Clinical trial NCT02518191
Conditions: Breast Cancer
Keywords: GnRHa ovarian function anti-mullerian hormone
Sponsor: Xiangyun Zong
Start date: 2015-09-01; Completion date: 2021-01-12
Enrollment: 345 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This prospective randomized controlled study is conducted to analyze the effect of Goserelin on ovarian function in women with breast cancer in China.

Detailed description:

Arms: arm 1: Eligible patients with breast cancer treated with GnRHa while receiving chemotherapy. arm 2: Eligible patients with breast cancer treated without GnRHa while receiving chemotherapy.
Interventions: intervention 1: GnRHa
Intervention descriptions: intervention 1: 3.6mg subcutaneous injection every 28 days.Initiated 1-2 weeks before chemotherapy and ended 4-8 weeks after chemotherapy.

Protocol documents:
Prot_SAP_000.pdf: 
Effects of GnRHa on Ovarian Function Against Chemotherapy-
induced-gonadotoxicity in Women With Breast Cancer in China 
(EGOFACT) 
NCT02518191 
 
 
 
March 10, 2021 
 
 


Trial Oversight 
 
The trial was an investigator-initiated, two-center, randomized, phase 3, 
open-label, superiority, controlled trial involving premenopausal female breast cancer 
patients needed neoadjuvant or adjuvant chemotherapy in two parallel groups: 
chemotherapy with or without GnRHa treatment. The trial was funded by the Science 
and Technology Commission of Shanghai Municipality and Zhejiang Medical Society, 
and conducted in accordance with the provisions of the Declaration of Helsinki and 
Good Clinical Practice guidelines. 
The trial was conducted at the Shanghai Jiao Tong University Affiliated Shanghai 
Sixth People’s Hospital in Shanghai, China and Zhejiang Cancer Hospital in 
Hangzhou, China. The practitioners in these two hospitals treat approximately 3000 
breast cancer patients annually. The trial protocol and all amendments were approved 
by an independent ethics committee or the institutional review board at each site. 
Safety data were assessed by an independent data monitoring committee. Written 
informed consent was provided by all the patients. Representatives of the sponsor 
designed the trial and confirmed the accuracy of and compiled the data for analysis. 
All the authors had access to the data and vouch for the completeness and accuracy of 
the data and for the fidelity of the trial to the protocol. All the authors contributed to 
the writing and review of all manuscript drafts and were involved in the interpretation 
of the data. 
The trial protocol has not been published previously. The manufacturers of the 
GnRHa (goserelin & leuprorelin), did not provide support for the trial and were not 
involved its design or conduct or in the writing of the manuscript. There were no 
agreements concerning confidentiality of the data between the sponsors and the 
authors or their institutions. 


Participants 
 
Inclusion Criteria: 1. Premenopausal women 18 to 49 years of age were eligible 
for enrollment. ⒉ Patients had operable stage I to III breast cancer for which 
treatment with adjuvant or neoadjuvant cyclophosphamide-containing chemotherapy 
was planned. 3. Eligible participants had taken no estrogens, antiestrogens, selective 
estrogen-receptor modulators, aromatase inhibitors, or hormonal contraceptives 
within the month before enrollment. 4. Human chorionic gonadotropin negative by 
urine test before entering the group. 5. Informed consent, understanding and 
compliance with the requirements of the study. 6. No significant chronic disease and 
any organ dysfunction. 
Exclusion Criteria: 1. Exceptions were made for the use of hormonal 
contraception in women younger than 35 years of age that was discontinued before 
randomization. 2. Use of hormonal treatment for up to 2 months for the purposes of 
in vitro fertilization and cryopreservation of embryos or oocytes before randomization. 
3. Patients with metastatic lesions or history of bilateral ovariectomy, ovarian 
radiation were excluded. 4. Patients received previous adjuvant endocrine therapy for 
breast cancer were not suitable to this trial. 5. Patients with uterine and/or adnexal 
diseases needing medical or surgical treatment were not suitable. 6. Allergic to active 
or inactive excipients of GnRHa was an exclusion criterion. 
Trial Procedures and Interventions 
 
Considering ethical issues related to randomization of patients with  fertility 
desire, all patients enrolled in our study were comprehensively informed and 
volunteered to this trial. Crossover between the two groups was permitted. The 
randomization   procedure   was   prepared   by   an   independent   statistician.   The 


assignments remained concealed in opaque, sealed envelopes, with a 1:1 allocation 
ratio. All the patients as well as all investigators who administered treatment, assessed 
outcomes, and analyzed data were unaware of the trial-group assignments. However, 
after randomization, all patients and all researchers involved in the treatment and 
evaluation of the results were aware of the allocation of the trial group, except the 
investigators who analyzed the data. 
In eligible patients who were randomized to receive GnRHa, 3.6mg goserelin or 
3.75mg leuprorelin was injected subcutaneously once every 28 days, from 1-2 weeks 
before the first cycle of chemotherapy to 4 weeks after the last cycle of chemotherapy. 
Eligible patients with breast cancer were treated without GnRHa while receiving 
chemotherapy in the controlled group. 
Patients 
received 
chemotherapy 
according 
to 
one 
of 
the 
following 
cyclophosphamide-based regimens: TEC (docetaxel 75mg/m2 + epirubicin 60mg/m2 + 
cyclophosphamide 500mg/m2), EC-T(H) (epirubicin 90mg/m2 + cyclophosphamide 
600mg/m2 for 4 cycles followed with 4 additional cycles of docetaxel 100mg/m2 ± 
trastuzumab), TC(H) (docetaxel 75mg/m2 + cyclophosphamide 500mg/m2 ± 
trastuzumab), 
FEC 
(5-fluorouracil 
500mg/m2 
+ 
epirubicin 
90mg/m2 
+ 
cyclophosphamide 500mg/m2). All of the patients with human epidermal growth 
factor receptor 2 (HER2) positive tumors received trastuzumab (8mg/kg with first 
dose, followed by 6mg/kg for 1 year). Women with hormone receptor–positive 
disease received adjuvant endocrine therapy for 5 years starting from the end of 
chemotherapy. In both study groups, patients who resumed their ovarian function 
during the 12-month period of observation after the end of chemotherapy or at any 
time during the following 5 years of follow-up were allowed to receive GnRHa for at 
least 2 years as part of their endocrine treatment. 


Radiation therapy after completion of chemotherapy was mandatory for patients 
who underwent a lumpectomy or breast conserving surgery. For patients who 
underwent a mastectomy, radiation therapy was performed according to the guidelines 
of each participating institution. 
End points 
 
The primary objective was to compare the rate of chemotherapy-induced 
premature ovarian insufficiency (POI) between the GnRHa group and the Controlled 
group. POI was defined as AMH＜0.5ng/mL in this study. The serum levels of 
AMH were measured using human AMH ELISA kit (11351, Biofine)), and the AFC 
(antral follicle with 2–10mm in mean diameter) observed with transvaginal or 
endoanal ultrasonography was not calculated and analyzed due to low compliance. 
The levels of AMH were evaluated before treatment, at 6 months and 1 year after last 
cycle of chemotherapy. Ovarian function recovery was defined as an AMH 
concentration ≥0.5 ng/ml (Cohen et al., 2015). Patients who became pregnant were 
considered not to have had ovarian failure. 
The secondary outcomes were survival rates. Events in the analysis of overall 
survival (OS) included deaths due to any cause; Tumor free survival (TFS) events 
were defined by the occurrence of one of the following: local recurrence, distant 
metastases, contralateral or ipsilateral breast tumor, or death from breast cancer. Only 
adverse events related to hormonal effects and serious adverse events that occurred 
during chemotherapy with or without goserelin were routinely assessed, with 
assessment according to the Common Terminology Criteria for Adverse Events, 
version 4.03. Annual follow-up was planned to record recurrences, and deaths (last 
annual follow-up, December 31, 2020). 
Statistical Analysis 


A sample size of 368 was required for a 90% chance of detecting an absolute 
difference of 14 percentage points in the rate of POI between the GnRHa group and 
the Controlled group at a two-sided significance level of 5%. The allowable 
withdrawing rate is 10%, thus the max sample size estimated was 409. The incidence 
of POI refers to the results of POEMS/S0230: At year 1, data were available for 
153 patients (70%). Ovarian dysfunction was present in 28 of 75 patients (37%) 
in the chemotherapy-alone group and in 18 of 78 patients (23%) in the goserelin 
group (odds ratio, 0.64; 95% CI, 0.30 to 1.37; P = 0.25). 
OS interval was computed from the date of randomization to the date of death. 
TFS interval was computed from the date of randomization to the date of the first 
occurrence of a TFS event. For each end point, observation times of patients without 
the event were censored on the date of their last contact. Median TFS was estimated 
with the use of the Kaplan–Meier method, and hypothesis testing was carried out with 
the use of a stratified log-rank test. Hazard ratios, 95% confidence intervals, and P 
values for differences in TFS were derived with the use of multivariable Cox 
regression, with adjustment for stratification factors. 
Categorical data were recorded as frequency and percentage. Continuous data 
were recorded as mean ± standard deviation. The statistical analysis included both 
unadjusted and adjusted analyses. Outcome measures were compared between the 
groups with the use of the chi-square test or Fisher’s exact test (unadjusted analysis). 
Effect sizes were reported as relative risk with 95% confidence interval. There was no 
data loss in 330 cases that finally included in the analysis; hence, the main analysis 
was based on cases with complete data. All tests were two-sided, and a P value of less 
than 0.05 was considered to indicate statistical significance. Data were analyzed with 
the use of SPSS software, version 19.0.