Two Treatment Models Of Chemotherapy Combined With Endocrine Therapy In Breast Cancer:an Exploratory Study

ObjectiveIt is conventional for hormone receptor-positive breast cancer patients to undergo chemotherapy and endocrine therapy with sequential mode, both in the adjuvant treatment of early stage and rescue treatment of advanced stage. Yet there still exists debate on efficacy and safety of simultaneous use of chemotherapy and endocrine therapy,also very divergent views in whether the gonadotropin-re leasing hormone (GnRH-a) can prevent the chemotherapy-induced premature ovarian failure in premenopausal patients. In this study, we investigated the feasibility and potential value of two treatment models of chemotherapy combined with endocrine therapy--metronomic chemotherapy combined with aromatase inhibitor(AI) for postmenopausal patients and routine adjuvant chemotherapy plus GnRH-a in premenopausal patients--in clinical application.MethodsPartⅠThis was a Phase Ⅱ single-arm clinical study in which we retrospectively analyzed the follow-up data of all patients enrolled in the treatment of Capecitabine metronomic chemotherapy plus the third-generation AI from November2010to March2013.1.Purpose:To determine the adverse effects and clinical efficacy of AI combined with Capecitabine metronomic chemotherapy in postmenopausal breast cancer patients with ER and/or PR positive.2. Patients:1) ER and/or PR+,invasive breast cancer confirmed by histology;2) postmenopausal or premenopausal with both ovaries castration;3) ECOG≤3, at least3months of life expectancy;4) Primary breast lesions≥3cm or measurable metastases lesions; 5) Have not yet received endocrine therapy, or initial/first-line endocrine treatment failure;6) Informed consent.3. Methods:Aromatase inhibitor:1) The initial endocrine treatment group: Anastrozole1mg/dayp.o;2) Second-line endocrine treatment group: Exemestane25mg/day p.o; or Letrozole2.5mg/day p.o;Metronomic chemotherapy:Capecitabine (Xeloda)500mg tid p.o(Can be gradually reduced to500mg qd p.o due to adverse reactions)4. Objectives:1) Safety;2) Objective response rate (ORR) and clinical benefit response(CBR);3) Progress ion-free survival (PFS) and time to treatment failure (TTF).PartⅡThis was a Phase III prospective randomized study in which patients enrolled were randomly allocated to receive chemotherapy concurrent or sequential goserelin treatment and we analyzed the clinical and follow-up data from July2009to March2013.1.Pur pose:Assuming a lower rate of early menopause and non-inferiority therapeutic effect when used chemotherapy combined with GnRHa concurrently in premenopausal patients.2.Patients:1) Age≤45years;2) Premenopausal;3) Active contraception during the treatment;4) The main criteria for exclusion:presence of metastatic tumors; metachronous bilateral breast cancer; previously ovarian medical castration treatment.3.Methods:1)Registered patients randomized to chemotherapy combined with goserelin group or chemotherapy sequential goserelin group;2) Conventional standard treatment of breast cancer;3) Five years treatment of tamoxifen after chemotherapy and radiation treatment;4) The total of2-3years’Goserelin,3.6mg/28day,subcutaneous injection.4.Objectives:1) The proportion of menstruation resumption after more than lyear from the end of Goserelin;2) The amenorrhea and changes of hormone levels during and after the chemotherapy;3) The clinical efficacy of neoadjuvant subgroups.ResultsPartⅠ1.The general condition of patients:In this study(metronomic chemotherapy combined with AI for postmenopausal patients)52patients were enrolled,among whom12patient(23.1%) have not received endocrine therapy yet,40patients foiled in primary or first-line endocrine treatment(76.9%),30patients (57.7%) had two or more systemic diseases, and24patients (46.2%) had at least two metastatic sites.2. Safety analysis:There occurred4patients(7.7%) with Ⅲ-Ⅳ°hand-foot-syndrome,2patients(3.8%) with fractures,1patients (1.9%) with cerebral infarction.Most of other patients had no or mild hematologic and non-hematologic toxicities,8patients(15.4%) reduced and3patients(5.7%) discontinued treatment due to the adverse events. Good tolerance and compliance were showed among them.3.Efficacy analysis:The overall ORR was63.5%, while the overall CBR was80.8%.The ORR of the patients who have not received endocrine therapy yet and initial/first-line endocrine therapy failure group were75.0%and60.0%, respectively, CBR were91.7%and77.5%respectively,The median PFS of the initial/first-line endocrine therapy failure group was9.7months(95%CI:6.0-202.1-17.4months),median TTF was9.1months (95%CI:5.4-12.8months).PartⅡ 1.The general condition of patients:There were198patients enrolled,95patients in sequential group and103patients in combined group.All patients enrolled were premenopausal, and the general condition of patients, tumor stage and follow-up showed no statistical difference (P>0.05).2. Amenorrhea during the chemotherapy:Combined group induced earlier amenorrhea than sequential group. In sequential group, the younger patients were the later they had amenorrhea caused by chemotherapy.3.Menstrual recovery:The proportion of no-menstruation recovery over1year after stopping Goserelin were approximately25%in the combined group, and44%in the sequential group;the menstrual recovery rates were25.0%and25.0%, respectively.4. Efficacy of neoadjuvant subgroup:Clinical efficacy assessment of the proportion of PR or CR were66.7%in combined group and77.8%in the sequential group, with no statistically significant difference (P>0.05), there were2patients respectively achieved pathological complete response.Conclusion1.Metronomic chemotherapy combined with AI synchronously shows well safety,tolerance and compliance in initial or first-or second-line endocrine therapy of HR+postmenopausal breast cancer patients.2.1t’s worth further conduct phase Ⅲ randomized controlled study since metronomic chemotherapy with AI resynchronization therapy displays better efficacy.3.Chemotherapy plus GnRH-a can induce earlier amenorrhea in HR+premenopausal patients compared with chemotherapy alone.4.HR+premenopausal patients may have more chances in restoring menstruation when accept chemotherapy plus GnRH-a therapy.5.Simultaneous application of GnRH-a does not affect the sensitivity of HR+premenopausal early breast cancer to neoadjuvant chemotherapy.