Levonorgestrel intrauterine system (LNG-IUS) for endometrial protection in women with breast cancer taking tamoxifen to prevent recurrence

Review question:

Cochrane authors investigated whether the levonorgestrel-releasing intrauterine system (LNG-IUS) can reduce the risk of endometrial polyps, abnormal thickening of the lining of the uterus and endometrial cancer in women taking tamoxifen following breast cancer. The review also investigated whether use of the LNG-IUS influences the risk of abnormal vaginal bleeding or spotting, fibroids, breast cancer recurrence or death in women taking tamoxifen following breast cancer.

Background:

Tamoxifen is commonly used by women to reduce the risk of breast cancer recurrence. Tamoxifen can also cause abnormal changes to the lining of the uterus (endometrium), including polyps and cancer. The LNG-IUS is a uterine device that releases the synthetic hormone levonorgestrel into the endometrium and causes marked endometrial suppression. As levonorgestrel is a progestin, and many breast cancers are progesterone-sensitive, it is important to study the safety of the LNG-IUS in breast cancer survivors.

Study characteristics:

We included four randomised controlled trials involving 543 women. The studies took place in the United Kingdom, Turkey, Egypt and Hong Kong, and the primary outcome in all studies was abnormal changes in the lining of the uterus. Three studies reported on the outcome of fibroids. Three studies reported on abnormal vaginal bleeding or spotting. Two studies reported on the outcomes of breast cancer recurrence, and three studies reported on the outcomes of breast cancer-related death. The evidence is current to October 2015.

Key results:

This review suggests that the LNG-IUS can reduce the risk of endometrial polyps and endometrial hyperplasia over a long-term follow-up period (24 to 60 months) in women taking tamoxifen following breast cancer. At 12 and 24 months of follow-up, more women in the LNG-IUS group experienced abnormal vaginal bleeding or spotting. However by 60 months of follow-up, no abnormal vaginal bleeding or spotting was reported in either group. There were insufficient data to show whether there is any effect on incidence of endometrial cancer (a cancer originating in glandular tissue), fibroids, breast cancer recurrence, or breast cancer-related death.

Quality of the evidence:

The quality of the evidence was judged as moderate, due to limited sample sizes and low event rates for the outcome comparisons. Larger studies are necessary to assess the effects of the LNG-IUS on the incidence of endometrial cancer, and the impact of the LNG-IUS on the risk of secondary breast cancer events.

Authors' conclusions: 

The LNG-IUS reduces the incidence of benign endometrial polyps and endometrial hyperplasia in women with breast cancer taking tamoxifen. At 12 and 24 months of follow-up, the LNG-IUS increased abnormal vaginal bleeding or spotting among women in the treatment group compared to those in the control. There is no clear evidence from the available randomised controlled trials that the LNG-IUS prevents endometrial cancer in these women. There is no clear evidence from the available randomised controlled trials that the LNG-IUS affects the risk of breast cancer recurrence or breast cancer-related deaths. Larger studies are necessary to assess the effects of the LNG-IUS on the incidence of endometrial cancer, and to determine whether the LNG-IUS might have an impact on the risk of secondary breast cancer events.

Read the full abstract...
Background: 

Adjuvant tamoxifen reduces the risk of breast cancer recurrence in women with oestrogen receptor-positive breast cancer. Tamoxifen also increases the risk of postmenopausal bleeding, endometrial polyps, hyperplasia, and endometrial cancer. The levonorgestrel-releasing intrauterine system (LNG-IUS) causes profound endometrial suppression. This systematic review considered the evidence that the LNG-IUS prevents the development of endometrial pathology in women taking tamoxifen as adjuvant endocrine therapy for breast cancer.

Objectives: 

To determine the effectiveness and safety of levonorgestrel intrauterine system (LNG-IUS) in pre- and postmenopausal women taking adjuvant tamoxifen following breast cancer for the outcomes of endometrial and uterine pathology including abnormal vaginal bleeding or spotting, and secondary breast cancer events.

Search strategy: 

We searched the following databases: Cochrane Menstrual Disorders and Subfertility Group Specialised Register (MDSG), Cochrane Breast Cancer Group Specialised Register (CBCG), Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Database of Abstracts of Reviews of Effects (DARE), The Cochrane Library, clinicaltrials.gov, The World Health Organisation International Trials Registry, ProQuest Dissertations & Theses, MEDLINE, EMBASE, CINAHL (Cumulative Index to Nursing and Allied Health Literature), PsycINFO, Web of Science, OpenGrey, LILACS, PubMed, and Google. The final search was performed in October 2015.

Selection criteria: 

Randomised controlled trials of women with breast cancer on adjuvant tamoxifen that compared endometrial surveillance alone (control condition) versus the LNG-IUS with endometrial surveillance (experimental condition) on the incidence of endometrial pathology.

Data collection and analysis: 

Study selection, risk of bias assessment and data extraction were performed independently by two review authors. The primary outcome measure was endometrial pathology (including polyps, endometrial hyperplasia, or endometrial cancer) diagnosed at hysteroscopy or endometrial biopsy. Secondary outcome measures included fibroids, abnormal vaginal bleeding or spotting, breast cancer recurrence, and breast cancer-related deaths. The overall quality of evidence was rated using GRADE methods.

Main results: 

Four randomised controlled trials involving 543 women were identified and are included in this review. In the included studies, the active treatment arm was the 20 μg/day levonorgestrel-releasing intrauterine system (LNG-IUS) plus endometrial surveillance; the control arm was endometrial surveillance alone. In tamoxifen users, the LNG-IUS led to a reduction in the incidence of endometrial polyps over both a 12-month period (Peto OR 0.22, 95% CI 0.08 to 0.64, 2 studies, n = 212, I² = 0%) and over a long-term follow-up period (24 to 60 months) (Peto OR 0.22, 95% CI 0.13 to 0.39, 4 studies, n = 417, I² = 0%, moderate quality evidence). Also the LNG-IUS led to a reduction in the incidence of endometrial hyperplasia over a long-term follow-up period (24 to 60 months) (Peto OR 0.13, 95% CI 0.03 to 0.67, four studies, n = 417, I² = 0%, moderate quality evidence). However, it should be noted that the number of events of endometrial hyperplasia was low (n = 6). None of the trials were sufficiently powered to detect whether LNG-IUS leads to significant changes in the incidence of endometrial cancer in tamoxifen users. At 12 months of follow-up abnormal vaginal bleeding or spotting was more common in the LNG-IUS treatment group (Peto OR 7.26, 95% CI 3.37 to 15.66, 3 studies, n = 376, I² = 0%, moderate quality evidence). By 24 months of follow-up, abnormal vaginal bleeding or spotting occurred less frequently compared to 12 months of follow-up in the LNG-IUS treatment group but was still more common than the control group (Peto OR 2.72, 95% CI 1.04 to 7.10, 2 studies, n = 233, I² = 0%, moderate quality evidence). By 60 months of follow-up, no cases of abnormal vaginal bleeding or spotting were reported in either group. The numbers of events for the following outcomes were low: fibroids (n = 13), breast cancer recurrence (n = 18), and breast cancer-related deaths (n = 16). There was no evidence of a difference between the LNG-IUS treatment group and controls for these outcomes. The quality of the evidence was judged as moderate, due to limited sample sizes and low event rates for the outcome comparisons.

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