Objective
The objective of the study was to evaluate the regression, relapse, and live birth rates of early-stage endometrial cancer (EC) and atypical complex hyperplasia (ACH) with fertility-sparing treatment.
Study Design
This was a metaanalysis of the proportions from observational studies with a random-effects model and a meta-regression to explore for heterogeneity.
Results
Thirty-four observational studies, evaluating the regression, relapse, and live birth rates of early-stage EC (408 women) and ACH (151 women) with fertility-sparing treatment. Fertility-sparing treatment for EC achieved a pooled regression rate of 76.2%, a relapse rate of 40.6%, and a live birth rate of 28%. For ACH the pooled regression rate was 85.6%, a relapse rate of 26%, and a live birth rate of 26.3%. Twenty women were diagnosed with ovarian cancer (concurrent or metastatic) during follow-up (3.6%) and 10 progressed to higher than stage I EC (1.9%) from which 2 women died.
Conclusion
Fertility-sparing treatment of EC and ACH is feasible and selected women can satisfy their reproductive wishes.
In 2007, 7536 women in the United Kingdom were diagnosed with endometrial cancer (EC) and 239 of these women were younger than 45 years old (3.2%). Often these women have strong fertility desires because anovulatory infertility is strongly associated with the development of EC and atypical complex hyperplasia (ACH). It is known that these women are usually diagnosed with early clinical stage, well-differentiated EC, which carries a good prognosis. Traditionally, it is recommended that these women undergo a staging abdominal hysterectomy. However, multiple studies suggest that in selected women with early clinical stage disease, this can be managed with fertility-sparing hormonal therapy.
For Editors’ Commentary, see Contents
The use of progestogens can induce endometrial regression and prevent the progression of the disease. Oral progestogens are used to treat EC and ACH, but more recently, the levonorgestrel-releasing intrauterine system (LNG-IUS; Mirena, Bayer, Berkshire, UK) has also been used successfully to treat ACH. These options are also popular among clinicians for women who decline hysterectomy. Yet there is significant uncertainty about the efficacy of these therapies from observational studies with small sample sizes, which makes it difficult to counsel the women accordingly. To ascertain the efficacy of these therapies, we conducted a systematic review of observational studies evaluating the regression, relapse, and live birth rates for the treatment of EC and ACH, and we performed a metaanalysis of their treatment effects.
Materials and Methods
Identification of literature
The population of interest in this systematic review was women with early clinical stage (International Federation of Gynecology and Obstetrics stage I) EC or ACH, the intervention was fertility-sparing therapies, and the outcome was evidence of disease regression, relapse, and live births. The following electronic databases were searched: MEDLINE (1950 to September 2011), EMBASE (1980 to September 2011), Cochrane Central Register of Controlled Trials and Web of Science conference proceedings (ISI Proceedings, 1990 to September 2011).
A combination of medical subject headings (MeSH) and text words were used to generate 2 subsets of citations, 1 including studies of EC (“endometr* cancer,*” “malignant endometr*”) or endometrial hyperplasia (“endometr* hyperplas,*” “premalignant endometr,*” “precancer* endometr*”) and the other including studies of fertility-sparing therapies such as progestogens and intrauterine devices or systems (“intrauterine devices medicated,” “Levonorgestrel,” “Mirena,” “intrauterine progest,*” “LNG-IU,*” “progest,*” “gestag,*” “fertility-sparing therapy,” “conservative therapy,” “hormone* therapy”).
These subsets were combined with the word “and” and limited to the words “humans and female” to generate a subset of citations. The reference lists of all known primary and review articles were examined to identify cited articles not captured by electronic searches. Language or geographical restrictions were not applied during the search or selection.
Study selection and data extraction
Studies were selected if the participants were women diagnosed histologically with early clinical stage EC or ACH, the intervention was fertility-sparing therapy, and the outcomes were histological disease regression, relapse, or live birth rates. Case reports or series with fewer than 5 cases were excluded. Studies classifying women with endometrial hyperplasia in other than the World Health Classification 1994 (simple, complex, and atypical) were also excluded.
Studies were selected in a 2-stage process. First, the titles and abstracts from the electronic searches were scrutinized by 2 reviewers independently (I.D.G. and J.Y.), and full manuscripts of all citations that met the predefined selection criteria were obtained. Second, final inclusion or exclusion decisions were made on the examination of the full manuscripts. In cases of duplicates, the most recent or the most complete publication was used. Any disagreements about inclusion were resolved by consensus or arbitration by a third reviewer (A.C.). Two reviewers (I.D.G. and J.Y.) completed the quality assessment. The Methodological Index for Non-Randomised Studies (MINORS), which assesses the quality of the included studies, was implemented. From each study, outcome data were extracted in 2 × 2 tables by the 2 reviewers (I.D.G. and J.Y.).
Disease regression was defined as a lack of residual EC or complex hyperplasia during follow-up endometrial sampling. Disease relapse was defined EC or complex hyperplasia diagnosis during follow-up endometrial sampling following an endometrial sample that showed disease regression. Live births was defined as the birth of healthy infants during the follow-up period, and its rate was calculated as the number of women who had a birth of healthy infants divided by the number of total of women undergoing fertility-sparing therapy. We also counted the number of women who were diagnosed with concurrent or metastatic ovarian cancer or upgraded disease to higher than stage I and deaths from this disease during follow-up.
Statistical analysis
Regression, relapse, and live birth rates were extracted from each study, and we computed the log of the ratio and its corresponding standard error for each study. We performed the metaanalysis using inverse-variance weighting to calculate the random-effects summary estimates. We obtained an estimate of the between-study variance with a random-effects metaanalysis. The square root of this number is the estimated SD of the underlying effects across studies.
Because we had relative measures of effect, the confidence intervals were centered on the natural logarithm of the pooled estimate and the limits exponentiated to obtain an interval on the ratio scale. Forest plots were created for each outcome, showing individual study proportions with confidence intervals (CIs) and the overall DerSimmonian-Laird pooled estimate. Heterogeneity of the treatment effects was assessed graphically with forest plots and statistically analyzed using the χ 2 test. Exploration of the causes of heterogeneity for the live birth rate was planned according to the reproductive method, and it was assessed with the aid of meta-regression. Statistical analyses were performed using Stata 8.0 (StataCorp, College Station, TX).
Results
Selection, characteristics and quality of the primary studies
The electronic search strategy yielded 9516 citations, and we retrieved a further 10 citations from our manual checking of reference lists of all primary articles. Of these, 9477 citations were excluded because they did not fulfill the selection criteria. Examination of the full text of the remaining 54 manuscripts found a total of 34 primary studies, including 559 women, of which 408 were diagnosed with EC and 151 with ACH, for inclusion in this review ( Figure 1 ). The main characteristics of the 34 studies and the study methodological index are presented in the Table and Figure 2 .
| Author, year | Recruitment | Study population | Intervention or study groups | Outcomes (rates) | Follow-up (median, range in months) | ||
|---|---|---|---|---|---|---|---|
| Women treated | Investigations prior to treatment to rule out invasion | ||||||
| Imaging | Tumor markers | ||||||
| Bokhman et al, 1985 (n = 19) | Prospective | G1 (n = 11) or G2 (n = 8) EC | No | No | Hydroxyprogesterone 500 mg/d for at least 3 mo | Regression | n/a |
| Cade et al, 2010 (n = 16) | Retrospective | G1 EC | MRI | No | MPA only (n = 4) 60-400 mg/d, MPA 200-400 mg/d with LNG-IUS (n = 9), or LNG-IUS (n = 3) | Regression, relapse, and live birth | 27, 3–134 |
| Duska et al, 2001 (n = 12) | Retrospective | G1 EC | No | No | Progestogens at various doses | Regression, relapse, and live birth | 82, 6–358 |
| Eftekhar et al, 2009 (n = 21) | Prospective | G1 EC | MRI, CT, and USD | CA125 | MA 160 mg/d | Regression, relapse, and live birth | 39, 5–108 |
| Elizur et al, 2007 (n = 8) | Prospective cohort study | G1 EC | MRI | CA125 | MA 160 mg/d (n = 6), MPA 200 mg/d (n = 1), or 600 mg/d (n = 1) for at least 3 mo | Regression, relapse, and live birth | 51, 38–75 |
| Gotlieb et al, 2003 (n = 13) | Retrospective | G1 (n = 11) or G2-3 (n = 2) EC | MRI and CT | CA125 | MA 160 mg/d (n = 8), hydroxyprogesterone 8-12 g/d (n = 2), NET 5 mg/d (n = 1), MPA 200-600 mg/d (n = 2) for at least 3 mo | Regression, relapse, and live birth | 35, 10–146 |
| Hahn et al, 2009 (n = 35) | Retrospective | G1 (n = 31) or G1 and focal G2 (n = 4) EC | MRI, CT, and USD | CA125 | MA 160 mg/d (n = 8) or MPA 250-1500 mg/d (n = 20) or in combination (n = 7) | Regression, relapse, and live birth | 23, 2–72 |
| Han et al, 2009 (n = 10) | Retrospective | G1 (n = 5) or G2 (n = 2), EC or ACH (n = 3) | MRI and USD | CA125 | MA 80-160 mg/d (n = 7), MPA 20-1000 mg/d (n = 3) for at least 3 mo | Regression, relapse, and live birth | 31.5, 10–133 |
| Imai et al, 2001 (n = 14) | Retrospective | Stage I G1 (n = 5) or G2 (n = 1) and stage II G1 (n = 7) or G2 (n = 1) EC | No | No | MPA 400-800 mg/d | Regression, relapse, and live birth | 12.9, 7–46 |
| Jadoul and Donnez, 2003 (n = 7) | Retrospective | G1 EC (n = 5) or ACH (n = 2) | No | No | Endometrial resection followed by GnRH analogues | Regression, relapse, and live birth | 40, 26–40 |
| Kaku et al, 2001 (n = 30) | Retrospective | G1 (n = 10) or G2 (n = 2), EC or ACH (n = 18) | MRI, CT, and USD | No | MPA 200-800 mg/d for EC (n = 12) and 100-600 mg/d for ACH (n = 18) for 3-6 mo | Regression, relapse, and live birth | 38.7, 17–84 |
| Kim et al, 1997 (n = 7) | Retrospective | G1 EC | No | No | MA 160 mg/d for at least 3 mo | Regression, relapse, and live birth | 11.7, 3–30 |
| Laurelli et al, 2011 (n = 14) | Prospective | Stage IA G1 EC | MRI and USD | No | Hysteroscopic resection of the tumor followed by MA 160 mg/d for 6 mo (n = 6) or LNG-IUS (52 mg/d) (n = 8) for 12 mo | Regression, relapse, and live birth | n/a |
| Le Digabel et al, 2006 (n = 13) | Retrospective | Stage IA G1-2 (n = 3) or stage IB G2-3 (n = 2), EC or ACH (n = 8) | No | No | Progestogens at various doses (n = 6) or LHRH analogs (n = 3) or combination of the 2 (n = 2) or endometrial curettage (n = 2) | Regression, relapse, and live birth | 50.5, 32–77 |
| Lee et al, 2010 (n = 12) | Prospective | ACH (n = 1), other hyperplasia (n = 11) | No | No | Progesterone-releasing IUD system (20 μg/d) | Regression and relapse | 50.5, 21–82 |
| Li et al, 2008 (n = 5) | Prospective | ACH (n = 3), other hyperplasia (n = 2) | No | No | Letrozole 2.5 mg/d for 3 mo | Regression, relapse, and live birth | 40.7, 2–109 |
| Mao et al, 2010 (n = 6) | Prospective | G1 EC | MRI, CT, and USD | CA125 | MA 160 mg/d (n = 2), MPA 250-500 mg/d (n = 4) | Regression, relapse, and live birth | 29, 4–102 |
| Mazzon et al, 2010 (n = 6) | Prospective | Stage IA G1 EC | MRI | CA125 | Hysteroscopic resection of the tumor followed by MA 160 mg/d for 6 m | Regression, relapse, and live birth | 43, 3–75 |
| Minaguchi et al, 2007 (n = 31) | Prospective | Stage IaG1 EC (n = 19) or ACH (n = 12) | MRI, CT, and USD | No | MPA 2.5-600 mg/d, mostly 400-600 mg/d for 6 mo | Regression, relapse, and live birth | 55.8, 24–138 |
| Minig et al, 2011 (n = 34) | Prospective | Stage IaG1 EC (n = 14) or ACH (n = 20) | MRI and USD | CA125 | LNG-IUS (20 μg/d) for 12 mo and GnRH analog (3.75 mg depot) for 6 mo | Regression, relapse, and live birth | 43.5, 13–127 |
| Montz et al, 2002 (n = 12) | Prospective | Stage IaG1 EC (n = 12) | MRI and USD | No | Progesterone-releasing IUD (65 μg/d) | Regression and relapse | 47.3, 18–135 |
| Niwz et al, 2005 (n = 12) | Prospective | Stage IaG1 EC | MRI and USD | CA125 | MPA 400-600 mg/d for at least 6 mo | Regression, relapse, and live birth | 60.2, 8–412 |
| Otz et al, 2005 (n = 12) | Retrospective | Stage IaG1 EC | MRI, CT, and USD | No | MPA 600 mg/d | Regression, relapse, and live birth | 40, 9–79 |
| Parz et al, 2012 (n = 14) | Retrospective | Stage IaG1 EC | MRI | No | MPA 250-500 mg/d (n = 10) or Provera 30 mg/d (n = 2) or MA 16-240 mg/d (n = 2) | Regression, relapse, and live birth | 98, 35–176 |
| Perri et al, 2011 (n = 27) | Retrospective | Stage I EC | MRI, CT, and USD | CA125 | MA 160-320 mg/d (n = 21), NET 5 mg/d (n = 1), hydroxyprogesterone 2-3 g/wk (n = 2), and MPA 100-600 mg/d (n = 3) | Regression, relapse, and live birth | 47.9, 25–73 |
| Randall and Kurman, 1997 (n = 33) | Retrospective | G1 EC (n = 14) or ACH (n = 19) | No | No | MPA 10-30 mg/d or MA 40-160 mg/d (n = 29), ovulation induction (n = 2), Bromocriptine (n=1), oral contraceptive (n = 1) for 3-12 mo | Regression, relapse, and live birth | 69, 25–113 |
| Signorelli et al, 2009 (n = 21) | Prospective | Stage IaG1 EC (n = 11) or ACH (n = 10) | MRI, CT, and USD | CA125, CA19.9 | Natural progesterone 200 mg/d, days 14-25 | Regression, relapse, and live birth | 11, n/a |
| Ushijima et al, 2007 (n = 45) | Prospective | Stage IaG1 EC (n = 28) or ACH (n = 17) | MRI | CA125 | MPA 600 mg/d with low-dose (81 mg) aspirin | Regression, relapse, and live birth | 76.5, 21–118 |
| Wang et al, 2002 (n = 9) | Prospective | Stage IaG1 EC | MRI and USD | CA125 | MA 160 mg/d and tamoxifen 30 mg/d for 6 mo | Regression, relapse, and live birth | 39, 24–69 |
| Wheeler et al, 2007 (n = 44) | Retrospective | G1 EC (n = 26) or ACH (n = 18) | No | No | Oral progestogens (n = 29) or progesterone-releasing IUD (n = 15) | Regression and relapse | 48.8, 14–132 |
| Yahata et al, 2006 (n = 8) | Prospective | Stage IaG1 EC | MRI and USD | No | MPA 1800 mg/d for at least 3 mo | Regression, relapse, and live birth | 34.6, 7–114 |
| Yamazawa et al, 2007 (n = 9) | Prospective | Stage IaG1 EC | MRI and CT | CA125 | MPA 400 mg/d for at least 6 mo | Regression, relapse, and live birth | 82, 6–358 |
| Yang et al, 2005 (n = 6) | Prospective | Stage IaG1 EC | MRI, CT, and USD | No | MA 160 mg/d for at least 6 mo | Regression, relapse, and live birth | 39, 5–108 |
| Yu et al, 2006 (n = 25) | Retrospective | Stage IaG1 EC (n = 8) or ACH (n = 17) | MRI, CT, and USD | CA125 | MPA 250-500 mg/d for EC and 100-500 mg/d for ACH (n = 22) or MA or hydroxyprogesterone (n = 3) | Regression, relapse, and live birth | 51, 38–75 |
The primary studies included women with well-differentiated EC with 386 women being classified as G1 and 22 women with moderate or poor differentiation (G2 or G3). In 24 studies, the women enrolled underwent diagnostic imaging to rule out myometrial invasion or distant disease. In 11 of these 24 studies, the serum CA-125 marker was measured to also rule out concurrent ovarian malignancy.
The quality of the studies on the MINORS checklist is shown in Figure 2 . More in detail, half of the studies were prospective cohorts (17 of 34) including consecutive patients (31 of 34) with adequate definition of outcomes (30 of 34). No studies had a blinded assessment of the outcomes or performed a prospective calculation of the study size. We defined appropriate follow-up to be at least 5 years, and we found that in only 6 of 34 studies, follow-up was more than 5 years.
Regression, relapse, and live birth rates of fertility-sparing treatment for EC
Metaanalysis of the 32 studies (408 women) of women with EC managed with fertility-sparing treatment found that 301 women regressed with a pooled regression rate of 76.2% (95% CI, 68–85.3, Figure 3 ). The P value for the χ 2 test for heterogeneity was .976, indicating an insignificant variability in the regression rates between the studies. In 29 of these studies (267 women), women were followed up over time with the median ranging from 11 to 76.5 months, and the relapse rates were reported. We found that 89 women after an initial regression of the EC relapsed during follow-up, which amounts to a pooled relapse rate of 40.6% (95% CI, 33.1–49.8) without significant variability ( P = .566, Figure 4 ). Metaanalysis of the 26 studies reporting pregnancy outcomes showed that from 325 women undergoing fertility-sparing treatment for EC, 75 women achieved at least 1 live birth, with a pooled live birth rate of 28% (95% CI, 21.6–36.3) with minimal heterogeneity ( P = .197, Figure 5 ).
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
