5. Therapy of precancerous lesions and early endometrial carcinoma – Endometrial Cancer
5.1 Endometrial hyperplasias
5.1.1 Endometrial hyperplasia without atypia
Simple endometrial hyperplasia without atypia should not be treated by hysterectomy.
- Recommendation grade
- B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
- Level of evidence
- 3
- Consensus
- Strong consensus
- References
- [339] [462]
Change note
Endometrial hyperplasia without atypia should not be treated by hysterectomy.Evidence tables (1)
5.1.1 EvT 5.1Hysterectomy may be considered for complex endometrial hyperplasia without atypia.
- Recommendation grade
- 0: offene Empfehlung (Option) bzgl. einer Maßnahme - verwendete Ausdrucksweise = kann
- Level of evidence
- 3
- Consensus
- Strong consensus
- References
- [462]
Background
In its current nomenclature, WHO defines endometrial hyperplasia without atypia and atypical endometrial hyperplasia (AEH) synonymously: endometrial intraepithelial neoplasia = EIN [339].
Endometrial hyperplasia without atypia is a benign change that is usually observed or treated conservatively (e.g. systemic progestins, oral contraceptives, progestin IUD, weight reduction; caveat: estrogen/androgen-producing tumor) and is operated on only in exceptional cases. The risk of developing invasive carcinoma is 1% [339].
The group “complex endometrial hyperplasia without atypia” included in the previous WHO classification has been abandoned and is now included in the group “endometrial hyperplasia without atypia” [339] .
A recent systematic review and meta-analysis analyzed 12 studies of 804 patients with endometrial hyperplasia without atypia in curettage material or endometrial biopsy who subsequently underwent hysterectomy (HE). In 566 women with simple nonatypical endometrial hyperplasia, occult EC was found in 2% in the HE specimen In the 238 patients with complex nonatypical hyperplasia on curettage or biopsy, EC was present in the HEspecimen in 12.4% [462].
5.1.2 Atypical endometrial hyperplasia (AEH)
5.1.2.1 Approach to AEH in postmenopausal women or premenopausal women with completed family planning
In postmenopausal patients and in premenopausal patients with completed family planning and presence of atypical hyperplasia of the endometrium, total hysterectomy with bilateral salpingectomy and, if necessary, bilateral ovariectomy shall be performed.
- Recommendation grade
- A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
- Level of evidence
- 1
- Consensus
- Strong consensus
- References
- [339] [232]
Evidence tables (1)
5.1.2.1 EvT 5.2Background
Endometrial hyperplasia with atypia has a risk of progression of up to 30% [339]. In up to 60%, invasive carcinoma is already present in the hysterectomy specimen when the diagnosis “endometrial hyperplasia with atypia” is made in the curettage or biopsy [463].
The group “complex endometrial hyperplasia without atypia” included in the previous WHO classification has been abandoned and is now included in the group “endometrial hyperplasia without atypia“ [339] .
For atypical endometrial hyperplasia (AEH) and EC pT1a, G1, total hysterectomy (+ adnexal extirpation) results in disease-specific 5-year survival of at least 99% [464]. With supracervical hysterectomy or endometrial ablation, endometrium remains in the uterus or cervical stump, respectively, so these operations are not recommended for AEH [465].
Considering the high risk of progression of atypical endometrial hyperplasia, possible limitations of quality of life due to hysterectomy (see S3 Guideline “Indication and methodology of hysterectomy for benign diseases”, version 1.2, April 2015, AWMF register number: 015/070, http://www.awmf.org/leitlinien/detail/ll/015-070.html) [466] recede into the background. Only an unfulfilled desire to have a child should open up a waiver of hysterectomy for atypical endometrial hyperplasia as an option.
5.1.2.2 Approach to AEH in premenopausal women.
In the presence of atypical hyperplasia, the ovaries may be left in place when performing hysterectomy and bilateral salpingectomy in premenopausal women, provided there is no evidence of a hereditary predisposition to ovarian cancer (e.g., BRCA mutation or certain forms of Lynch syndrome).
- Consensus
- Strong consensus
Background
There are no studies on the risks of leaving the adnexa in premenopausal women undergoing hysterectomy for AEH. Based on current knowledge, removal of both salpinges can be discussed with the patient for prophylaxis of tubal/ovarian/peritoneal carcinoma [467].
In endometrioid EC pT1, a meta-analysis of 5 case/control studies found no difference in overall survival when the ovaries were removed or left in place [468]. A later meta-analysis of 7 retrospective cohort studies of women with stage I EC (1,419 patients with ovarian preservation, 15,826 women with hysterectomy and bilateral adnexal extirpation found no significant differences in overall and disease-free survival between the two groups, even in premenopausal women (HR overall survival=0.99 ; 95%-CI= 0.56-3.93) [469]. If one accepts these results (LoE 3) for early EC, it could also apply to AEH.
In women with AEH and with a familial predisposition to ovarian cancer, the ovaries should not be left in place. Since not all forms of Lynch syndrome are associated with an increased risk of ovarian cancer, if a germline mutation in the Lynch genes is detected, a consultation with a human geneticist competent in this field should be obtained before deciding on ovarian preservation (see Chapter 10).
5.1.2.3 Fertility preservation in women with AEH
If uterus preservation is desired, the uterus and adnexa may be left in place in the presence of atypical hyperplasia if the patient has been informed that the standard treatment almost always leading to cure is total hysterectomy, agrees to close monitoring and has been informed of the need for hysterectomy after the desire for a child has been fulfilled or abandoned.
- Consensus
- Strong consensus
If uterus preservation is desired, the uterus and adnexa may be left in place in the presence of atypical hyperplasia if a hysteroscopy with targeted biopsy or with curettage was performed to confirm the diagnosis and the diagnosis “atypical hyperplasia” was made or confirmed by a pathologist experienced in gynecologic pathology.
- Consensus
- Strong consensus
If uterus preservation is desired, the uterus and adnexa may be left in place in the presence of atypical hyperplasia if laparoscopy with vaginal ultrasound or MRI has been performed to best assess the risk of adnexal involvement and/or myometrial infiltration.
- Consensus
- Strong consensus
If complete remission of AEH is seen after 6 months of conservative treatment, planned pregnancy should be pursued.
- Consensus
- Strong consensus
If there is currently no desire to have a child, maintenance therapy should be performed. An endometrial biopsy shall be performed every 6 months.
- Consensus
- Strong consensus
After fulfillment or abandonment of the desire to have children, a total hysterectomy ( +/- bilateral salpingectomy +/-, bilateral ovariectomy) shall be performed.
- Recommendation grade
- A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
- Level of evidence
- 4
- Consensus
- Strong consensus
- References
- [470] [471] [472] [473] [474]
Evidence tables (1)
5.1.2.3 EvT 5.9Background
Conservative therapy of AEH may be considered when there is still an unfulfilled desire to have children and fertility should be preserved.
To date, numerous papers have been published on conservative therapy for patients with atypical endometrial hyperplasia (AEH) and early EC [465], [475]. Few of these publications meet the quality criteria (minimum number of patients, minimum treatment duration, sufficient follow-up, and others) that would make them usable for a systematic review.
Since 2012, 5 meta-analyses and systematic reviews have appeared, which, although based on the same pool of publications, reached varying conclusions [476], [475]. The conservative therapies used varied considerably: hydroxyprogesterone 500 mg/d orally, medroxyprogesterone acetate 10–1800 mg/d orally, megestrol acetate 160 mg/d orally, natural progesterone 200 mg/d orally 14th–25th day of cycle, progestogen IUD among others [476], [475].
The group led by Bristow, a US gynecologic oncologist, found 45 eligible trials involving 391 patients. 66% of these women with AEH had complete remission with conservative therapy. AEH persisted in 14% of patients, and 23% relapsed after initial remission. 41% of women with conservatively treated AEH became pregnant [476].
A UK study group selected 34 publications with 154 patients; 86% of women had remission, 26% had recurrence, and 26% had a live birth [477].
An Australian working group found only 12 publications that met their criteria, with 117 patients. Here, 74% of women with AEH had a complete remission, 2.7% had persistent AEH, and 20% relapsed after an initial response [478].
A French study group found 24 trials that met their quality requirements, but published the pooled results for AEH and EC (see below) [479].
Therapy of AEH with a levonorgestrel IUD theoretically offers the advantage of high local progestin concentration with low systemic progestin exposure [475]. The available studies provide contradictory results and are methodologically inadequate (too small case numbers, retrospective case collections) [475]. The 2013 Cochrane Collaboration analysis concludes that there are no adequate studies demonstrating the safety and efficacy of a levonorgestrel IUD for the treatment of AEH [475].
Mandelbaum et al. retrospectively analyzed 245 patients with complex atypical endometrial hyperplasia who had been treated systemically (n=176) with progestogens or with a levonorgestrel –IUD (n=69). The progestin IUD resulted in complete remission in 79%, and systematic progestin treatment in 47%. (HR=3.32; 95% KI=2.39- 4.62). Progression to carcinoma occurred in 4.5% of women with progestin IUD and in 16% of patients with systemic progestin treatment (HR=0.28; 95%-CI=0.11-0.73). Especially morbidly obese patients benefited from progestin-IUD treatment [480].
5.1.2.4 Metformin and progestin therapy for endometrial hyperplasia.
The oral antidiabetic drug metformin (MET) has been evaluated in a number of clinical trials as a therapeutic agent for the treatment of endometrial hyperplasia (EH). A Cochrane meta-analysis analyzing data through 2017 identified 3 randomized trials with a total of only 77 subjects and found no therapeutic effect for MET in terms of remission, progression or recurrence rates [481]. However, some recent studies found evidence of a therapeutic effect of MET. Tehrani et al. compared 40 mg megestrol acetate (MA) daily for 4 weeks combined with 1000 mg MET daily for 3 months or placebo [482] in 60 women with EH without atypia. After 3 months, remission rates (27/30 [93%] vs. 19/30 [70%]) differed significantly in favor of the MET group. In a retrospective analysis of 245 women with complex EH, concomitant MET use was associated with increased remission rates with levonorgestrel IUD (LNG-IUD) (87% vs. 59% at 6 months) but not with increased rates with oral progestin therapy (23% vs. 28% at 6 months) [483]. Yang et al. randomized 150 women with atypical EH or early EC G1/2 to megestrol acetate (160 mg 1x1 daily) with/without MET (500 mg 3x1 daily) [484]. After 4 months, combination therapy achieved higher complete remission rates (34% vs. 21%; p=0.09). However, after 8 months, this difference was no longer detectable.
Overall, based on the available data, MET cannot currently be recommended as an additional therapeutic agent for the treatment of EH due to the lack of clear evidence of efficacy.
Given the potential clinical consequences (including unnecessary hysterectomy in younger women versus inadequate appreciation of a potentially life-threatening cancer) and the great difficulties in pathologic differential diagnosis (EH without atypia, EH with atypia, well-differentiated endometrioid EC), it is reasonable to seek a second opinion from a pathologist particularly familiar with this problem [323].
Since there is no study-proven conservative treatment for AEH, only consensus-based recommendations can be made.
Since synchronous invasive EC is often not detected, it is advisable to also treat AEH conservatively with a dosage that is effective in manifest EC (medroxyprogesterone acetate 200–250 mg/d orally; megestrol acetate 160–200 mg/d) (see Chapter 9, as well as Statement 5.18 in Chapter 5.2).
Histologic controls (Pipelle, hysteroscopy, dilatation and fractional curettage) at 6 months are recommended. If AEH persists or progression to EC occurs, hysterectomy is indicated [323]. Given the relevant recurrence rate after initially successful conservative treatment of AEH, hysterectomy should be performed after fulfillment or abandonment of the desire to have children [323], [479]. Studies on the quality of life under conservative therapy of AEH are not available.
5.2 Early endometrial cancer
5.2.1 Procedure for early endometrial carcinoma
In the presence of early endometrial carcinoma (endometrioid, pT1a G1), total hysterectomy with bilateral adnexal extirpation results in a disease-specific 5-year survival of 99%.
- Level of evidence
- 3
- Consensus
- Strong consensus
- References
- [485]
Evidence tables (1)
5.2.1 EvT 5.10Background
In the presence of early endometrial carcinoma (endometrioid pT1a, G1), total hysterectomy with bilateral adnexal extirpation results in a disease-specific 5-year survival of 99% [464].
5.2.2 Leaving the adnexa in premenopausal women with early endometrial cancer.
In the presence of endometrioid endometrial carcinoma G1, G2 pT1a, the ovaries may be left in place when performing hysterectomy and bilateral salpingectomy in premenopausal women, provided there is no evidence of hereditary predisposition to ovarian cancer (e.g., BRCA mutation, certain forms of Lynch syndrome) and the patient is informed of the risk.
- Consensus
- Consent
Change note
In the presence of endometrioid EC G1, G2 pT1a, the ovaries may be left in place when performing hysterectomy and bilateral salpingectomy in premenopausal women, provided there is no evidence of hereditary predisposition to ovarian cancer (e.g., BRCA mutation, e.g., Lynch syndrome) and the patient is informed of the risk.Background
The data on preservation of the ovaries in early endometrial carcinoma are provided in the background text on AEH. However, it should be noted that even in young women with early endometrial carcinoma G1 or pT1a, synchronous ovarian carcinomas or ovarian metastases may occur in up to 25.5% [486].
It should be noted that preoperative imaging and even intraoperative assessment of the ovaries did not reveal a proportion of these tumors [486].
In a retrospective cohort study of 282 young women (15–49 years) with endometrial cancer, 27 had Lynch syndrome (9.6%), 151 (53.4%) had estrogen dominance (obesity, PCOS, etc.), and 104 (36.8%) had neither Lynch syndrome nor estrogen dominance. Synchronous ovarian cancer was found in 23.1% of patients with Lynch syndrome, in 6.6% of women with estrogen dominance and in 21% of EC patients from the “neither nor” group [381].
5.2.3 Synchronous endometrial and ovarian cancer
Women with endometrial cancer (EC) rarely have synchronous ovarian cancer. In an analysis of the U.S. Surveillance, Epidemiology and End Results Program (SEER) file, among 56,986 patients with ovarian cancer, synchronous EC was found in 1709 (3%) cases [487]. In contrast, young women with EC have a significantly increased risk of synchronous endometrial and ovarian cancer (SEOC), reported in the literature to range from 11% to 36% [488], [489], [490], [486], [491]. This fact has important consequences for the counseling and therapy of young women with EC.
In >70% of cases, SEOC are synchronous endometrioid adenocarcinomas in both the endometrium and ovary. Based on this histological concordance and on clonality analyses, a common monoclonal origin has been proposed for SEOC [492]. In most cases of SEOC, both EC and ovarian cancer are diagnosed at an early stage of disease, and the prognosis of women with SEOC is therefore good. For example, Oranratanaphan et al. [488] report a 5-year survival rate of 64% in women with SEOC compared with only 48% in women with EC and ovarian metastasis.
The distinction between SEOC and EC with ovarian metastasis is sometimes difficult and is based on both clinicopathological criteria and immunohistochemical analyses such as PAX-8, which is expressed in primary ovarian cancer but not in EC metastases [493]. In the literature, the rate of ovarian metastases varies widely, ranging from 12% [486] to 87% [488], indicating difficult histopathological assignment.
However, accurate diagnosis and differentiation between SEOC and EC with ovarian metastasis is of great clinical importance, as patients with EC and ovarian metastasis are candidates for adjuvant chemotherapy or radiotherapy, but not patients with two early cancers, as would be the case with a diagnosis of SEOC. Therefore, in case of ambiguity, consultation with a reference pathologist is recommended.
Young women with SEOC are at increased risk for carrying a hereditary non-polyposis colon cancer (HNPCC) syndrome-associated mutation (Lynch syndrome). While the rate of Lynch syndrome in women with EC is approximately between 4% and 11% [494], young women with SEOC have Lynch syndrome in approximately 40% of cases [491]. Lynch syndrome screening should therefore be performed in young women with SEOC (see also Chapter 10 Recommendation 10.6).
5.2.4 Fertility preservation in women with early endometrial cancer.
In women with incomplete family planning and endometrioid cT1a without myometrial infiltration, G1, p53-wt and L1CAM-negative endometrial carcinoma and a desire for fertility preservation, the uterus and adnexa can be left in place if the patient has been informed that the standard treatment almost always leading to cure is total hysterectomy and that the patient temporarily forgoes curative treatment of a malignancy on her own responsibility, knowing the potentially fatal consequences (progression of the disease, metastasis) even if a pregnancy is carried to term.
- Consensus
- Strong consensus
Change note
In women with incomplete family planning and endometrial cancer and a desire for fertility preservation, the uterus and adnexa may be left in place if the patient has been informed that the standard treatment almost always leading to cure is total hysterectomy and the patient temporarily forgoes curative treatment of a malignancy on her own responsibility, knowing the potentially fatal consequences (progression of the disease, metastasis), even if a pregnancy is carried to term.If uterus preservation is desired, the uterus and adnexa can be preserved in the presence of endometrioid cT1a, without myometrial infiltration G1, p53-wt, and L1CAM-negative endometrial carcinoma if the patient has been recommended a consultation with a specialist in reproductive medicine to assess the chances of fulfilling a childbearing desire.
- Consensus
- Strong consensus
Change note
If uterus preservation is desired, the uterus and adnexa can be preserved in the presence of early endometrial carcinoma if the patient has been recommended a consultation with a reproductive physician to assess the chances of fulfilling a childbearing desire.If uterus preservation in endometrioid cT1a, without myometrial infiltration G1, p53-wt and L1CAM-negative endometrial carcinoma are desired, the uterus and adnexa can be left in place if the patient agrees to close monitoring and has been informed of the need for hysterectomy after fulfillment or abandonment of the desire to have children.
- Consensus
- Strong consensus
Change note
In cases of desire for uterine preservation and early endometrial cancer, the uterus and adnexa may be left in place if the patient agrees to close monitoring and has been informed of the need for hysterectomy after fulfillment or abandonment of the desire to have children.In endometrioid cT1a without myometrial infiltration, G1, p53-wt and L1CAM- negative endometrial carcinoma and desire for fertility preservation, the uterus and adnexa can be left in place if a diagnosis of well-differentiated (G1) endometrioid EC expressing progesterone receptors has been made by hysteroscopy with targeted biopsy or with diatation and curettage and evaluation by a pathologist experienced in gynecologic pathology.
- Consensus
- Strong consensus
Change note
In cases of early endometrial cancer and desire for fertility preservation, the uterus and adnexa may be left in place if a diagnosis of well-differentiated (G1) endometrioid EC expressing progesterone receptors has been made by hysteroscopy with targeted biopsy or with abrasion and evaluation by a pathologist experienced in gynecologic pathology.In endometrioid cT1a without myometrial infiltration, G1, p53-wt, and L1CAM-negative endometrial cancer and desire for fertility preservation, the uterus and adnexa can be left in place if laparoscopy with vaginal ultrasound or if MRI has ruled out adnexal involvement or myometrial infiltration as much as possible.
- Consensus
- Strong consensus
Change note
In early endometrial cancer (pT1a, G1) and desire to preserve fertility, the uterus and adnexa can be left in place if laparoscopy with vaginal ultrasound or with MRI has ruled out adnexal involvement or myometrial infiltration as much as possible.In endometrioid cT1a without myometrial infiltration, G1, p53-wt, and L1CAM-negative endometrial cancer and desire for fertility preservation, the uterus and adnexa can be left in place if sufficient drug treatment is given with medroxyprogesterone acetate 200-250 mg/d/p.o.) or megestrol acetate (160-200 mg/d/p.o.) or a levonorgestrel IUD (52 mg).
- Consensus
- Strong consensus
Change note
In early endometrial cancer and desire for fertility preservation, the uterus and adnexa can be left in place if sufficient drug treatment with medroxyprogesterone acetate or megestrol acetate or a levonorgestrel IUD is given.If a complete remission of the endometrial carcinoma is diagnosed after six months of conservative treatment, the planned pregnancy should be pursued in cooperation with a specialist in reproductive medicine if necessary.
- Consensus
- Consent
Patients with endometrioid cT1a without myometrial infiltration, G1, p53-wt, and L1CAM-negative endometrial cancer without a current desire to have children should receive maintenance therapy (levonorgestrel-IUD, oral contraceptives, cyclic progestins) and have an endometrial biopsy every 6 months.
- Consensus
- Strong consensus
Change note
EC patients (pT1a without myometrial infiltration, G1) without a current desire to have children should receive maintenance therapy (levonorgestrel-IUD, oral contraceptives, cyclic progestins) and have an endometrial biopsy every 6 months.If there is no remission of the carcinoma after six months of conservative treatment, hysterectomy should be performed.
- Consensus
- Strong consensus
If uterus preservation is desired, the uterus and adnexa can be left in the presence of endometrioid endometrial cancer (cT1a, G1, p53-wt, and L1CAM-negative) if the following conditions are met:
- Information that the standard treatment almost always leading to cure is total hysterectomy,
- Consent with close follow-up,
- Information about the necessity of hysterectomy after fulfillment or abandonment of the desire to have a child,
- Hysteroscopy with targeted biopsy or dilatation and curettage to confirm diagnosis,
- Laparoscopy with vaginal ultrasound or MRI to rule out adnexal involvement/myometrial infiltration,
- Diagnosis made or confirmed by a pathologist experienced in gynecologic pathology,
- Treatment with MPA or MGA or LNG-IUD (52 mg),
- After 6 months, repeat hysteroscopy withdilatation and curettage as well as imaging. If no remission , hysterectomy,
- If complete remission, aim for pregnancy (expert in reproductive medicine),
- If no current desire to have children: maintenance therapy and endometrial biopsy every 6 months,
after fulfillment or abandonment of the desire to have children: total hysterectomy and bilateral adnexal extirpation recommended.
- Consensus
- Consent
Change note
If uterus preservation is desired, uterus and adnexa can be left in the presence of endometrioid adenocarcinoma of the endometrium cT1A, G1 without evidence of myometrial infiltration, with expression of the progesterone receptor, if the following conditions are met: Information that the standard treatment almost always leading to cure is total hysterectomy, consent with close follow-up, education about the need for hysterectomy after fulfillment or abandonment of the desire to have children, for confirmatory diagnosis hysteroscopy with targeted biopsy or abrasion, Laparoscopy with vaginal ultrasound or with MRI to rule out adnexal infestation/myometrial infiltration, diagnosis made or confirmed by a pathologist experienced in gynecologic pathology, treatment with MPA or MGA or LNG-IUD, after 6 months, repeat hysteroscopy with abrasio as well as imaging. If no response, hysterectomy, if complete remission, strive for pregnancy (reproductive physician), if no current desire to have children: maintenance therapy and endometrial biopsy every 6 months, after fulfillment or abandonment of desire to have children: recommend total hysterectomy and bilateral adnexal extirpation.Background
EC are malignancies that usually lead to death if left untreated. The majority of early stage EC with good differentiation are cured in almost 100% of cases by hysterectomy. Forgoing this curative surgery requires a strict indication. There should be a concrete desire to have children and not just an abstract desire to preserve fertility. It should be explained to the patient that she is foregoing curative treatment of a malignancy, at least temporarily, with potentially fatal consequences (disease progression, metastasis), even if a pregnancy is carried to term [477].
Ruiz et al. analyzed data from 23,231 patients with EC stage I who were <50 years old. 873 of them had been treated conservatively. In multivariate analysis, stage IA patients had a 5-year survival of 97.5% (hysterectomy) and 97.5% (conservative therapy with progestogens), respectively. For stage IB patients, survival rates were 97.5% (hysterectomy) and 75% (progestins) [495].
Gonthier et al. identified from the SEER database 1,106 women with EC G2 or G3 confined to the endometrium who were younger than 45 years of age. Uterus-preserving therapy was performed in 49 patients. The 5-year overall survival was 94.8% (hysterectomy) and 78.2% (uterus preservation) (HR=6.6; 95%-CI=3.3-13.4). Disease-specific survival was 99.3% (hysterectomy) and 86.2% (uterine preservation) (HR=15.8%; 95%-CI=5.5-45.2) [496].
Greenwald et al. determined the 15-year survival of 6,339 women with EC stage I G1/G2 from the SEER database (1993-2012). After propensity score matching, cancer-specific mortality was 9.2% (95%-CI=3.4%-24%) in women treated conservatively and 2.1% (95%-CI=1.5-2.8%) in patients after hysterectomy. However, by using other definitions, no significant difference in mortality was then found [497].
Gunderson et al [476] reported 48% remissions of EC G1 with conservative therapy in a systematic review. The median time to response was 6 months. 35% of women whose EC initially responded ,relapsed subsequently. 35% of patients with EC became pregnant.
Gallos et al. [477] reported a remission rate of 76%, a recurrence rate of 40% and a live birth rate of 28%. 3.6% of women developed ovarian cancer, 2% had progression to higher stages and 2 of 408 conservatively treated EC patients died from their disease.
An Australian analysis of the literature found complete remission with oral progestin therapy in 72% of EC patients and a recurrence rate of 20%. 3% of women had progression of EC while on progestin therapy [478].
A French analysis that pooled data for AEH and EC, found a remission rate of 81% and a recurrence rate (after initial response) of 30%; the pregnancy rate was 32% and progression occurred in 15% of patients with EC [479]. The French analysis showed that after nine months of conservative treatment, further remissions were not expected. However, the probability of recurrence after initially successful conservative treatment increased continuously [479].
Another meta-analysis by this group found that the remission rate was higher with conservative therapy when specimen collection for diagnosis had been performed by operative hysteroscopy (OR for remission 2.31; 95%-CI=1.10-4.84) [498].
No data are available on the dependence of the success rate of conservative therapy for early EC in childbearing on p53 and L1CAM –expression. However, it is logical to advise against fertility-preserving procedures in early EC that have a p53 mutation or L1CAM –overexpression, given the unfavorable prognosis. Immunohistochemical determination of L1CAM, which is generally recommended with a recommendation grade of 0, should be performed generously if fertility-preserving therapy is planned.
In a recent meta-analysis, estrogen and/or progesterone receptor expression had no predictive value regarding the response of endometrial hyperplasia with atypia or early EC to conservative therapy with oral progestogens. For therapy with a levonorgestrel IUP, ER and or PR expression had significant predictive value. However, the accuracy was too low to recommend clinical use [499]. The aforementioned meta-analysis by Guillon et al. also found no significant predictive value for expression of either steroid receptor [498].
In the studies that were analyzed, widely varying progestin doses were used. Therefore, a definite dose recommendation cannot be made. It seems logical to the Guideline group to apply doses that are effective in the therapy of advanced EC (medroxyprogesterone acetate 200–250 mg/d orally; megestrol acetate 160–200 mg/d orally) [500], [501].
The statements, recommendations and background texts on fertility preservation in endometrial cancer have been adopted one-to-one in the S2k Guideline “Fertility preservation in oncological diseases” (AWMF register number: 015-082, http://www.awmf.org/leitlinien/detail/anmeldung/1/ll/015-082.html) after the consensus conference of this Guideline had agreed on them again. This resulted in 100% agreement between the experts of the S3 Guideline on endometrial cancer and the S2k Guideline on fertility preservation.
Evidence tables
5.1.1 EvT 5.1
|
Referenz |
Studientyp/ |
Untersuchte Population |
Intervention |
Kontrolle |
Untersuchte Endpunkte |
Hauptergebnisse |
Methodische Bemerkungen |
|
Zaino 2014
|
Keine Studie: Buchkapitel; methodologische Einordnung: S1-Empfehlung auf höchstem Niveau (WHO). |
|
|
|
|
|
|
5.1.2.1 EvT 5.2
|
Referenz |
Studientyp/ |
Untersuchte Population |
Intervention |
Kontrolle |
Untersuchte Endpunkte |
Hauptergebnisse |
Methodische Bemerkungen |
|
Zaino 2014
|
Keine Studie: Buchkapitel; methodologische Einordnung: S1-Empfehlung auf höchstem Niveau (WHO). |
|
|
|
|
|
|
|
Antonsen 2012 |
Retrospektive Kohortenstudie (Datenbankanalyse aller Fälle mit AEH in Dänemark = Vollerhebung) LoE 1 |
778 Frauen mit präoperativer Diagnose atypische Endometrium-hyperplasie (AEH). |
Präoperative endometriale Histologie, gewonnen per Pipelle, Dilatation und Kürettage oder Hysteroskopie: bewertet und eingestuft (Staging) von einem lokalen Pathologen. |
Die postoperative Diagnose wurde aufgrund der histologischen Befunde der Hysterektomien, durchgeführt von den Pathologen verschiedener Kliniken, gestellt.
|
1. Outcome: Übereinstimmung prä- und postoperative Diagnose atypische endometriale Hyperplasie. 2. Outcome: Korrelation der o.g. Endpunkte mit Alter, BMI und Menopause. |
In 59 % der Fälle liegt bei präoperativer Diagnose atypische endometriale Hyperplasie ein invasives Endometrium-karzinom vor. 60 % der Frauen mit Diagnose atypische endometriale Hyperplasie hatten ein Endometrium-karzinom, 20 % davon sogar FIGO IB; da bei IB die Lymphadenek-tomie erfolgen sollte, ist die Therapie besser in onkologischen Zentren aufgehoben. Effektschätzer: Krebs korreliert signifikant mit Alter (p < 0,0001) und Menopause (p < 0,001). 80 % der postmenopausalen Frauen hatten ein höheres postoperatives Krebsrisiko, verglichen mit der prämenopausalen Gruppe (OR 2,8). Kein signifikanter Unterschied bestand in Korrelation zu BMI (p = 0,25). |
Die Aussage „besser in Zentren aufgehoben“ ist nicht evidenz-basiert. |
5.1.2.3 EvT 5.9
|
Referenz |
Studientyp/ |
Untersuchte Population |
Intervention |
Kontrolle |
Untersuchte Endpunkte |
Hauptergebnisse |
Methodische Bemerkungen |
|
Gunderson 2012 |
Systematischer Review (Literatur-Review von 45 Studien: 5 prospektive Serien, 20 retrospektive Fallserien, 20 Fallberichte) LoE 4
|
391 Frauen mit atypischer endometrialer Hyperplasie (AEH) oder Endometrium-karzinom (EC) G1 und endokriner Therapie. |
Systematische Literatursuche in MEDLINE 2004 bis 2011. Intervention: Endokrine Therapie: 49 % Medroxypro-gesteron (MPA); 25 % Megestrolacetat (MGA); 19 % Levonor-gestrel-Intrauterinpessar; Rest: weitere, nicht näher definierte Gestagene (u. a. Hydroxypro-gesteroncaproat). |
n.a. |
Responserate, Rezidivrate, Schwangerschaftsrate unter Gestagen-Therapie. |
Atypische endometriale Hyperplasien sprechen besser auf die Gestagen-Therapie an als Endometrium-karzinome. Effektschätzer: 65,8 % versus 48,2 % (p = 0,002). 78 % Responserate (n = 344); dauerhafter Response in 53 %; durchschnittliche Zeit bis zum kompletten Ansprechen: 6 Monate (Range von 1–18 Monaten); Rezidivraten nach ursprünglichem Response: 23 % (AEH) und 35 % (EC) (p = 0,03); anhaltende Erkrankung wurde beobachtet in 14 % (AEH) und 25 % (EC) (p = 0,02); Schwanger-schaftsrate: 41 % (AEH) und 35 % (EC) (p = 0,39): 117 Lebendgeburten. |
Einschluss fast nur von retrospektiven Fallserien und Fallberichten, nur 1 Studie als „high quality“ eingestuft. Angaben zu Publication Bias vorhanden (Reporting Bias). Analyse durch renommierte gynäkologische Onkologen. |
|
Luo 2013 |
Systematischer Review (Cochrane Review) LoE 1 |
[Einschluss-kriterium] Frauen mit atypischer endometrialer Hyperplasie oder mit einem frühen Endometrium-karzinom. |
[Einschluss-kriterium] Levonorgestrel-Intrauterinpessar. |
[Einschluss-kriterium] Orale Anwendung von Gestagenen. |
[zu untersuchende Endpunkte/Outcomes] Effektivität und Sicherheit von intrauterin angewendeten Gestagenen bei atypischer endometrialer Hyperplasie. 1. Outcome: Regressionsrate; direkte Nebenwirkungen der endokrinen Therapie. 2. Outcome: Rezidivrate; Rate an Hysterektomien; weitere Nebenwirkungen; Behandlungszufriedenheit; Lebensqualität. |
Keine Aussage auf Basis von randomisiert-kontrollierten Studien möglich, da keine geeigneten Studien gefunden wurden. |
Systematische Literatursuche Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 8); Menstrual Disorders and Subfertility Specialised Register; MEDLINE (1948 bis 2012/November); EMBASE (1986 bis 2012 November); Chinese National Knowledge Infrastructure (CNKI) (1977 bis 2012/November); CBM (China Biomedicine Database) (1995 bis 2012 November); PsycINFO (1988 bis 2012/November). Weitere Suchen in: National Research Register; Meta-Register of Controlled Trials; Chinese Clinical Trial Registry; World Health Orga-nization (WHO) International; Clinical Trials Registry Platform; Clinical Trials gov.; graue Literatur. |
|
Koskas 2014 |
Systematischer Review und Metaanalyse (Register-Nummer: CRD42013004557) LoE 4 |
370 Frauen mit atypischer endometrialer Hyperplasie (AEH) oder Endometrium-karzinom (EC) mit fertilitäts-erhaltender Therapie. |
Systematische Literatursuche in MEDLINE 1950 bis 2011. Intervention: Diverse Gestagene ohne Dosisangabe; Tamoxifen, Bromocriptin, Metformin, GnRH-Agonisten, Levonorgestrel-Intrauterinpessar. |
n.a. |
Remissionsrate, Rezidivrate, Progressions-rate Schwangerschaftsrate unter fertilitätserhaltender Therapie. |
Fertilitätserhaltende Therapien können auch bei älteren Patientinnen mit vorhergehender Infertilität und Adipositas ange-wandt werden. Effektschätzer: Remissionsrate AEH und EC gepoolt: 78 % (12 Mo.), 81 % (24 Mo.). Remissionsrate am höchsten (multiva-riate Analyse) nach vorhergegangener Schwangerschaft (OR 2,70; 95 % CI: 1,23–5,89), Unfruchtbarkeit (OR 2,26; 95 % CI: 1,05– 4,87), Megestrolacetat (OR 2,70; 95 % CI: 1,20–6,02). Rezidivrate nach 24 Mon.: 30 %; Schwangerschafts-rate: 32 %; Progressionsrate: 15 %; Remissionsrate erreicht nach 9 Mon. Plateau; Rezidivrate steigt kontinuierlich an. |
Einschluss von Fallserien mit schwacher Qualität. Keine Angaben zu Publication Bias. |
|
Baker 2012 |
Metaanalyse und systematischer Literatur-Review
LoE 4 |
|
Systematische Literatursuche von 1950 bis 2011 in MEDLINE, Cochrane Library, ScienceDirect, Dynamed und MD Consult Australia.
|
Verschiedene Dosen Medroxypro-gesteronacetat (MPA) oder Megestrolacetat (MGA) oral in Fallserien (prospektiv oder retrospektiv). |
Pathologische Remissionsrate, Progressionsrate, Rezidivrate. |
Es fehlt an belastbarer Evidenz für die Effektivität von Progesteron bei komplexen atypischen endometrialen Hyperplasien oder frühen Endometrium-karzinomen. Die zur Verfügung stehende Evidenz zeigt, dass eine Behandlung mit oralen Progesteronen genauso effektiv zu sein scheint wie die intrauterine. Effektschätzer: Orale Gestagene: pathologische Komplettremission (pCR) 74 % (AEH) (CI: 95 % 65–81 %), 72 % (Endometrium-karzinome) (95 % CI: 62–80 %); Progression unter Therapie 2,7 %; n = 6/219); Rezidiv nach initialem Ansprechen: 20 %; n = 32/159). Intrauterine Gestagene: pCR 68 % (n = 22 Endometrium-karzinome) (95 % CI: 45–86 %). |
Eingeschlossene Fallserien von niedriger Qualität; unterschiedliche Medikamente und Dosierungen in den einzelnen Studien. Angaben zu Publication Bias vorhanden. |
|
1 prospektive, 1 retrospektive Fallserie mit Levonorgestrel-Intrauterin-pessaren. |
|||||||
|
Gallos 2012 |
Systematischer Review und Metaanalyse LoE 4
|
559 Frauen mit atypischer endometrialer Hyperplasie (AEH) oder frühem Endometrium-karzinom und fertilitätserhalten-der Therapie. |
Systematische Literatursuche in MEDLINE 1950 bis 2011, EMBASE 1980 bis 2011, im Cochrane Register of Controlled Trials und in ISI Proceedings 1990 bis 2001. |
n.a. |
Remissionsrate, Rezidivrate und Lebendgeburt-Rate unter fertilitätserhaltenden Maßnahmen. |
Fertilitätserhaltende Behandlungen sind machbar: 451 Frauen mit fertilitätserhaltender Therapie; 142 Frauen erhielten assistierte Reproduktions-maßnahmen (56 Schwangerschaften, mind. 1 Lebendgeburt) = Lebendgeburt-Rate: 39,4 %. Spontane Schwangerschaften (aus 309 Frauen; 36 Schwangerschaften, mind. 1 Lebendgeburt) = Lebendgeburt-Rate: 14,9 %. Unterschied statistisch signifikant (p = 0,001). Effektschätzer: Für Endometrium-karzinom: Remissionsrate 76 % (95 % CI: 68– 85,3); Rezidivrate 40 % (95 % CI: 33,1–49,8); Lebendgeburt-Rate: 28 % (95 % CI: 21,6–36,3). Für atypische endometriale Hyperplasien: Remissionsrate 86 % (95 % CI: 72–100); Rezidivrate 26 % (95 % CI: 18–37,6); Lebendgeburt-Rate 26 % (95 % CI: 18,5–37,4). 20 Frauen hatten während Follow-up ein Ovarialkarzinom (3,6 %), 10 hatten einen Progress des Endometrium-karzinoms und 2 verstarben daran. |
Einschluss kleiner, meist retrospek-tiver Fallserien. Angaben zu Publication Bias vorhanden. Random-effects-Modell wurde verwendet. |
|
Diverse endokrine Therapien: Gestagene in unterschiedlicher Dosierung, Levonorgestrel-Intrauterinpessar, Gnrh-Analoga, Aromatase-hemmer. |
|||||||
|
|
5.2.1 EvT 5.10
|
Referenz |
Studientyp/ |
Untersuchte Population |
Intervention |
Kontrolle |
Untersuchte Endpunkte |
Hauptergebnisse |
Methodische Bemerkungen |
|
Chan 2007 |
Retrospektive Datenbankanalyse von Fallserien LoE 3 |
39.396 Frauen (Durchschnittsalter 65 Jahre) mit Endometrium-karzinom. Interventionsarm: 12.333 (31,3 %) Frauen. Kontrollarm: 27.063 Frauen, davon hatten 24.436 eine Hysterektomie (90,3 %); 2.627 Frauen hatten keine Hysterektomie. Staging gemäß FIGO (1988). |
Hysterektomie, beidseitige Salpingo-ophorektomie + Lymphade-nektomie (LNE), hier definiert als Entfernung von mindestens einem Lymphknoten.
|
Keine Lymphade-nektomie. |
Krankheitsspezifisches 5-Jahres-Überleben. |
Lymphadenektomie ist mit einem verbesserten krankheitsspezi-fischen Überleben bei Endometrium-karzinom Stadium I G 3 und höher assoziiert. Bei Stadium I G1 oder G2 bringt die Lymphadenektomie keinen Vorteil. Effektschätzer: Krankheits-spezifisches-5-Jahres-Überleben; Stadium I–IV mit LNE: 95,5 %, 90,4 %, 73,8 %, 53,3 %.; ohne LNE: 96,6%, 82,2 %, 63,1 %, 26,9 %. (p Krankheitsspezi-fisches 5-Jahres-Überleben mit Hysterektomie 94,2 % versus 57,9 % ohne Hysterektomie; Stadium I G1: 98 % und II G2 96 % Gesamtüberleben. |
Keine Randomi-sierung. Keine Kriterien, wann Lymphadenektomie angewandt wurde und wann nicht. Hoher Selection Bias: Patientinnen, die eine LNE bekamen, waren jünger und gesünder. |
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