Systematic Reviews
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GYNECOLOGY
Levonorgestrel-releasing intrauterine system vs oral progestins for non-atypical endometrial hyperplasia: a systematic review and metaanalysis of randomized trials Hatem Abu Hashim, MD, MRCOG, PhD; Essam Ghayaty, MD; Mohamed El Rakhawy, MD
E
ndometrial hyperplasia (EH) is a histological diagnosis characterized by proliferation of endometrial glands resulting in a greater gland-to-stroma ratio than observed in normal endometrium. It is typically classified into simple or complex hyperplasia, with or without cytological atypia.1,2 Recently, among women aged 18-90 years, the overall incidence of EH was 133/100,000 woman-years and it peaks in the early 50s and early 60s.3 It is worth remembering that EH is a commonly seen clinical entity, presenting mainly with abnormal uterine bleeding including heavy, prolonged, or irregular perimenopausal bleeding as well as postmenopausal bleeding.4,5 Apart from this problematic symptomatology, the real clinical significance of EH is the potential risk of progression to endometrial carcinoma, which is low for women with non-atypical EH compared with women with cytologic atypia (2 in LNG-IUS vs NET groups, respectively
LNG-IUS (n ¼ 59) for 1 y
NET (n ¼ 61); 15 mg/d for 3 wk/cycle for 3e6 mo
Histological responsec (PEB) after 3, 6, and 12 mo of treatment; frequency of irregular vaginal bleeding; and hysterectomy rate
Behnamfar et al,24 2014
Iran
60 women with non-atypical SEH and CEH
Mean age: LNG-IUS: 38.3 5.1 y, MPA: 38.6 4.6 y; mean BMI: LNG-IUS: 26.5 3.4 kg/m2, MPA: 27.6 1.5 kg/m2
Not stated
LNG-IUS (n ¼ 30) for 3 mo
MPA (n ¼ 30), 10 mg/d for 12 d/cycle for 3 m
Histological responseb (PEB) after 3 mo of treatment
Dolapcioglu et al,16 2013
Turkey
104 women 50% of women in each group was >25 kg/m2 Ørbo et al,23 2014
Norway
N ¼ 170, of them 134 with non-atypical EH (111 CEH and 23 SEH); majority were premenopausal and perimenopausal
Paritya Mean age and BMI Country Population RCT
Characteristics of included studies (continued)
TABLE 2
Intervention Comparison
Outcomes
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Data synthesis The data analysis was performed using RevMan software 5.1 (2011; Nordic Cochrane Centre, Cochrane Collaboration, Copenhagen, Denmark) The results were combined using the fixed effects model. All specified outcomes were dichotomous and summarized by calculating the odds ratio (OR) with 95% confidence intervals (CIs). If any heterogeneity existed (by the c2 test, with P < .1), random effects model was employed. If I2 was 50%, sensitivity analysis was performed by excluding the trials that potentially biased the results. Funnel plots were planned to test publication bias. Subgroup analysis was conducted by grouping the trials according to the type of the non-atypical EH: simple or complex. The weighting coefficients of the studies were computed by MantelHaenszel method (default statistical method of metaanalysis programmed in RevMan) and based on the estimated effect measure. A pooled effect estimate was calculated as a weighted average of the intervention effects estimated in the individual studies according to the following formula: weighted average sum of ðestimate weightÞ sum of weights P Y i Wi ¼ P Wi
¼
where Yi is the intervention effect estimated in theith study (for OR, Yi is the natural logarithm of the measure), Wi is the weight given to theith study, and the summation is across all studies. The weights reflect the amount of information that each study contains. The bigger the weight given to theith study, the more it contributed to the weighted average.19 OCTOBER 2015 American Journal of Obstetrics & Gynecology
473
Systematic Reviews FIGURE 2
Risk of bias summary for included studies
þ ¼ yes (low risk of bias); ¼ no (high risk of bias); ? ¼ unclear risk of bias. Abu Hashim. LNG-IUS in non-atypical EH. Am J Obstet Gynecol 2015.
Results Study selection The PRISMA flow diagram (Figure 1) illustrates the search process. Of 229 articles screened, 19 studies were identified as potentially eligible for inclusion. Only 7 RCTs fulfilled the inclusion criteria.15-17,21-24 A total of 12 trials (Table 1) were excluded for the following reasons: 5 studies were not RCTs; 3 RCTs compared oral progestins vs other treatment options rather than LNG-IUS; and 4 RCTs evaluated prophylactic use of LNG-IUS in tamoxifen-treated women. Study characteristics and risk of bias of included studies Of the 7 eligible studies, 3 were performed in Egypt15,21,22; 3 in Turkey,16 Kuwait,17 and Iran24; and 1 in Norway.23 A total of 766 participants were enrolled (329 belonged to the LNG-IUS group and 437 to oral progestin treatment). The sample size varied across the
Gynecology trials from 60-170 patients. There were 5 different comparisons made with LNGIUS across the 7 RCTs as follows: 3 RCTs compared LNG-IUS vs oral MPA in 334 patients16,23,24; 2 RCTs compared LNG-IUS vs oral NET in 204 patients15,21; 1 RCT compared LNG-IUS vs oral MPA and NET in 90 patients17; and 1 RCT compared LNG-IUS vs oral dydrogesterone in 138 patients.22 The baseline of all trials was comparable. The characteristics of the included studies are listed in Table 2. Figure 2 demonstrates the risk of bias summary for included studies. Synthesis of results Therapeutic effect rate was reported in all 7 RCTs. Successful therapeutic response, based on the histopathology of the posttreatment endometrial specimens, was defined as follows: atrophic-pattern endometrium with pseudodecidualized stroma15,22; proliferative or atrophicpattern endometrium with pseudodecidualized stroma16,23; and secretory, atrophic, or proliferative-pattern endometrium17,21,24 (Table 2). There was evidence of highly significant therapeutic response following LNG-IUS compared with oral progestins (OR, 2.30; 95% CI, 1.39e3.82; P ¼ .001, 5 trials, n ¼ 376; OR, 3.16; 95% CI, 1.84e5.45; P 20%, leaving a total of 259 patients (132 in the LNG-IUS group and 127 in oral progestin group). Noteworthy, the superiority of LNG-IUS was reassured (OR, 2.63; 95% CI, 1.22e5.67; P ¼ .01), without significant heterogeneity across the studies (P ¼ .97, I2 ¼ 0%). The evidence of beneficial therapeutic effect at the different time points was considered to be of moderate quality being downgraded 1 level for imprecision (wide 95% CI).
474 American Journal of Obstetrics & Gynecology OCTOBER 2015
ajog.org Subgroup analysis showed evidence of highly significant therapeutic response following LNG-IUS compared with oral progestins for the non-atypical simple EH (OR, 2.51; 95% CI, 1.14e5.53; P ¼ .02, 6 trials, n ¼ 290) as well as for the non-atypical complex EH (OR, 3.31; 95% CI, 1.62e6.74; P ¼ .001, 4 trials, n ¼ 216) without significant heterogeneity across the studies (P ¼ .92, I2 ¼ 0% and P ¼ .86, I2 ¼ 0% in non-atypical simple and complex EH, respectively) (Figure 4 and Table 3). The evidence complied for the beneficial therapeutic effect with regard to type of non-atypical EH either simple or complex was considered to be of moderate quality due to wide 95% CIs. The rate of irregular vaginal bleeding was reported in only 3 trials including 345 women.15,22,23 There was evidence of significantly more frequent irregular vaginal bleeding following LNG-IUS compared with oral progestins for the non-atypical EH (OR, 1.92; 95% CI, 1.14e3.23; P ¼ .01) with significant heterogeneity across the studies (P ¼ .01, I2 ¼ 77%). After exclusion of 1 study by sensitivity analysis because of significant attrition rate,22 a total of 207 patients (106 in the LNG-IUS group and 101 in oral progestin group) were included. Pooled analysis showed no significant difference in the rate of irregular vaginal bleeding between the 2 groups (OR, 1.12; 95% CI, 0.54e2.32; P ¼ .76) with significant heterogeneity across the studies (P ¼ .04, I2 ¼ 77%) (Table 3). The observed substantial heterogeneity can be explained by the different progestins used for comparisons. However, the CI was very wide and we did not have sufficient precision to identify whether LNG-IUS is associated with substantial harm, no effect, or substantial benefit; thereby the evidence was considered of low quality (Table 3). The hysterectomy rate was reported in only 3 trials including 362 women.15,16,22 There was evidence of significantly fewer hysterectomies following LNG-IUS compared with oral progestins for the non-atypical EH (OR, 0.26; 95% CI, 0.15e0.45; P
ajog.org
GYNECOLOGY
Levonorgestrel-releasing intrauterine system vs oral progestins for non-atypical endometrial hyperplasia: a systematic review and metaanalysis of randomized trials Hatem Abu Hashim, MD, MRCOG, PhD; Essam Ghayaty, MD; Mohamed El Rakhawy, MD
E
ndometrial hyperplasia (EH) is a histological diagnosis characterized by proliferation of endometrial glands resulting in a greater gland-to-stroma ratio than observed in normal endometrium. It is typically classified into simple or complex hyperplasia, with or without cytological atypia.1,2 Recently, among women aged 18-90 years, the overall incidence of EH was 133/100,000 woman-years and it peaks in the early 50s and early 60s.3 It is worth remembering that EH is a commonly seen clinical entity, presenting mainly with abnormal uterine bleeding including heavy, prolonged, or irregular perimenopausal bleeding as well as postmenopausal bleeding.4,5 Apart from this problematic symptomatology, the real clinical significance of EH is the potential risk of progression to endometrial carcinoma, which is low for women with non-atypical EH compared with women with cytologic atypia (2 in LNG-IUS vs NET groups, respectively
LNG-IUS (n ¼ 59) for 1 y
NET (n ¼ 61); 15 mg/d for 3 wk/cycle for 3e6 mo
Histological responsec (PEB) after 3, 6, and 12 mo of treatment; frequency of irregular vaginal bleeding; and hysterectomy rate
Behnamfar et al,24 2014
Iran
60 women with non-atypical SEH and CEH
Mean age: LNG-IUS: 38.3 5.1 y, MPA: 38.6 4.6 y; mean BMI: LNG-IUS: 26.5 3.4 kg/m2, MPA: 27.6 1.5 kg/m2
Not stated
LNG-IUS (n ¼ 30) for 3 mo
MPA (n ¼ 30), 10 mg/d for 12 d/cycle for 3 m
Histological responseb (PEB) after 3 mo of treatment
Dolapcioglu et al,16 2013
Turkey
104 women 50% of women in each group was >25 kg/m2 Ørbo et al,23 2014
Norway
N ¼ 170, of them 134 with non-atypical EH (111 CEH and 23 SEH); majority were premenopausal and perimenopausal
Paritya Mean age and BMI Country Population RCT
Characteristics of included studies (continued)
TABLE 2
Intervention Comparison
Outcomes
ajog.org
Data synthesis The data analysis was performed using RevMan software 5.1 (2011; Nordic Cochrane Centre, Cochrane Collaboration, Copenhagen, Denmark) The results were combined using the fixed effects model. All specified outcomes were dichotomous and summarized by calculating the odds ratio (OR) with 95% confidence intervals (CIs). If any heterogeneity existed (by the c2 test, with P < .1), random effects model was employed. If I2 was 50%, sensitivity analysis was performed by excluding the trials that potentially biased the results. Funnel plots were planned to test publication bias. Subgroup analysis was conducted by grouping the trials according to the type of the non-atypical EH: simple or complex. The weighting coefficients of the studies were computed by MantelHaenszel method (default statistical method of metaanalysis programmed in RevMan) and based on the estimated effect measure. A pooled effect estimate was calculated as a weighted average of the intervention effects estimated in the individual studies according to the following formula: weighted average sum of ðestimate weightÞ sum of weights P Y i Wi ¼ P Wi
¼
where Yi is the intervention effect estimated in theith study (for OR, Yi is the natural logarithm of the measure), Wi is the weight given to theith study, and the summation is across all studies. The weights reflect the amount of information that each study contains. The bigger the weight given to theith study, the more it contributed to the weighted average.19 OCTOBER 2015 American Journal of Obstetrics & Gynecology
473
Systematic Reviews FIGURE 2
Risk of bias summary for included studies
þ ¼ yes (low risk of bias); ¼ no (high risk of bias); ? ¼ unclear risk of bias. Abu Hashim. LNG-IUS in non-atypical EH. Am J Obstet Gynecol 2015.
Results Study selection The PRISMA flow diagram (Figure 1) illustrates the search process. Of 229 articles screened, 19 studies were identified as potentially eligible for inclusion. Only 7 RCTs fulfilled the inclusion criteria.15-17,21-24 A total of 12 trials (Table 1) were excluded for the following reasons: 5 studies were not RCTs; 3 RCTs compared oral progestins vs other treatment options rather than LNG-IUS; and 4 RCTs evaluated prophylactic use of LNG-IUS in tamoxifen-treated women. Study characteristics and risk of bias of included studies Of the 7 eligible studies, 3 were performed in Egypt15,21,22; 3 in Turkey,16 Kuwait,17 and Iran24; and 1 in Norway.23 A total of 766 participants were enrolled (329 belonged to the LNG-IUS group and 437 to oral progestin treatment). The sample size varied across the
Gynecology trials from 60-170 patients. There were 5 different comparisons made with LNGIUS across the 7 RCTs as follows: 3 RCTs compared LNG-IUS vs oral MPA in 334 patients16,23,24; 2 RCTs compared LNG-IUS vs oral NET in 204 patients15,21; 1 RCT compared LNG-IUS vs oral MPA and NET in 90 patients17; and 1 RCT compared LNG-IUS vs oral dydrogesterone in 138 patients.22 The baseline of all trials was comparable. The characteristics of the included studies are listed in Table 2. Figure 2 demonstrates the risk of bias summary for included studies. Synthesis of results Therapeutic effect rate was reported in all 7 RCTs. Successful therapeutic response, based on the histopathology of the posttreatment endometrial specimens, was defined as follows: atrophic-pattern endometrium with pseudodecidualized stroma15,22; proliferative or atrophicpattern endometrium with pseudodecidualized stroma16,23; and secretory, atrophic, or proliferative-pattern endometrium17,21,24 (Table 2). There was evidence of highly significant therapeutic response following LNG-IUS compared with oral progestins (OR, 2.30; 95% CI, 1.39e3.82; P ¼ .001, 5 trials, n ¼ 376; OR, 3.16; 95% CI, 1.84e5.45; P 20%, leaving a total of 259 patients (132 in the LNG-IUS group and 127 in oral progestin group). Noteworthy, the superiority of LNG-IUS was reassured (OR, 2.63; 95% CI, 1.22e5.67; P ¼ .01), without significant heterogeneity across the studies (P ¼ .97, I2 ¼ 0%). The evidence of beneficial therapeutic effect at the different time points was considered to be of moderate quality being downgraded 1 level for imprecision (wide 95% CI).
474 American Journal of Obstetrics & Gynecology OCTOBER 2015
ajog.org Subgroup analysis showed evidence of highly significant therapeutic response following LNG-IUS compared with oral progestins for the non-atypical simple EH (OR, 2.51; 95% CI, 1.14e5.53; P ¼ .02, 6 trials, n ¼ 290) as well as for the non-atypical complex EH (OR, 3.31; 95% CI, 1.62e6.74; P ¼ .001, 4 trials, n ¼ 216) without significant heterogeneity across the studies (P ¼ .92, I2 ¼ 0% and P ¼ .86, I2 ¼ 0% in non-atypical simple and complex EH, respectively) (Figure 4 and Table 3). The evidence complied for the beneficial therapeutic effect with regard to type of non-atypical EH either simple or complex was considered to be of moderate quality due to wide 95% CIs. The rate of irregular vaginal bleeding was reported in only 3 trials including 345 women.15,22,23 There was evidence of significantly more frequent irregular vaginal bleeding following LNG-IUS compared with oral progestins for the non-atypical EH (OR, 1.92; 95% CI, 1.14e3.23; P ¼ .01) with significant heterogeneity across the studies (P ¼ .01, I2 ¼ 77%). After exclusion of 1 study by sensitivity analysis because of significant attrition rate,22 a total of 207 patients (106 in the LNG-IUS group and 101 in oral progestin group) were included. Pooled analysis showed no significant difference in the rate of irregular vaginal bleeding between the 2 groups (OR, 1.12; 95% CI, 0.54e2.32; P ¼ .76) with significant heterogeneity across the studies (P ¼ .04, I2 ¼ 77%) (Table 3). The observed substantial heterogeneity can be explained by the different progestins used for comparisons. However, the CI was very wide and we did not have sufficient precision to identify whether LNG-IUS is associated with substantial harm, no effect, or substantial benefit; thereby the evidence was considered of low quality (Table 3). The hysterectomy rate was reported in only 3 trials including 362 women.15,16,22 There was evidence of significantly fewer hysterectomies following LNG-IUS compared with oral progestins for the non-atypical EH (OR, 0.26; 95% CI, 0.15e0.45; P
