was also a significant predictor (P < 0.001). In multivariate analysis, age (P < 0.001), the type of chemotherapy regimens (P = 0.009) and tamoxifen use (P = 0.003) were all significant predictors.ConclusionsAge and administration of tamoxifen were found to be significant predictive factors of CIA, whereas docetaxel and navelbine based regimens were not associated with higher rates of CIA than epirubicin-based regimen.

Incidence and time course of bleeding after long‐term amenorrhea after breast cancer treatment

The incidence of chemotherapy-induced amenorrhea (CIA) and the time to subsequent menstrual bleeding in premenopausal breast cancer patients treated with current standard chemotherapy regimens was examined. Four hundred sixty-six women ages 20 to 45 years at the time of diagnosis of a stage I to III breast cancer were recruited between January 1998 and July 2002. Patients completed monthly bleeding calendars from the time of study recruitment. Updated medical history data were obtained at 6-month intervals. Most women received doxorubicin and cyclophosphamide (AC); doxorubicin, cyclophosphamide, and paclitaxel (ACT); or cyclophosphamide, methotrexate, and 5-fluorouracil (CMF). Approximately 41% of women experienced an initial 6 months of CIA, and an additional 29% had at least 1 year of CIA. Approximately half of the women with 6 months of CIA and 29% of those with 1 year of CIA resumed bleeding within the subsequent 3 years, usually in the year after their amenorrheic episode. Resumption of bleeding differed significantly by treatment regimen after 6 months of CIA (P = .002; 68% with AC, 57% with ACT, and 23% with CMF), but not after 1 year of CIA (P = .5). Of the 23% of women who experienced an initial 2-year period of CIA, 10% resumed bleeding within the ensuing 3 years after their amenorrheic episode, but none had regular menses. A considerable proportion of women treated with chemotherapy will experience periods of CIA, but many will resume bleeding. Newer treatment regimens such as ACT appear to have a higher resumption of bleeding compared with CMF. This finding may have implications for choice of anti-estrogen treatment and for future potential pregnancies/fertility.

375 Taxane based regimen as a risk factor for chemotherapy induced amenorrhea (CIA)

Findings regarding the protective effect of social role functioning on suicide ideation in individuals with schizophrenia have been mixed. One reason for such inconsistencies in the literature may be that individuals with prominent negative symptoms of schizophrenia may not experience a desire for social closeness, and therefore social role functioning may not influence suicide risk in these individuals. The aim of this study was to examine the moderating effects of self-reported desire for social closeness and interviewer-rated negative symptoms on the relationship between social role functioning and suicide ideation. Our sample consisted of 162 individuals who had been diagnosed with schizophrenia-spectrum disorders; all participants completed self-report questionnaires and clinician-administered interviews, and moderation hypotheses were tested with a non-parametric procedure. The results indicated that motivation and pleasure-related negative symptoms moderated the relationship between social role functioning and suicide ideation; self-reported desire for social closeness and negative symptoms related to expression did not have such a moderating effect. Specifically, better social role functioning was associated with less suicide ideation only in those individuals who had low motivation and pleasure-related negative symptoms; no significant relationship was observed between social role functioning and suicide ideation among those with elevated motivation and pleasure-related negative symptoms. These findings suggest that assessing for negative symptoms and social role functioning may inform suicide risk assessments in individuals with schizophrenia, and improving social role functioning may reduce suicide ideation among those with few motivation and pleasure-related negative symptoms.

Effects of age on chemotherapy-induced amenorrhoea

Effects of age on chemotherapy-induced amenorrhoea

53 Chemotherapy-induced amenorrhea and adjuvant endocrine therapy for premenopausal women with early breast cancer

The protein-coding ability of circular RNAs (circRNAs) has recently been a hot topic, but the expression and roles of protein-coding circRNAs in triple-negative breast cancer (TNBC) remain uncertain. By intersecting circRNA sequencing data from clinical samples and cell lines, we identified a circRNA, termed circ-EIF6, which predicted a poorer prognosis and correlated with clinicopathological characteristics in a cohort of TNBC patients. Functionally, we showed that circ-EIF6 promoted the proliferation and metastasis of TNBC cells in vitro and in vivo. Mechanistically, we found that circ-EIF6 contains a 675-nucleotide (nt) open reading frame (ORF) and that the −150-bp sequence from ATG functioned as an internal ribosome entry site (IRES), which is required for translation initiation in 5′ cap-independent coding RNAs. circ-EIF6 encodes a novel peptide, termed EIF6-224 amino acid (aa), which is responsible for the oncogenic effects of circ-EIF6. The endogenous expression of EIF6-224aa was further examined in TNBC cells and tissues by specific antibody. Moreover, EIF6-224aa directly interacted with MYH9, an oncogene in breast cancer, and decreased MYH9 degradation by inhibiting the ubiquitin-proteasome pathway and subsequently activating the Wnt/beta-catenin pathway. Our study provided novel insights into the roles of protein-coding circRNAs and supported circ-EIF6/EIF6-224aa as a novel promising prognostic and therapeutic target for tailored therapy in TNBC patients.

Inhibin A Is Downregulated during Chemotherapy in Patients with Early Breast Cancer.

Abstract Introduction: Inhibins are dimeric glycoproteins, composed of an alpha-subunit (INH-a) and one of two possible beta-subunits (ßA or ßB), with substantial roles in human reproduction and in endocrine-responsive tumours. In breast cancer tissue, the growth factor Inhibin A is involved in cell differentiation and proliferation, thus suggesting a possible role as tumor marker. Aims of this study were to determine the serological measurement of Inhibin A (a- bA) in breast cancer patients during chemotherapy.Material and Methods: A series of 28 high risk N0 and N+ breast cancer patients who underwent standardized chemotherapy (3 x FEC and 3 x Docetaxel) followed by two years of zoledronate in the German SUCCESS trial were prospectively evaluated before chemotherapeutic treatment as well as after chemotherapy and two years after chemotherapy for the serological expression of Inhibin A. For serological analysis the ultrasensitive Inhibin A ELISA (DSL – U.S.A.) was used according to manufactures instruction. For statistical analysis the Wilcoxon rang sum test was used for paired samples. Statistical significance was assumed at p&amp;lt; 0.05.Results: The concentration of Inhibin A showed a significant decrease between data obtained before chemotherapy and after chemotherapy (p&amp;lt;0.005) and two-year follow up (p&amp;lt;0.001). Interestingly, there were seen no differences between the time point four weeks after chemoherapy and at two years (p=0.744).Discussion: Therefore, chemotherapy decreases significantly the Inhibin A concentration during chemotherapy. This might reflect a suppression of ovarian function and might be a marker for chemotherapy-induced amenorrhoea. Moreover, it has been suggested that Inhibin A might be a tumour marker for breast cancer, and therefore a sudden increase of its concentration might be indicative of breast cancer recurrence. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3028.

Facilitating consensus by examining patterns of treatment effects

Randomized clinical trials are necessary to provide reliable evidence concerning the effectiveness and safety of adjuvant therapies for breast cancer. Such trials, however, are not sufficient to provide information needed to tailor therapies to individual patients. Trials focus on testing treatments on average for heterogeneous patient populations, while attention to the specific characteristics of the disease and the patient are needed to assess the potential benefit for the individual. While 'across the board' results are useful from a population perspective, examination of patterns of treatment response during the course of follow up and for subpopulations of patients is required to make progress and solidify consensus on how to treat individual patients. For example, for several decades it has been known that the pattern of recurrence risk from time of diagnosis is different for estrogen receptor (ER)-negative and ER-positive disease. Assuming that ER status is accurately assessed and distinguishing absence of receptors from low, intermediate and high expression cohorts, one can recognize patterns of relapse risk that are early versus later during follow up. Treatments effective against ER-negative disease reduce the risk of early relapse, while those acting on ER-positive disease demonstrate effectiveness later during the course of follow up. Another example is HER2-positive disease, where a relatively high proportion of patients tend to relapse early, and treatments such as trastuzumab that reduce the risk of early relapse have demonstrated efficacy. For premenopausal patients with ER-positive disease, ovarian function suppression and endocrine effects of chemotherapy are effective to reduce the risk of late occurring relapses. Examining the influence of patient and disease-related factors on the patterns of recurrence over time and treatment responsiveness within subpopulations in multiple randomized trials can facilitate consensus on progress that has been made and identify areas for improving the care of patients with breast cancer.

Late effects of adjuvant systemic therapies in women diagnosed with breast cancer at a young age

Adjuvant systemic therapies – chemotherapy, endocrine therapy and biological therapy – for breast cancer carry risk of substantial side effects. Fortunately, many of these side effects prove short lived. In particular, the acute side effects of chemotherapy such as alopecia, nausea/vomiting and other gastrointestinal side effects, myelosuppression, and neuropathy typically resolve in the months following treatment. However, some side effects including fatigue, possibly cognitive dysfunction, and the rare instances of cardiotoxicity or secondary leukemias remain concerns in long-term follow-up. Patients who receive adjuvant endocrine therapies do so for multiple years, and thus have persistent jeopardy for ongoing symptoms of anti-estrogen treatment. The late consequences of newer biological therapies, particularly trastuzumab, are not yet characterized. Concerns over cardiotoxicity, in particular, remain to be fully detailed in long-term follow-up. Young women have unique concerns regarding long-term toxicity of adjuvant therapies. Younger women have a greater life expectancy in the absence of breast cancer, and fewer co-morbid conditions. Younger women are more likely to receive adjuvant chemotherapy, owing to both traditional treatment selection factors and the differing patterns of tumor subsets that arise in younger women. Younger women are at jeopardy for chemotherapy-induced menopause, with the attendant side effects of impaired fertility and symptoms of estrogen deprivation. Younger women often differ from older women in the professional, family and economic demands placed upon them, yielding different consequences for late side effects of adjuvant treatment. Finally, it is reasonable to

Incidence of chemotherapy-induced amenorrhea in hormone-sensitive breast cancer patients: the impact of addition of taxanes to anthracycline-based regimens

Adjuvant chemotherapy prolongs survival in patients with breast cancer, but it also causes side effects such as ovarian-function suppression. The incidence of chemotherapy-induced amenorrhea (CIA) varies depending on the patients' age, dose and the type of chemotherapy that they receive. CIA produced by anthracycline-based regimens has been widely studied, but less is known about the incidence of CIA caused by the combined use of taxanes and anthracyclines. It has been suggested that tamoxifen might influence the maintenance of amenorrhea. However, most studies of CIA have explored series of patients with hormone-sensitive and hormone-resistant tumors, so data about CIA could be strongly influenced by endocrine adjuvant therapy. The aims of our study were to assess the incidence of CIA with the addition of taxanes to anthracyclines regimens in pre- or perimenopausal patients diagnosed with hormone-sensitive breast cancer and to determine predictive factors for CIA. A retrospective non-randomized study was conducted in the Hospital Clinico Universitario of Valencia, Spain. Three hundred and five premenopausal and perimenopausal patients were recruited between January 1998 and May 2005, 212 of whom had been treated with anthracycline-based regimens and 93 with a combination of anthracyclines and taxanes. Amenorrhea was permanent in 222 patients (93.7%) and menses returned in 6.3%. CIA was present in 75.5% of patients treated with anthracyclines and in 82.7% of patients treated with anthracyclines and taxanes. This difference did not reach statistical significance (p = 0.16). CIA appeared in 95% of patients older than 45 years, while the proportion of CIA decreased to 52% in patients younger than 40 years. This suggests age as an important predictive factor for CIA (p < 0.001). Although a slightly superior incidence of CIA in patients with hormone-sensitive tumors treated with combination regimens was observed, no statistically significant difference in incidence was found. Age was found to be the main predictive factor for CIA in both groups.

Determinants of recovery from amenorrhea in premenopausal breast cancer patients receiving adjuvant chemotherapy in the taxane era

Chemotherapy-induced amenorrhea occurs in about 20-70% of premenopausal breast cancer patients. Chemotherapy-induced amenorrhea can affect choice of hormonal therapy, fertility, and quality of life of breast cancer survivors. We retrospectively analyzed the incidence of amenorrhea after adjuvant chemotherapy and the subsequent recovery of the menses in 145 breast cancer patients. Age, smoking, alcohol consumption, body mass index, chemotherapy regimen, previous hormonal therapies, and previous childbearing were analyzed as potential predictive factors of ovarian function recovery. Median age was 42 years at the beginning of adjuvant chemotherapy with 30.3% of patients below 40 years of age. The majority (87.6%) of patients received anthracycline-based chemotherapy, 35.2% of patients received a cyclophosphamide-methotrexate-5-fluorouracil regimen and 42.8% received a taxane. The incidence of chemotherapy-induced amenorrhea was 80, and 35.3% of these patients resumed menses after a median of 8 months. In multivariate analysis, younger age (<40 years, P=0.01) and taxane-based chemotherapy (P=0.03) were associated with increased probability of recovery of menses after chemotherapy-induced amenorrhea. In contrast, cyclophosphamide-methotrexate-5-fluorouracil-based chemotherapy (P=0.07) and previous childbearing (P=0.04) were associated with an increased probability of permanent chemotherapy-induced amenorrhea. Recovery of menses after chemotherapy-induced amenorrhea occurs more probably in younger women, with no pregnancies and receiving taxanes.

Controversies in hormonal adjuvant therapy for premenopausal patients

The major controversy concerning adjuvant hormonal therapy for premenopausal patients is the absence of appropriate clinical trial data to indicate the appropriate way to treat patients presenting with oestrogen receptor (ER)-positive operable breast cancer. This is despite the fact that the first randomized trial in breast cancer, begun in 1947, was a comparison of ovarian irradiation versus no further treatment after primary surgery for breast cancer [1] and the availability of recent overviews [2,3]. The Oxford overview indicates that tamoxifen is as effective in premenopausal women as in postmenopausal women. It also indicates that ovarian ablation is effective alone but not in addition to chemotherapy [3]. Subsequent studies indicate that ovarian suppression is effective in addition to chemotherapy in young women who do not develop chemotherapy-induced amenorrhoea. Multiple randomised studies indicate in patients with ER-positive tumours that ovarian suppression with or without tamoxifen is as effective as chemotherapy. All of these studies have been of poor design since none has had a third arm where both endocrine therapy and chemotherapy are given. It is likely that in the chemotherapy-alone arm there would be additional patients who would have responded to endocrine therapy and vice versa so that, although no differences between endocrine and chemotherapy were seen in these trials, it is not logical to conclude that either treatment alone is optimal without appropriate trial data. Because trials comparing methods of ovarian suppression have relatively few patients, we do not know the most effective method. LHRH agonists are associated with temporary ovarian suppression. The ZEBRA trial demonstrated that 2 years of goserelin was as effective as chemotherapy, but in this and subsequent trials of the use of LHRH agonists we do not have a clear indication of the duration of treatment required. Finally, no adequate trials indicate whether an LHRH agonist adds to the effectiveness of tamoxifen as adjuvant therapy. Given the uncertainties of treatment of premenopausal ER-positive early breast cancer, it is vital that patients are entered into appropriate trials such as SOFT.

Bone Health and Falls: Fracture Risk in Breast Cancer Survivors With Chemotherapy-Induced Amenorrhea

Purpose/Objectives: To describe risk factors for fracture-bone health and falls-among breast cancer survivors with chemotherapy-induced amenorrhea.Design: Cross-sectional and prospective cohort.Setting: National Cancer Institute-designated cancer center in the Pacific northwest region of the United States.Sample: Breast cancer survivors with chemotherapy-induced amenorrhea (N = 35; X age = 46 years; one year after chemotherapy) compared to cancer-free controls (N = 26; X age = 41 years).Methods: One two-hour testing session at baseline, 12-month follow-up, monthly postcards.Main Research Variables: Clinical characteristics and number of falls, leg strength, bone mineral density (BMD), body composition, and bone turnover.Findings: No significant differences between groups for BMD at either time point. Significantly more breast cancer survivors had low-spine BMD based on T scores and elevated bone turnover versus controls at baseline and follow-up. Breast cancer survivors with low-spine BMD have significantly lower body mass index, lean mass, and leg strength, and had stage II disease more often than breast cancer survivors with normal BMD. Significantly more breast cancer survivors (75%) experienced at least one fall compared to 46% of controls. Among breast cancer survivors, those who had fallen had significantly lower leg strength and calcium intakes than those who had not.Conclusions: Breast cancer survivors with chemotherapy-induced amenorrhea, particularly those with muscle weakness, may be at increased risk of fracture.Implications for Nursing: Breast cancer survivors with chemotherapy-induced amenorrhea should be evaluated for low bone mass and fall risk and considered for therapeutic intervention to lower fracture risk.

The Incidence of Chemotherapy-induced Amenorrhea and Recovery in Young (&lt;45-year-old) Breast Cancer Patients

Purpose: Although adjuvant chemotherapy improves the survival of premenopausal breast cancer patients, it could induce the premature menopause. The objective of this study was to investigate the incidence and risk factors of chemotherapy-induced amenorrhea (CIA) and recovery for young ( 30 mIU/mL. Results: A total of 324 patients were included in this study. Of these patients, 261 patients (80.6%) developed amenorrhea just after the completion of chemotherapy. During follow-up, 77 patients (29.5%) resumed menstruation. Amenorrhea rates at 6, 12, 24, and 36 months after chemotherapy were 72.2%, 66.6%, 58.1%, and 55.5%. Women who recovered from amenorrhea were significantly younger than the women who did not recover (p<0.001). Patients treated with cyclophosphamide, methotrexate and 5-fluorouracil (CMF) less frequently recovered from amenorrhea than patients who were treated with anthracycline or taxane-based chemo- therapy (p<0.001). Conclusion: The age of the patient was the most important factor for the development of CIA. Patients treated with a CMF regimen and older patients showed poor recovery from CIA. These results could be helpful to make decisions about the treatment strategies for premenopausal young women.

Do estroprogestinic hormones protect against chemotherapy-induced amenorrhea in multiple sclerosis?

This commentary discusses a paper by Cocco et al. that addresses the treatment of multiple sclerosis (MS) with the drug mitoxantrone in women of childbearing age. This is a very important issue, as mitoxantrone is thought to be associated with the development of chemotherapy-induced amenorrhea (CIA) in women with MS. CIA is a condition characterized by cessation of menstrual bleeding that can be associated with either temporary or permanent infertility. In the study, a clear cumulative dose effect of mitoxantrone on the development of CIA was demonstrated. The risk of CIA was also shown to increase with age. However, the incidence of CIA was lower in women who took estroprogestinic hormones concurrently with mitoxantrone. The authors concluded that mitoxantrone may markedly affect reproductive capacity in women with MS and that estroprogestinic drugs should be administered alongside mitoxantrone to guard against these possible effects. The potential for estroprogestinic drugs to guard against CIA is intriguing and warrants further investigation.

Frequency and risk factors of mitoxantrone-induced amenorrhea in multiple sclerosis: the FEMIMS study

Background Improved prognosis in women with multiple sclerosis (MS) undergoing immunosuppressive treatment with mitoxantrone (MITO) has led to an increased interest in the effect of such treatments on fertility. FErtility and Mitoxantrone In MS (FEMIMS) is a collaborative retrospective study aimed at evaluating the impact of MITO treatment on fertility in women with MS. Methods Occurrence of chemotherapy-induced amenorrhea (CIA) was evaluated in 189 women with MS treated with MITO before the age of 45. An “ad hoc” questionnaire, paying particular attention to onset of CIA either during or post-MITO treatment, was administered to each patient. The probability of CIA was calculated using a multivariate logistic regression analysis taking into account age at exposure, cumulative dose, and use of estroprogestinic (EP) drugs during treatment. Results Forty-eight (26%) patients presented CIA following MITO. The probability of CIA was increased by 2%/mg/m2 of cumulative dose and by 18% for each year of age, whereas it was reduced by administration of EP during treatment. Conclusions MITO treatment may affect reproductive capacity in women with MS. Patients of childbearing age should be properly counseled before MITO treatment and EP therapy should be administered to reduce the risk of CIA.

Analysis of chemotherapy-induced amenorrhea rates by three different anthracycline and taxane containing regimens for early breast cancer

Chemotherapy-induced amenorrhea (CIA) by newer taxane-containing regimens was evaluated in early breast cancer (EBC) patients. A prospective cohort of 122 premenopausal EBC patients participated in a phase III trial of preoperative docetaxel/capecitabine (TX) versus doxorubicin/cyclophosphamide (AC); 34 patients received adjuvant AC followed by paclitaxel (T) and 129 patients received 5-fluorouracil/doxorubicin/cyclophosphamide (FAC). The CIA rate was 90.2% with TX/AC, 73.5% with AC followed by T, and 72.1% with FAC at 1 year (P = 0.002), and 66.7%, 73.3%, and 58.9%, respectively, at 3 years (P = 0.268). At one year, age (P < 0.001) and taxane use (P = 0.002), and after two years, age and tamoxifen use were significant factors for CIA in multivariate analysis. Serum estradiol and follicle-stimulating hormone levels were significantly correlated with menstrual status, age, and tamoxifen use. Taxanes resulted in higher CIA rates in the first year, but age and tamoxifen use were significant factors for persistent CIA.

Meta-analysis examining the efficacy of serotonin and/or norepinephrine reuptake inhibitors in the treatment of women with hot flashes

20606 Background: Hot flashes can be particularly troublesome in post-menopausal women, as well as those who are on medications such as tamoxifen or aromatase inhibitors for breast cancer treatment. Patients with chemotherapy-induced amenorrhea may also develop hot flashes that can impact on their quality of life. Serotonin and/or norepinephrine reuptake inhibitors have been studied to determine if they reduce the frequency or severity of hot flashes. The objective of this study is to provide a systematic review and meta-analysis of the randomised controlled trials evaluating SSRI and SNRI use in women experiencing hot flashes. Methods: Five medical literature databases were searched to identify all potential randomised placebo-controlled trials evaluating SSRI/SNRI’s in women with hot flashes. The methodological quality of the trials were also assessed. The results of all studies that met the inclusion criteria were compiled and systematically reviewed. The primary outcome for the pooled analysis was the...

Cyclophosphamide, epirubicin, and 5-fluorouracil versus epirubicin plus paclitaxel in node-positive early breast cancer patients: A randomized, phase III study of Gruppo Oncologico Nord Ovest-Mammella Intergruppo Group

516 Background: This trial is aimed at comparing the efficacy and tolerability of 2 regimens of adjuvant therapy for patients (pts) with node-positive breast cancer. Methods: Women with operable, N+ breast cancer and less than 10 involved axillary nodes were eligible. Therapy was as follows: Arm 1 (CEF): cyclophosphamide 600 mg/m2, epirubicin 60 mg/m2 and 5-fluorouracil 600 mg/m2 given every 3 weeks for 6 cycles; Arm 2 (ET): epirubicin 90 mg/m2, paclitaxel 175 mg/m2 3-hour infusion given every 3 weeks for 4 cycles. Tamoxifen (20 mg/die) was given to all pts with ER and/or PgR positive tumor. Primary endpoint was overall survival (OS) and secondary endpoints were event free survival (EFS) and tolerability. The study was designed to detect a hazard ratio of 0.80, assuming an alpha error of 0.05 (two sided) and a power of 0.80. This required 500 pts per arm. Results: From Nov 1996 to Jan 2001, 1,055 pts were randomized: 520 pts received CEF and 535 ET regimens. Main pts characteristics were age <50 years (35% and 42% in arm 1 and 2, respectively); N+1–3 (68% and 69%); ER and PgR negative status (24% and 19%). Pts treated with CEF experienced more frequently nausea/vomiting (85% in arm 1 and 76% in arm 2, p=0.0001), mucositis (46% vs 37%, p=0.003) and leukopenia (52% vs 40%, p=0.0002). Toxicities occurring more frequently in ET arm were anemia (17% vs 25% in arm 1 and 2, respectively, p=0.006); fever (7% vs 15%, p=0.0001); myalgia (1% vs 19%, p=0.0001); neurotoxicity (6% vs 38%, p <0.0001) and allergic reaction (1% vs 5%, p=0.03). Among 412 premenopausal pts, chemotherapy-induced amenorrhea occurred in 51% of pts treated with CEF and in 45% of pts treated with ET (p=0.16). The median follow-up in surviving pts was 8.2 years. At Dec 2007, 223 deaths and 344 events were recorded. The 5-year EFS was 71% and 70% in arm 1 and 2 respectively; 10-year EFS was 46% in both arms. The 5-year OS was 89% and 88% in arm 1 and 2, respectively; the 10-year OS was 72% (95% CI: 66–78) and 76% (95% CI: 71–80) (p=0.8). Conclusions: CEF for 6 cycles and ET for 4 cycles are associated with a different toxicity profile. At 5- and 10 years, no significant difference in OS and EFS was observed between CEF and ET regimens. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bristol-Myers Squibb