Long-Term Effectiveness of Adjuvant Goserelin in Premenopausal Women With Early Breast Cancer

Allan Hackshaw; Michael Baum; Tommy Fornander; Bo Nordenskjold; Antonio Nicolucci; Kathryn Monson; Sharon Forsyth; Krystyna Reczko; Ulla Johansson; Helena Fohlin; Miriam Valentini; Richard Sainsbury

Disclosures

J Natl Cancer Inst. 2009;101(5):341-349. 

In This Article

Abstract and Introduction

Abstract

Background: Systematic reviews have found that luteinizing hormone-releasing hormone (LHRH) agonists are effective in treating premenopausal women with early breast cancer.
Methods: We conducted long-term follow-up (median 12 years) of 2706 women in the Zoladex In Premenopausal Patients (ZIPP), which evaluated the LHRH agonist goserelin (3.6 mg injection every 4 weeks) and tamoxifen (20 or 40 mg daily), given for 2 years. Women were randomly assigned to receive each therapy alone, both, or neither, after primary therapy (surgery with or without radiotherapy/chemotherapy). Hazard ratios and absolute risk differences were used to assess the effect of goserelin treatment on event-free survival (breast cancer recurrence, new tumor or death), overall survival, risk of recurrence of breast cancer, and risk of dying from breast cancer, in the presence or absence of tamoxifen.
Results: Fifteen years after the initiation of treatment, for every 100 women not given tamoxifen, there were 13.9 (95% confidence interval [CI] = 17.5 to 19.4) fewer events among those who were treated with goserelin compared with those who were not treated with goserelin. However, among women who did take tamoxifen, there were 2.8 fewer events (95% CI = 7.7 fewer to 2.0 more) per 100 women treated with goserelin compared with those not treated with goserelin. The risk of dying from breast cancer was also reduced at 15 years: For every 100 women given goserelin, the number of breast cancer deaths was lower by 2.6 (95% CI = 6.6 fewer to 2.1 more) and 8.5 (95% CI = 2.2 to 13.7) in those who did and did not take tamoxifen, respectively, although in the former group the difference was not statistically significant.
Conclusions: Two years of goserelin treatment was as effective as 2 years of tamoxifen treatment 15 years after starting therapy. In women who did not take tamoxifen, there was a large benefit of goserelin treatment on survival and recurrence, and in women who did take tamoxifen, there was a marginal potential benefit on these outcomes when goserelin was added.

Introduction

Estrogen plays a fundamental role in the pathogenesis and development of breast cancer, and the risk of this disease is associated with several factors related to the level and length of exposure to this hormone.[1,2] In women diagnosed with breast cancer, after initial treatment with surgery, the concentration of circulating estrogen can be reduced by ovarian ablation using surgery, irradiation, or luteinizing hormone-releasing hormone (LHRH) agonists. These treatments, designed to prevent recurrence after surgery, have a clear beneficial effect in premenopausal women with breast cancer. In 2005, the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) conducted a meta-analysis of several randomized trials investigating the effect of ovarian ablation or suppression. They reported a 17% reduction in recurrence and a 13% reduction in breast cancer mortality among women younger than 50 years with estrogen receptor (ER)-positive or unknown disease.[3] The meta-analysis was based on an average follow-up of 8 years for trials of surgery or irradiation and 5 years for trials of LHRH agonists.

In 2007, a more detailed systematic review and analysis focused on adjuvant randomized trials that used LHRH agonists[4] and was based largely on 9022 women with tumors positive for ER, progesterone receptor, or both. In these trials, women were randomly assigned to receive an LHRH agonist or not, with other comparisons based on chemotherapy or tamoxifen. The analysis revealed statistically significant reductions in recurrence and death after recurrence of 13% and 15%, respectively, with the addition of an LHRH agonist to women who received tamoxifen, chemotherapy, or both.

The Zoladex in Premenopausal Patients (ZIPP) study evaluated goserelin and tamoxifen separately and in combination in premenopausal women with early breast cancer.[5] We have obtained long-term follow-up data on all the patients, probably longer than any other trial of an LHRH agonist, allowing us to examine differences in survival and risk of recurrence many years after the start of therapy.

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