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 UK, 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 breast cancer recurrence, and three studies reported on breast cancer-related death. The evidence is current to June 2020.
Key results
This review suggests that the LNG-IUS probably slightly reduces the risk of endometrial polyps and endometrial hyperplasia over two to five years in women taking tamoxifen following breast cancer. The evidence suggests that if the incidence of endometrial polyps following endometrial surveillance alone is assumed to be 23.5%, the incidence following LNG-IUS plus endometrial surveillance would be between 3.8% and 10.7%. Evidence also suggests that if 2.8% of women who only had endometrial surveillance developed endometrial hyperplasia, the chance following LNG-IUS plus endometrial surveillance would be between 0.1% and 1.9%.
The LNG-IUS probably increases abnormal vaginal bleeding or spotting. After one year, the evidence suggests that if the incidence of abnormal vaginal bleeding or spotting following endometrial surveillance alone is assumed to be 1.7%, the incidence following LNG-IUS plus endometrial surveillance would be between 5.6% and 21.5%. After two years, if 4.2% of women who only had endometrial surveillance experienced abnormal vaginal bleeding or spotting, between 4.4% and 23.9% of women who had both surveillance and LNG-IUS would be expected to experience this. However by five years of follow-up, no women in either group reported abnormal vaginal bleeding or spotting.
We found insufficient evidence to reach a conclusion regarding the effect on incidence of endometrial cancer (a cancer originating in glandular tissue), fibroids, breast cancer recurrence, or breast cancer-related death.
Certainty of the evidence
We judged the certainty of the evidence to be moderate because the studies only included a limited number of women and there were not many events. 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.
The LNG-IUS probably slightly 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 probably increases abnormal vaginal bleeding or spotting among women in the treatment group compared to those in the control. Data were lacking on whether the LNG-IUS prevents endometrial cancer in these women. There is no clear evidence from the available RCTs 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.
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.
To determine the effectiveness and safety of the 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.
We searched the following databases on 29 June 2020; The Cochrane Gynaecology and Fertility Group specialised register, Cochrane Central Register of Controlled Trials, MEDLINE, Embase, PsycINFO and Cumulative Index to Nursing and Allied Health Literature. We searched the Cochrane Breast Cancer Group specialised register on 4 March 2020. We also searched two trials registers, checked references for relevant trials and contacted study authors and experts in the field to identify additional studies.
We included randomised controlled trials (RCTs) of women with breast cancer on adjuvant tamoxifen that compared the effectiveness of the LNG-IUS with endometrial surveillance versus endometrial surveillance alone on the incidence of endometrial pathology.
We used standard methodological procedures recommended by Cochrane. 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. We rated the overall certainty of evidence using GRADE methods.
We included four RCTs (543 women analysed) in this review. We judged the certainty of the evidence to be moderate for all of the outcomes, due to imprecision (i.e. limited sample sizes and low event rates). In the included studies, the active treatment arm was the 20 μg/day LNG-IUS plus endometrial surveillance; the control arm was endometrial surveillance alone.
In tamoxifen users, the LNG-IUS probably reduces the incidence of endometrial polyps compared to the control group over both a 12-month period (Peto odds ratio (OR) 0.22, 95% confidence interval (CI) 0.08 to 0.64, I² = 0%; 2 RCTs, n = 212; moderate-certainty evidence) and over a long-term follow-up period (24 to 60 months) (Peto OR 0.22, 95% CI 0.13 to 0.39; I² = 0%; 4 RCTs, n = 417; moderate-certainty evidence). For long-term follow-up, this suggests that if the incidence of endometrial polyps following endometrial surveillance alone is assumed to be 23.5%, the incidence following LNG-IUS with endometrial surveillance would be between 3.8% and 10.7%.
The LNG-IUS probably slightly reduces the incidence of endometrial hyperplasia compared with controls over a long-term follow-up period (24 to 60 months) (Peto OR 0.13, 95% CI 0.03 to 0.67; I² = 0%; 4 RCTs, n = 417; moderate-certainty evidence). This suggests that if the chance of endometrial hyperplasia following endometrial surveillance alone is assumed to be 2.8%, the chance following LNG-IUS with endometrial surveillance would be between 0.1% and 1.9%. However, it should be noted that there were only six cases of endometrial hyperplasia.
There was insufficient evidence to reach a conclusion regarding the incidence of endometrial cancer in tamoxifen users, as no studies reported cases of endometrial cancer.
At 12 months of follow-up, the LNG-IUS probably increases abnormal vaginal bleeding or spotting compared to the control group (Peto OR 7.26, 95% CI 3.37 to 15.66; I² = 0%; 3 RCTs, n = 376; moderate-certainty evidence). This suggests that if the chance of abnormal vaginal bleeding or spotting following endometrial surveillance alone is assumed to be 1.7%, the chance following LNG-IUS with endometrial surveillance would be between 5.6% and 21.5%. By 24 months of follow-up, abnormal vaginal bleeding or spotting occurs less frequently than at 12 months of follow-up, but is still more common in the LNG-IUS group than the control group (Peto OR 2.72, 95% CI 1.04 to 7.10; I² = 0%; 2 RCTs, n = 233; moderate-certainty evidence). This suggests that if the chance of abnormal vaginal bleeding or spotting following endometrial surveillance alone is assumed to be 4.2%, the chance following LNG-IUS with endometrial surveillance would be between 4.4% and 23.9%. By 60 months of follow-up, there were no cases of abnormal vaginal bleeding or spotting 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). As a result, there is probably little or no difference in these outcomes between the LNG-IUS treatment group and the control group.