3. Epidemiology and risk factors, prevention of endometrial cancer – Endometrial Cancer
3.1 Epidemiology and risk factors
3.1.1 Age
The risk of endometrial cancer increases with age.
- Level of evidence
- 1
- Consensus
- Strong consensus
- References
- [4]
Evidence tables (1)
3.1.1 EvT 3.1Background
Endometrial cancer (EC) (ICD-10 C54.1 [1]) ranks 7th among malignancies in women worldwide, with an annual incidence of 142,000 new cases. Regional variations in incidence are found, with North America and Western European countries in the lead with an age-standardized annual incidence of EC between 9.9 and 15.0 per 100,000 women. The cumulative risk of developing EC by age 75 is reported to be 1.7% in the United States, the country with the highest rate of disease.
Annually, 42,000 women worldwide die from EC. These cases account for 1.9% of all cancer-related deaths of women. The median 5-year survival rate in the highest incidence countries is reported to range from 72% in Europe to 84% in the United States.
Approximately 11,000 new cases are diagnosed annually in Germany. EC is the fifth most common malignancy in women, accounting for 4.8%, and the most common pelvic malignancy. The incidence of EC increases steadily with age until 70 years of age. Endometrial cancers are most commonly diagnosed between the ages of 70 and 84. Thereafter, there is a decline in incidence. The lifetime risk of developing EC in Germany is 1.9%. The median age at diagnosis of EC is 68 years [4].
Table 1: Overview of the most important epidemiological figures for Germany, ICD-10 C54-C55
| Women (2011) | Women (2012) | Women (forecast for 2022) | |
| New cases | 10.990 | 11.090 | 10.600 |
| Crude morbidity rate * | 26.5 | 26.6 | 25.7 |
| Standardized disease rate *,** | 16.2 | 16.5 | 15.1 |
| Mean age of onset | 69 | 68 | - |
| Deaths | 2.602 | 2.600 | 2.659 |
| Crudemortality rate * | 6.3 | 6.2 | 6.3 |
| Standardized mortality rate *,** | 3.0 | 3.0 | 3.0 |
| Prevalence | 45,700 after 5 years | 83,300 after 10 years | |
| after 5 years | after 10 years | ||
| Absolute survival rate (2015-2016)**** | 70 (66-73) | 57 (52-61) | |
| Relative survival rate (2015-2016)**** | 78 (75-82) | 74 (69-79) | |
|
* per 100,000 persons ** age-standardized according to old European population statistics *** median **** in percent (lowest and highest value of the included federal states) Source: Robert Koch Institute (ed.) and the Society of Epidemiological Cancer Registries in Germany (ed.), Cancer in Germany 2017/2018. 13th edition, Berlin, 2021. |
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3.1.2 Hormone replacement therapy (HRT) without progesterone protection
Hormone replacement therapy with estrogens alone without progestin protection is a risk factor for the occurrence of endometrial cancer in non-hysterectomized women. The effect depends on the duration of use.
Evidence tables (1)
3.1.1 EvT 3.2Background
In the development of hormone-dependent type I EC, long-term use of estrogens without progestin protection is considered an important risk factor. In the prospective Million Women cohort study, the relative risk (RR) versus no hormone replacement therapy was 1.45 (95% confidence interval [CI] 1.02–2.06) [13]. In a prospective cohort study of > 30,000 users, the relative risk was higher for estrogen monotherapy and was 2.7 (95%-CI 2.2–3.4) [14]. Nelson et al. [15] also report a similarly high relative risk of 2.3 (95%-CI 2.1–2.5) for estrogen monotherapy in a meta-analysis of 29 observational studies. This is also consistent with older data from Grady et al. [16]. In this meta-analysis, long-term estrogen therapy ≥ 10 years even resulted in a 9.5-fold increased risk of EC [16] (meta-analysis of 30 case-control and cohort studies; RR = 2.3 [95%-CI 2.1–2.5] for users versus nonusers; RR = 9.5 [95%-CI 7.4–12.3] for the subgroup of users ≥ 10 years).
Finally, the prospective cohort study by Allen et al. [17] of > 115,000 women also found a doubling of the risk of EC for users of estrogen monotherapy with intact uterine mucosa (HR = 2.52 [95%-CI 1.8–3.6]) [17].
Overall, the risk of EC appears to be significantly increased with estrogen therapy without progestin protection, and such therapy should therefore not be undertaken in non-hysterectomized women.
In a recent review of 31 studies and 21,306 women, 9 of 12 studies of estrogen monotherapy with a uterus found a significantly increased risk of EC with ORs/HRs ranging from 1.46 to 4.46 [11]. The EC risk was most pronounced for obese women.
For further assessment, also refer to the current S3 Guideline ‘Peri- and Post-menopause – Diagnostics and Interventions’ (as of January 2020) (https://www.awmf.org/uploads/tx_szleitlinien/015-062l_S3_HT_Peri-Postmenopause-Diagnostik-Interventionen_2020-01_1.pdf).
3.1.3 Combined estrogen-progestin therapy
3.1.3.1 Continuous combined estrogen-progestin therapy
Continuous combined hormone replacement therapy with estrogens and synthetic progestins has no or a protective effect on endometrial cancer risk.
- Level of evidence
- 2
- Consensus
- Strong consensus
- References
- [18]
Using progesterone or dydrogesterone as part of combined hormone replacement therapy, an increase in the risk of developing endometrial cancer has been observed when used for more than 5 years.
Change note
A reduction in endometrial cancer risk was observed with continuous combined hormone therapy with conjugated equine estrogens and medroxyprogesterone acetate as progestin with an average duration of use of 5.6 years.No increase in endometrial cancer risk has been observed with the use of sequential combined hormone replacement therapy with a duration of use < 5 years and use of a synthetic progestin for at least 10 days per month.
Change note
Sequential-combined hormone therapy with duration of use <5 years and using a synthetic progestin for at least 12-14 days per month may be considered safe with respect to endometrial cancer risk.Background
In women with uterus and intact uterine mucosa, the proliferative effect of estradiol and the resulting increased risk of EC can be antagonized by combination with a progestin. Whether this can fully compensate for the increased risk of EC depends on the duration of progestogen therapy (based on the number of days per month with progestogen use), the type of progestogen, the dose of estrogen, and the total duration of use of hormone replacement therapy.
In the prospective randomized Women’s Health Initiative (WHI) trial, a significantly reduced risk of EC (HR 0.59 [95%-CI 0.40–0.88]) was observed with continuous-combination hormone replacement therapy with conjugated equine estrogens (0.625 mg CEE) and medroxyprogesterone acetate (2.5 mg MPA) as a progestin in the postintervention phase of the trial with 13 years of follow-up [23]. However, EC risk was not a primary study endpoint in the WHI trial.
In contrast, data from observational studies regarding the risk of EC with continuous combined hormone replacement therapy are inconsistent. For example, in the prospective Million Women Cohort Study [13], use of continuous-combined hormone replacement therapy was associated with a significantly reduced risk of EC (RR = 0.71 [95%-CI 0.6–0.9]), as was a case-control study of > 1800 long-term users [24] (OR = 0.37 [95%-CI 0.2–0.6]) and the European prospective cohort study EPIC [17], (HR = 0.24 [95%-CI 0.08–0.8]). In contrast, other studies found neither an increase nor a decrease in risk, such as a meta-analysis of 7 observational studies by Nelson et al. [15]. In contrast, studies of long-term use of continuous-combination hormone replacement therapy with >10 years of use documented a significant increase in risk of developing EC (OR = 2.1 [95%-CI 1.3–3.3]) [25].
However, further observational studies did not confirm an increase in risk even with longer durations of use of ≥ 5 years, ≥ 6 years, and > 10 years [11].
In a recent review of 31 studies and 21,306 women, 10 of 19 studies of continuous combined hormone replacement therapy with synthetic progestins found a significantly reduced risk of EC, with ORs/HRs ranging from 0.24 to 0.71 [11].
It is possible that the type of progestin used may influence EC risk. For example, the use of micronized progesterone or dydrogesterone as part of continuous combined HRT may result in inadequate endometrial protection. This is suggested by the results of the prospective E3N cohort study of > 65,000 French women assigned to continuous combined hormone replacement therapy ith natural progestogens such as micronized progesterone and dydrogesterone, a synthetic progestin that is structurally very similar to progesterone and is similarly termed retroprogesterone, show an increased risk of EC at > 5-year duration of use (for progesterone HR = 2.7 [95%-CI 1.9–3.8], for dydrogesterone HR = 1.7 [95%-CI: 1.06- 2.70]) [26].
The mean number of days of use per month was 22.5 for micronized progesterone and 23.5 for dydrogesterone. The authors conclude that the combination of estradiol with natural progestins such as progesterone and dydrogesterone is not sufficiently effective for endometrial protection even when used continuously. It should be noted that the number of days of progestin use was not recorded in this study. Furthermore, a duration of therapy < 5 years was not associated with an increased risk of EC.
In the prospective randomized five-arm PEPI study, the impact of 1) CEE 0.625 mg/day, 2) CEE 0.625 mg/day + MPA 10 mg/day for 12 days/month, 3) CEE 0.625 mg/day + MPA 2,5 mg/day, and 4) CEE 0.625 mg/day + oral micronized progesterone 200 mg/day for 12 days/month versus placebo in 596 postmenopausal women studied over a 3-year period [27]. In this study, rates of endometrial hyperplasia with or without atypia were not increased in all 3 combination arms compared with placebo. However, because of the low statistical power, with approximately 120 women per study arm, it cannot be concluded with certainty from the results of this study that a dose of oral micronized progesterone of 200 mg/day for at least 12 days per month is adequate for endometrial protection as part of combined hormone replacement therapy. Data from randomized trials of endometrial protection of vaginally administered micronized progesterone or lower doses than 200 mg/day of orally administered micronized progesterone are not available.
The BMI represents another important influencing factor. In a meta-analysis of 9 observational studies, combined hormone replacement therapy reduced the increased risk of EC in obese women in all BMI categories studied (see table below) [28].
Table 2: Risk of endometrial cancer in relation to BMI and combined HRT use
| BMI | RR | EC risk in non-users | EC risk in users |
| 27 | 1.22 (1.19-1.24) | 1.31 (95% Cl 1.2-2.4) | 1.08 (95% Cl 1.0-1.1) |
| 32 | 2.09 (1.94-2.26) | 2.74 (95% Cl 2.0-3.4) | 1.34 (95% Cl 1.1-1.6) |
| 37 | 4.36 (3.75-5.10) | 7.54 95% Cl 4.1-13.9) | 1.78 (95% Cl 1.2-2.7) |
| 42 | 9.11 (7.26-11.51) | 20.70 (95% Cl 8.3-51.8) | 2.38 (95% Cl 1.3-4.5) |
| Source: [28] | |||
Background
Sequential use of a progestogen is also used as part of combined hormone replacement therapy to reduce endometrial stimulation. In general, the number of days of progestin use per month correlates with the level of EC risk in terms of an inverse relation. However, for sequential combined hormone replacement therapy, the data are also inconsistent with respect to EC risk. For example, the aforementioned Million Women Cohort Study [13] and the meta-analysis by Nelson et al. [15] describe a neutral effect of sequential-combined hormone replacement therapy, i.e., no increase in EC risk. However, the study by Nelson et al. [15] was a systematic literature review and meta-analysis of 7 observational studies of the incidence of endometrial cancer in users of combined hormone replacement therapy, and no distinction was made between sequential and continuous hormone replacement therapy.
In contrast, Lacey et al. [14] (RR = 3.0 [95%-CI 2.0–4.6] for < 15 progestin use days/month) and Allen et al. [17] (HR = 1.52 [95%-CI 1.0–2.3] (progestin use days/month not reported) described a significant increase in risk, as did Razavi et al. [25], for a shorter duration of use with < 10 progestogens per month (OR = 4.4 [95%-CI 1.7–11.2]).
In a recent review of 31 studies and 21,306 women, 6 of 12 studies of sequential combined hormone replacement therapy with synthetic progestins found a significantly increased risk of EC, with ORs/HRs ranging from 1.38 to 4.35 [11]. No increased risk of EC was found in the remaining 6 studies. The number of days of progestin use per month was a significant modulator of EC risk. A reduced risk of EC was observed only in a subgroup analysis of one study (< 5 years of use).
Also, in a Danish registry study of > 900,000 women, Morch et al. found an increased risk of EC for sequential combined estrogen-progestin therapy (RR 2.06; 95%-CI 1.88-2.27) [20], as did Sjögren et al. in a systematic review of 28 studies [22].
One reason for the heterogeneity of the study results is probably the different number of days the progestin was taken and the different types of progestins used. For example, in the aforementioned European prospective cohort study EPIC, an analysis of the risk of EC depending on the type of progestin used in the context of sequential hormone replacement therapy showed a significantly increased risk for micronized progesterone (HR = 2.42 [95%-CI 1.5–3.8]) but not for progesterone derivatives (HR = 1.23 [95%-CI 0.8–1.8]) and testosterone derivatives (HR = 1.09 [95%-CI 0.7–1.6]) [17]. As a caveat, the number of days of progestin use and the progesterone dose were not recorded in this study. For further assessment, reference is also made to the current S3 Guideline ‘Peri- and Post-Menopause – Diagnostics and Interventions’ (as of January 2020) (https://www.awmf.org/uploads/tx_szleitlinien/015-062l_S3_HT_Peri-Postmenopause-Diagnostik-Interventionen_2020-01_1.pdf).
Based on the published studies, the Guideline authors are of the opinion that sequential combined hormone replacement therapy with a duration of use < 5 years and using a synthetic progestogen can be considered safe with regard to the risk of EC.
3.1.4 Tamoxifen
Background
Tamoxifen use is considered an established risk factor for the occurrence of EC. In a meta-analysis of 23 randomized trials, Braithwaite et al. [34] calculated a 2.7-fold increase in the relative risk of developing EC (RR = 2.7 [95%-CI 1.9–3.7]). Also, in a meta-analysis of three tamoxifen prevention trials, Nelson et al. [35] reached a similar conclusion and quantified the relative risk increase over placebo as 2.13 (95%-CI 1.4–3.3).
A Cochrane collaboration analysis of the effects and side effects of tamoxifen in women with hormone receptor-positive breast cancer indicates a doubling of EC risk in the case of 1 to 2 years of tamoxifen therapy and a quadrupling in the case of at least 5 years of tamoxifen therapy [36]. Al-Mubarak et al. [37] examined the impact of tamoxifen therapy >5 years versus 5 years of therapy and calculated a further doubling of EC risk in the case of prolonging tamoxifen therapy to 10 years (RR = 2.06 [95%-CI 1.6–2.6]). The number needed to harm, that is, the number of women who can be treated before a woman is harmed by therapy in terms of additional EC, was 89 in this analysis.
A recent review indicates that there is a 2- to 7-fold increased risk of EC with tamoxifen use of > 2 years, especially in women with pre-existing endometrial pathologies [38].
Tamoxifen-induced endometrial carcinomas have a higher proportion of type II carcinomas (8/34 [24%] versus 28/495 [6%]) [39]. With regard to weighing the therapeutic benefit of tamoxifen in adjuvant therapy of estrogen receptor-positive breast carcinoma and the increased risk of developing EC, reference is made to the interdisciplinary S3 Guideline ‘Early detection, diagnosis, therapy and follow-up of breast carcinoma’ (as of February 2020; AWMF registry number 032–045OL; https://www.awmf.org/uploads/tx_szleitlinien/032-045OLk_S3_Mammakarzinom_2020-02.pdf).
3.1.5 Oral contraceptives
Oral contraceptives reduce the risk of developing endometrial cancer. The strength of the effect depends on the duration of use.
Evidence tables (1)
3.1.6 EvT 3.11Background
Use of oral contraceptives is uniformly associated in the literature with a reduced risk of developing EC. Numerous prospective and retrospective observational studies consistently describe a risk-reducing effect. Schlesselman et al. [43] analyzed 10 case-control studies in 1997 and calculated a risk-reducing effect dependent on duration of use (RR = 0.44 [95%-CI not reported in this paper]; RR = 0.33 and RR = 0.28 for 4, 8, and 12 years of use, respectively). Numerous recent studies reached a similar conclusion, such as Gorenoi et al. 2007 [44] (RR = 0.7 [95%-CI not reported in this paper]) and Gierisch et al. 2013 [45] (OR = 0.57 [95%-CI 0.4–0.8]). From data from the prospective EPIC study of > 300,000 pill users and control subjects, Dossus et al. 2010 [46] calculated a risk reduction of more than one-third (HR = 0.65 [95%-CI 0.6–0.7]), with long-term pill use resulting in an even greater risk reduction (HR = 0.58 [95%-CI 0.4–0.8] for pill use ≥ 10 years versus ≤1 year).
A recent review of 4 case-control studies and 5 cohort studies involving 308,198 women and 3.9 million years of follow-up showed a risk reduction of about half (OR 0.57; 95%-CI 0.43-0.77) for women who had used or were using a pill [42].
The protective effect of the pill affects endometrial cancers and ovarian cancers, with the protective effect persisting until 30 years after discontinuation of the pill [47]. Other uterine malignancies such as uterine sarcomas occur as frequently in pill users as in non-users [47].
3.1.6 Ovarian stimulation therapy
Background
Controlled ovarian stimulation using gonadotropins, clomiphene and selective estrogen receptor modulators (SERMs) is used to obtain oocytes in the context of assisted reproduction. Endometrial proliferation also occurs as part of these therapies. Case-control studies and cohort studies have reported an increased risk of EC in women after such therapies. Parazzini et al. [51] found a threefold increase in EC risk (OR = 3.26 [95%-CI 1.1–9.9]) in a case-control study of 1,362 women. However, Siristatidis et al. [52] demonstrated in a meta-analysis of 9 case-control studies that the increase in EC risk was detectable only when compared with population-based controls (RR = 2.04 [95%-CI 1.2–3.4]), but not when compared with infertile controls (RR = 0.45 [95%-CI 0.2–1.1]). Therefore, the reason for the EC risk associated with ovarian stimulation is likely due to the infertility itself rather than the infertility treatment. In a Cochrane meta-analysis, there was also no effect of stimulation treatment in 6 studies with subfertile women as controls while 15 studies with population-based controls showed an increased risk of EC after stimulation treatment [50]. Possibly the number of cycles and the dose of drugs used also play a role. In 5/15 studies in the Cochrane meta-analysis, only subfertile women were studied, and an association was seen between an increased risk of EC and a high number of stimulation cycles (> 7) or a high cumulative dose of clomiphene (> 2000 mg).
3.1.7 Tibolone
An increased risk of developing endometrial cancer has been observed with tibolone.
Evidence tables (1)
3.1.4 EvT 3.9Background
The synthetic steroid tibolone, a 19-testosterone derivative, has estrogenic, gestagenic and weak androgenic effects, especially via its active metabolites. Tibolone has been approved in Germany since 1999 for the treatment of menopausal symptoms resulting from the natural and iatrogenic onset of menopause. In the prospective Million Women cohort study, tibolone use versus no hormone replacement therapy was associated with a significantly increased risk of developing endometrial cancer (RR = 1.79 [95%-CI 1.4–2.2]) [13].
This increase in risk was confirmed in another prospective cohort study by Allen et al. [17], involving > 115,000 women (HR = 2.96 [95%-CI 1.7–5.3]). In a prospective randomized placebo-controlled study of 3,519 postmenopausal women with osteoporosis, use of 1.25 mg tibolone once daily for 3 years also resulted in a fourfold increase in the rate of vaginal bleeding (2.8% versus 10.8%), a doubling of the rate of endometrial hyperplasia, and a borderline significant increase in the risk of EC [54], (4 versus 0 cases; p = 0.06).
The review by Sjögren et al. (28 studies; systematic review) also showed an increased risk of EC for tibolone [22].
In the Cochrane meta-analysis by Formoso et al., an analysis of 8 RCTs showed no increase in EC risk compared with placebo (OR 2.04; 95%-CI 0.79-5.24), with only 21 EC cases occurring in the 8 included studies [55].
3.1.8 Other biological risk factors
Late menarche age and late age at birth of last child are associated with reduced risk, and late menopausal age is associated with increased risk of endometrial cancer.
Evidence tables (1)
3.1.8 EvT 3.13Diabetes mellitus, impaired glucose tolerance, metabolic syndrome, and polycystic ovary syndrome (PCOS) increase the risk of endometrial cancer.
- Level of evidence
- 3
- Consensus
- Strong consensus
- References
- [59] [60] [61] [62] [63] [64] [65] [66] [67] [68] [69] [70] [71] [72] [73]
Evidence tables (1)
3.1.8 EvT 3.14Hereditary predisposition in the context of Lynch syndrome or Cowden syndrome increases the risk of endometrial cancer.
Change note
A positive family history of endometrial cancer and/or colon cancer is associated with an increased risk of developing endometrial cancer.Evidence tables (1)
3.1.8 EvT 3.16Background
The association between EC risk and age at menarche and menopause and age at birth of last child is well established by epidemiologic studies. Specifically, late menarche age and late age at birth of last child reduce the risk of EC occurrence, whereas late menopausal age increases the risk. Setiawan et al. [82] calculated a relative risk reduction of 13% per 5-year increase in age at birth of last child in a meta-analysis of 17 case-control and cohort studies. In a prospective cohort study of > 121,000 women, the risk of EC was halved if the last child was born at age 40 or later. If menarche age was ≥15 years, the relative risk reduction was 34% (RR = 0.76 [95%-CI 0.5–0.9]). If age at menopause ≥ was 55 years, EC risk increased 1.53-fold (95%-CI 1.1–2.1) [83]. The large prospective cohort study EPIC with > 300,000 women came to similar conclusions [46]. In this study, the relative risk reduction at menarche age ≥ 15 years was 36% [RR = 0.64; 95%-CI 0.5–0.8]. A late menopausal age (≥ 55 years) doubled the risk (HR = 2.36 [95%-CI 1.7–3.2]).
Metabolic factors play an important role in the development of estrogen-dependent type I EC. The association between EC risk and metabolic diseases associated with impaired glucose tolerance is well established by epidemiological studies and has been known for decades. A number of systematic reviews and meta-analyses put the risk increase for diabetic women at a factor of 1.7 to 2.1 [84], [85], [86], [87], [88], [89]. However, whether cancer-specific mortality is also increased in diabetic women is controversial. Liao et al. [88] found significantly increased EC-specific mortality (RR = 1.32 [95%-CI 1.1–1.6]) in a meta-analysis of 23 cohort studies, although there was significant heterogeneity among the studies examined. Huang et al. [86] and Zhang et al. [87] failed to demonstrate this effect in a meta-analysis of 15 and 21 cohort studies, respectively.
Other parameters for impaired glucose tolerance, such as increased glycemic index and increased glycemic load are also associated with increased risk of EC [90], [91], [92], [93]. The metabolic syndrome, characterized by the factors of abdominal obesity, hypertension, hypertriglyceridemia, and lowered HDL cholesterol, as well as increased glucose concentration in the blood or insulin resistance, also leads to an increase in the incidence of EC. In a large prospective cohort study of 290,000 women, the relative risk increase was 1.37 (95%-CI 1.3–1.5) [94]. Esposito et al. [95] give a relative risk of 1.61 (95%-CI 1.2–2.2) in a meta-analysis of 3 cohort studies.
Polycystic ovary syndrome (PCOS) also leads to impaired glucose tolerance in 50 to 80% of cases probably due to endocrine and metabolic disorders and/or genetic predisposition [96], [97]. In addition, anovulation results in reduced progestin exposure of the uterine mucosa. In women with PCOS, the risk of EC is significantly increased according to epidemiological studies. Retrospective cohort studies report an approximately 4-fold increased risk [98], [99]. Meta-analyses of a total of 14 case-control studies indicate a similar, although somewhat smaller, increase in risk (OR = 2.70 [95%-CI 1.0–7.3] to 4.05 [95%-CI 2.4–6.8]) [100], [101], [102].
Body mass index (BMI) level correlates linearly with EC risk. Ward et al. [103] calculated an 11% relative risk increase (95%-CI 1.09–1.13) in 6,905 women with hysterectomy per BMI step (+1). In a meta-analysis of 24 case-control and cohort studies, Crosbie et al. [28] report a 1.6-fold increase in risk (95%-CI 1.5–1.7) per 5 BMI steps. A similar result was found by Renehan et al. [104] (RR = 1.59 [95%-CI 1.5–1.7] per 5 BMI increments), based on a meta-analysis of 141 case-control and cohort studies). A BMI ≥ 30 doubles the risk of developing EC compared with normal weight individuals (BMI 18.5 to 24.9 as defined by the World Health Organization (WHO) [105], [106], [107].
The influence of ethnic factors on EC risk is not well established. Whether the increased proportion of Caucasians in collectives of women with EC is due to sociocultural or genetic factors is not known [107], [108].
Genetic factors may promote the development of EC. A very high lifetime risk of developing EC, as well as a broad spectrum of other malignancies, exists in several monogenic-hereditary tumor syndromes based on specific germline mutations, notably Lynch syndrome (HNPCC) (ICD-10 C18.9) [1], and Cowden syndrome (ICD-10 Q89.8) [1], or PTEN hamartoma tumor syndrome (see Chapter 10 “Hereditary endometrial carcinomas”) [80]. Regardless of the proven carrier of specific germline mutations, a conspicuous family history increases the risk of developing EC. In a family constellation with at least one first-degree relative with EC, the risk increases almost twofold. In a meta-analysis of 16 case-control studies, Win et al. [109] calculated a relative risk of 1.82 (95%-CI 1.7–1.9) in the presence of a first-degree relative with EC and of 1.17 (95%-CI 1.0–1.3) in the presence of a first-degree relative with colon cancer. In contrast, a prominent family history of breast carcinoma, ovarian carcinoma, or cervical carcinoma was not associated with an increased risk of EC.
In an analysis of the US SEER database, a significantly increased risk of metachronous development of EC was found among 289,933 breast cancer survivors. This increased risk was independent of hormone receptor type and therefore cannot be explained by tamoxifen use alone [110]. Therefore, a positive history regarding breast carcinoma may also be a risk factor for the development of EC.
Dietary influences play an important role in carcinogenesis. Numerous dietary influencing factors have also been identified for EC in epidemiological studies. Although no clearly defined diet for EC prevention can be recommended based on the available data and the lack of dietary intervention studies, indications of which dietary components are more likely to be beneficial and which are more likely to be detrimental emerge from the study results. Bandera et al. [111] examined the proportion of dietary fiber in 7 case-control studies and calculated a risk reduction for developing EC of 18% (RR = 0.82; 95%-CI 0.8–0.9) per 5 grams dietary fiber/1000 kcal diet. A high proportion of soy in the diet is also associated with a reduced risk of EC (meta-analysis of 3 case-control and cohort studies; RR = 0.7 [95%-CI 0.6–0.9]) [112]. A multiethnic, prospective cohort study with > 46,000 participants examined the proportion of phytoestrogens in the diets of postmenopausal women and identified high isoflavone, daidzein and genistein levels as protective factors [113]. Other factors associated with reduced EC risk identified in meta-analyses of case-control studies include high beta-carotene from dietary sources [114], high vitamin C and vitamin E from dietary sources [114], and low total fat [111] and red meat [111]. Avoidance of sugary beverages (“soft drinks”) was also associated with reduced risk of type I EC in the prospective cohort study “Iowa Women’s Health Study” [115]. As a caveat, quantification of specific dietary details in these studies was collected using questionnaires for retrospective assessment of dietary components. Thus, there is a considerable risk of bias.
Coffee and tea consumption were identified as further influencing factors with a partially unexplained biological background that are associated with a reduced risk of EC. For reasons of space and not entirely clarified relevance, statements and recommendations were not made.
On the reduced risk of EC by coffee consumption:
[116][117] (RR = 0.74 [95%-CI 0.6–0.8]; meta-analysis of 4 cohort studies;
[117]; RR = 0.71 [95%-CI 0.6–0.8]; meta-analysis of 16 case-control and cohort studies;
[118]; RR = 0.80 [95%-CI 0.7–0.9]; meta-analysis of 9 case-control and cohort studies;
[119]; RR = 0.65 [95%-CI 0.5–0.9]; prospective cohort study).
On the reduced risk of EC by tea consumption:
[120]; RR 0.85 [95%-CI 0.8–0.9]; meta-analysis of 7 case-control and cohort studies.
The following also lead to reduced EC risk:
Breastfeeding: [121]; RR 0.76 [95%-CI 0.59–0.98]; meta-analysis of 11 case-control studies and 3 cohort studies.
Calcium supplements:[122]; RR = 0.62 [95%-CI 0.4–0.9]; meta-analysis of 2 case-control studies.
Acetylsalicylic acid (ASA): [123]; RR = 0.78 [95%-CI 0.6–0.9]; meta-analysis of 9 case-control and cohort studies identified.
Cigarette smoking: Cigarette smoking is also associated with reduced endometrial cancer risk, particularly in postmenopausal smokers [124]: RR = 0.81 (95%-CI 0.7–0.9) for smokers versus non-smokers; RR = 0.71 (95%-CI 0.7–0.8) for postmenopausal smokers versus non-smokers; meta-analysis of 34 case-control and cohort studies.
Risk increase due to night work: In contrast to the above risk-reducing factors, night work is a risk factor for the development of EC. Night work was associated with a significantly increased risk of EC in a prospective cohort study [125]; RR = 1.47 [95%-CI 1.0–1.1]).
In a recent review of 171 published meta-analyses on a total of 53 risk factors for developing EC, BMI, waist-to-hip ratio and parity were found to be the strongest risk factors for developing EC [126].
3.2 Risk-reducing factors
The use of intrauterine devices (copper IUD or levonorgestrel IUD used therapeutically) is associated with a reduced risk of endometrial cancer.
Evidence tables (1)
3.2 EvT 3.18Background
Epidemiological data, physiological considerations and data from observational studies suggest that EC risk can be reduced by approximately one-third by endurance-based physical activity. Randomized intervention trials on this question do not exist, so no specific physical activity can be named as optimal for protection against EC. However, the approximate amount of activity needed can be stated as at least 1 hour per week. In a meta-analysis of 6 case-control and cohort studies, Keum et al. [136] calculated a 5% risk reduction (RR = 0.95; 95%-CI 0.93–0.98) per 1 hour of physical activity per week, demonstrating a dose-dependent effect between 0 and 15 hours per week. In a prospective cohort study of > 109,000 individuals, Gierach et al. [137] found that marked physical activity of at least 5 hours per week reduced relative risk by 23% (RR = 0.77; 95%-CI 0.6–0.9). A comparable magnitude of protective effect was also found in other reviews, such as Moore et al. [138] (RR = 0.73 [95%-CI 0.6–0.9] for recreational exercise; meta-analysis of 9 cohort studies) and Voskuil et al. [139] (RR = 0.77 [95%-CI 0.7–0.9]; meta-analysis of 7 cohort studies).
Consistent with the association between physical activity and reduced EC risk, a meta-analysis of 8 case-control and cohort studies demonstrated an association between intensive TV consumption and an increase in EC risk (RR = 1.66 [95%-CI 1.2–2.3]) [140].
In a meta-analysis of 13 studies, Zhang et al. confirmed the risk-reducing influence of weight loss and bariatric surgery, but also indicated that alternating between weight loss and weight gain (‘weight cycling’) likely increased EC risk [133].
Intrauterine devices with and without local delivery of levonorgestrel reduce EC risk. In particular, a levonorgestrel intrauterine device results in effective and long-term suppression of uterine mucosal proliferation. This results in a halving of the risk of developing EC. Soini et al. [141], observed a significant 50% reduction in the incidence of endometrial cancer (IR 0.50; [95%-CI 0.3–0.7]) under and after use of the levonorgestrel IUD in a Finnish population-based cohort study of > 93,000 women receiving a levonorgestrel intrauterine device for hypermenorrhea with 855,000 years of observation [141]. A copper IUD without local hormone release also reduces EC risk, but with a lower degree of efficacy. In a meta-analysis of 17 case-control and cohort studies, the relative risk reduction was 19% (OR = 0.81; 95%-CI 0.7–0.9) [142].
Bariatric surgery is now an established form of surgical therapy for patients with marked obesity. The resulting caloric reduction and weight loss may also lead to a reduction in the risk of EC. Ward et al. report a significant risk reduction with a relative risk of 0.29 (95%-CI 0.3–0.3) in women after bariatric surgery using a retrospective cohort study with > 7 million records [143]. Bariatric surgery in highly obese women (BMI > 40) with EC has been described in a theoretical Markov model by Neff et al. as an effective intervention in terms of overall survival, increase in quality of life and overall cost-effectiveness [144].
A recent meta-analysis of 7 studies of 150,537 women after bariatric surgery and 1,461,938 controls demonstrates an EC risk reduction of 67% (RR 0.33; 95%-CI 0.21-0.51) [145].
3.3 Summary of risk-increasing and risk-reducing factors
Table 3: Risk of occurrence of endometrial carcinoma
|
... is increased... |
... is decreased... |
|
|
Evidence tables
3.1.1 EvT 3.1
|
Studientyp/ |
Untersuchte Population |
Intervention |
Kontrolle |
Untersuchte Endpunkte |
Hauptergebnisse |
Methodische Bemerkungen |
|
|
Robert Koch-Institut 2015 |
Bevölkerungsbezogene Vollerhebung (Datenregistrierung/Zensus) LoE 1 |
Stationäre oder ambulante Patienten: Daten nach Einwilligung übermittelt durch Ärzte und Zahnärzte: Für Endometriumkarzinom mittleres Erkrankungsalter = 69 Jahre. |
------------------------- |
---------------------------- |
---------------------------------------- |
Für Endometrium-karzinom (ICD-10 C541): Mit 10.930 Neuerkrankungen und einem Anteil von 4,8 % ist das Endometriumkarzinom die vierthäufigste Krebserkrankung der Frauen in Deutschland. Das relative 5-Jahres-Überleben liegt bei ca. 80 %. Risikofaktoren: Östrogenexposition, höheres Alter, Bestrahlung der Gebärmutter. |
Deutschlandweite Erfassung der Krebsinzidenz (alle 16 Bundesländer). Zentrum für Krebsregisterdaten (ZfKD) schätzt jährlich den Erfassungsgrad der epidemiologischen Krebsregister in Deutschland per Mortalität-/ |
3.1.1 EvT 3.2
|
Referenz |
Studientyp/ |
Untersuchte Population |
Intervention |
Kontrolle |
Untersuchte Endpunkte |
Hauptergebnisse |
Methodische Bemerkungen |
|
Lacey 2005 |
Retrospektive Kohortenstudie LoE 3 |
30.379 postmenopausale Teilnehmerinnen der postmenopausal Breast Cancer Detection Demonstration Project follow-up study (BCDDP): https://epi.grants.cancer.gov/Consortia/members/bcddp.html). |
Hormontherapie (HRT) – diverse Regime. |
Keine Hormontherapie. |
Endometriumkarzinom-Inzidenz 1979–1998. |
Alle untersuchten Formen der Hormontherapie erhöhten das Endometrium-karzinom-Risiko: „Both estrogen plus progestin regimens significantly increased endometrial carcinoma risk in this study. Risks among unopposed estrogen users remained elevated long after last use.“ Effektschätzer: RR 3,0: 95 % CI: 2,0–4,6 für sequenziell-kombinierte HRT mit < 15 Tagen Gestagen/Monat; RR 2,3; 95 % CI: 1,3–4,0) für kontinuierlich-kombinierte HRT. |
Unterschiedliche HRT-Regimes in einer Studie analysiert. |
|
Allen 2010 |
Kohortenstudie (mit Daten aus der European Prospective Investigation into Cancer and Nutrition [EPIC]-Studie: http://epic.iarc.fr) LoE 2 |
115.474 postmenopausale Frauen insgesamt. Durchschnittsalter bei Einschluss: 57 Jahre. Mittelwert des Alters bei Diagnose: 65 Jahre. Interventionsarm: 50.894 Frauen. Kontrollarm: 64.580 Frauen.
|
Hormontherapie (HRT). |
Keine Hormontherapie. |
Endometriumkarzinom-Risiko. |
Hormontherapie erhöht das Endometrium-karzinom-Risiko in Abhängigkeit vom Hormontherapie-Regime. Effektschätzer: Östrogenmono-Therapie: HR 2,52, 95 % CI: 1,77–3,57); Tibolon: HR 2,96, 95 % CI: 1,67 –5,26). Kombinations-HRT: HR 1,41, 95 % CI: 1,08–1,83). |
Unterschiedliche Hormontherapie-Regimes in einer Studie analysiert. Kohortenstudie mit dramatischen Effekten. |
|
Beral 2005 |
Retrospektive Kohortenstudie LoE 2 |
716.738 postmenopausale Frauen insgesamt. Interventionsarm: 320.953 Frauen. Davon mit kontinuierlich-kombinierter Hormontherapie: Kontrollarm: 395.785 Frauen. |
Hormontherapie (HRT) |
Keine Hormontherapie. |
Endometriumkarzinom-Inzidenz während 3,4 Jahren Beobachtungs-zeitraum. |
Unterschiedliche Endometrium-karzinom-Inzidenz, je nach Hormontherapie-Regime. Effektschätzer: RR 0,71 (95 % CI: 0,56–0,90 für kontinuierlich-kombinierte Hormontherapie; RR 1,79 (1,43–2,25) für Tibolon; RR 1,45 (1,02–2,06); p = 0,04) für Östrogen-Mono-Therapie; RR 1,05 (0,91–1,22) für zyklische, kombinierte Hormontherapie. |
Hohe Aussagekraft durch Größe der Kohorte gegeben; Verminderung der Aussagekraft durch die Verschreibung der Hormontherapie durch Hausärzte, die im Gegensatz zu Gynäkologen keine endokrinologische Expertise aufweisen. Kohortenstudie mit dramatischen Effekten. |
|
Nelson 2002 |
Metaanalyse von Beobachtungs-studien und 2 randomisiert-kontrollierten Studien (WHI: ClinicialTrials.gov Identifier: NCT000000611; HERS: ClinicalTrials.gov Identifier: NCT00319566) LoE 2 |
Unterschiedliche Anzahl von Studien und Teilnehmer-innen, je nach Zielgröße. |
Hormontherapie (HRT). |
Keine Hormontherapie. |
Unterschiedliche Outcomes („harms & benefits“), z. B. auch Endometrium-karzinom. |
Hormontherapie reduziert osteoporo-tische Frakturen und Kolonkarzinome. Effektschätzer: RR 2,3 (95 % CI: 2,1–2,5) für „unopposed estrogen“; RR 0,8 (95 % CI: 0,6–1,2 für Kombinations-präparate. |
Kombination unterschiedlicher Studien in einer Arbeit, z. T. auch in einer Tabelle, Kombination von Beobachtungs-studien, Metaanalysen und randomisiert-kontrollierten Studien in einer Arbeit. Publication Bias nicht endgültig berechnet; Random-effects-Modell verwendet. |
|
Grady 1995 |
Metaanalyse von Beobachtungs-studien; 37 eingeschlossene Studien, davon 4 Kohortenstudien zum Endometrium-karzinom LoE 3 |
n.a. |
Hormontherapie (HRT) – diverse Regime. |
Keine Hormontherapie. |
Endometriumkarzinom-Inzidenz. |
Hormontherapie als Östrogenmono-therapie erhöht Endometrium-karzinom-Risiko. Effektschätzer: Östrogentherapie ohne Progesteron: RR 2,3 und RR 9,5 >10 Jahre. Kombinations-therapien: RR 0,4 (Kohorten-studien) und RR 1,8 (Fallkontrollstudien). |
Kohortenstudie mit dramatischen Effekten, aber keine grafische Darstellung der Metaanalysen; keine Beurteilung hinsichtlich Publication Bias; keine Beurteilung der Qualität der Studien; kein Einfluss der Qualität der Studien auf die Beurteilung. Zudem bereits recht alt. |
|
Razavi 2010 |
Eingebettete Fall-Kontroll-Studie (in die California Teachers Study Cohort CTS: https://www.cal LoE 4 |
Aus 133.479 Frauen aus der Kohorte (bestehend seit 1995): Interventionsarm: 311 Frauen mit der Erstdiagnose eines Endometrium-karzinoms. Alter: 50–85 Jahre. Kontrollarm: 570 Frauen. |
Hormontherapie (HRT) ≥ 10 Jahre. |
Keine Hormontherapie. |
Endometriumkarzinom-Inzidenz. |
Alle untersuchten Formen der Hormontherapie erhöhen das Endometrium-karzinom-Risiko. Effektschätzer: OR 4,5; 95 % CI: 2,5 –8,1 für Östrogen-Monotherapie > 10 Jahre; OR 4,4; 95 % CI: 1,7–11,2 für Kombinations-therapie mit < 10 Tagen Gestagen/ Monat; OR 2,1; 95 % CI: 1,3–3,3 für kontinuierlich-kombinierte Hormontherapie. |
Heterogene Population mit unterschiedlichen Hormontherapie-Regimes in einer Studie analysiert. |
3.1.5 EvT 3.10
|
Referenz |
Studientyp/ |
Untersuchte Population |
Intervention |
Kontrolle |
Untersuchte Endpunkte |
Hauptergebnisse |
Methodische Bemerkungen |
|
Nelson 2013 |
Systematischer Review ohne Metaanalyse LoE 3 |
Keine individuellen Zahlenangaben; Studien nur deskriptiv gelistet, keine Metaanalyse. |
Diverse Medikamente, u. a. Tamoxifen, Raloxifen. |
Unterschiedlich in 7 untersuchten Studien; Placebo oder Tamoxifen versus Raloxifen. |
Inzidenz Mammakarzinom. |
Reduktion der Mammakarzinom-Inzidenz durch Tamoxifen und Raloxifen als Chemoprävention. Effektschätzer: RR, 2,3: 95 % CI: 2,1–2,5 für Östrogen-Monotherapie; RR 0,8 (95 % CI: 0,6–1,2 für Kombinations-präparate. Relevantes Outcome nur in Subgruppenanalyse (Inzidenz von Endometrium-karzinomen unter Tamoxifen und Raloxifen). Effektschätzer: RR, 2,13 (95 % CI: 1,36–3,32) für Tamoxifen; keine Erhöhung des Endometrium-karzinom-Risikos durch Raloxifen. |
Methodische Qualität und klinische Aussagekraft der Studie: hoch, Endometrium-karzinomrisiko allerdings nur Nebenzielgröße: sowohl der Primärstudien als auch der Metaanalyse. Angaben zu Publication Bias vorhanden. |
|
Braithwaite 2003
|
Metaanalyse randomisiert-kontrollierter Studien (n = 32) LoE 3 (da das Endometrium-karzinomrisiko nur Nebenzielgröße der Primärstudien war.) |
45.936 Frauen mit Endometrium-karzinom (aus insgesamt 52.929 Frauen in allen Studien; außer in 3 Studien [n = 363 Frauen] alle in Zusammenhang mit Mammakarzinom). Durchschnittsalter: 54,8 Jahre bei Randomisierung; 4,3 Jahre Tamoxifen-Einnahme.
|
Tamoxifen 20–40 mg/d (unterschiedliche Dosierungen). |
Unterschiedliche Kontrollen, teilweise Placebo. |
Kardiovaskuläre Ereignisse, Malignome, u. a. Endo-metriumkarzinom. |
Tamoxifen erhöht signifikant das Endometrium-karzinom-Risiko. Effektschätzer: Endometrium-karzinomrate in keiner der untersuchten Studien primärer Zielparameter. Tamoxifen/Risiko: RR 2,70; 95 % CI: 1,94–3,75. |
Angaben zu Publication Bias (Reporting Bias) vorhanden. Random-effects-Modell verwendet. |
|
Al-Mubarak 2014 |
Metaanalyse von 5 randomisiert-kontrollierten Studien LoE 2 (LoE 1 für Mammakarzinom-Rezidivrate, nicht jedoch für Endometrium-karzinomrate.) |
21.554 Frauen mit Mammakarzinom und Tamoxifen-Einnahme; keine Angaben zu den exakten Zahlen in den jeweiligen Armen. |
Adjuvante Tamoxifen-Gabe > 5 Jahre oder ohne Zeitlimit (in 4 Studien). |
Adjuvante Tamoxifen-Gabe < 5 Jahre. |
Mammakarzinom: Rezidivrate. Gemessen nach den Jahren 5–9 und ab Jahr 10 und weiter. |
Kein Vorteil für extended Tamoxifen in der Adjuvanz: „In unselected patients, extended adjuvant tamoxifen is not associated with a significant reduction in recurrence, or a reduction in all-cause death. Patients with lymph node positive breast cancer may derive some benefit. Reduction in the risk of recurrence appears to occur only after completion of extended adjuvant therapy.“ Effektschätzer: OR: 2,06, 95 % CI: 1,65–2,58 für erhöhtes Endometrium-karzinom-Risiko durch Tamoxifen-Gabe > 5 Jahre. |
Erhöhte Rate an Endometrium-karzinomen als Nebenzielgröße der Metaanalyse; auch postmenopausale Patientinnen hatten keinen Vorteil: „There was no apparent difference in the effect between pre- and post-menopausal patients.“ Keine Angaben zu Publication Bias. |
|
DeMichele 2008 |
Fall-Kontroll-Studie (populationsbasiert) LoE 3 |
Interventionsarm: 547 Frauen mit Endometrium-karzinom. Kontrollarm: 1.410 Frauen. Alter: 50–79 Jahre; Endometrium-karzinom-Diagnose gestellt: 1999/07–2002/06. |
Tamoxifen- oder Raloxifen-Anwendung. |
Zufällig ausgewählte Bewohnerinnen derselben geografischen Region. |
Endometriumkarzinom. |
Raloxifen-Anwenderinnen hatten ein geringeres Endometrium-karzinom-Risiko im Vergleich zu Kontrollen und Tamoxifen-Anwenderinnen. Effektschätzer: OR 0,50; 95 % CI: 0,29–0,85 für Endometrium-karzinom unter Raloxifen und OR 3,0; 95 % CI: 1,3–6,9 für Endometrium-karzinom unter Tamoxifen versus Raloxifen. |
Autoren schlagen weitere Untersuchungen von Raloxifen zur Endometrium-karzinom-Prävention vor: „Raloxifene users had significantly lower odds of endometrial cancer compared with both tamoxifen users and SERM nonusers, suggesting a role for raloxifene in endometrial cancer prevention and individualization of SERM therapy.“ |
3.1.6 EvT 3.11
|
Referenz |
Studientyp/ |
Untersuchte Population |
Intervention |
Kontrolle |
Untersuchte Endpunkte |
Hauptergebnisse |
Methodische Bemerkungen |
|
Collaborative Group on Epidemiological Studies on Endometrial Cancer 2015 |
Metaanalyse von 36 epidemiologischen Studien LoE 2 |
Interventionsarm: 27.276 Frauen mit Endometrium-karzinom, 9.459 (35 %) davon hatten jemals orale Kontrazeptiva genutzt.
Kontrollarm: 115.743 Frauen ohne Endometrium-karzinom, 45.625 davon (39 %) davon hatten jemals orale Kontrazeptiva genutzt. Drop-out-Rate: |
Frauen mit Endometrium-karzinom, 35 % davon mit Einnahme von oralen Kontrazeptiva (medianer Einnahmezeit-raum von 3,0 Jahren).
|
Frauen ohne Endometrium-karzinom, 39 % davon mit Einnahme von oralen Kontrazeptiva (medianer Einnahmezeitraum von 3,0 Jahren). |
Zusammenhang zwischen oralen Kontrazeptiva und Endometriumkarzinom-Risiko. |
Je länger Frauen orale Kontrazeptiva verwendet hatten, umso größer war die Risiko-Reduzierung für ein Endometrium-karzinom. Effektschätzer: 5 Verwendungsjahre waren hier mit einem RR von 0,76 (95 % CI: 0,73–0·78; p < 0,0001) assoziiert. Der Effekt hielt mehr als 30 Jahre nach Absetzen noch an. |
Studiendesign der inkludierten Studien: 15 prospektive, 10 retrospektive mit Populationskon-trollen, 11 retrospektive mit klinischen Kontrollen. Möglicher Publication Bias berücksichtigt. |
|
Gierisch 2013 |
Metaanalyse von Beobachtungs-studien (davon 9 Studien zum Endometrium-karzinom = 4 Fall-Kontroll-Studien, 5 Kohortenstudien) LoE 3 |
308.198 Frauen insgesamt + 3.981,072 Frauenjahre zusätzlich (sic!). Interventionsarm: n.a. Kontrollarm: n.a. |
Orale Kontrazeptiva. |
Keine oralen Kontrazeptiva. |
Krebsrisiko – diverse Krebsarten. |
Orale Kontrazeptiva reduzieren das Endometrium-karzinom-Risiko. Effektschätzer: OR 0,57: CI: 0,43–0,77. |
Hohe Qualität der Metaanalyse durch Beurteilung der Studienqualität. Keine Angaben zu Publication Bias; Random-effects-Modell verwendet. |
3.1.4 EvT 3.9
|
Referenz |
Studientyp/ |
Untersuchte Population |
Intervention |
Kontrolle |
Untersuchte Endpunkte |
Hauptergebnisse |
Methodische Bemerkungen |
|
Allen 2010 |
Kohortenstudie (mit Daten aus der European Prospective Investigation into Cancer and Nutrition [EPIC]-Studie: http://epic.iarc.fr) LoE 2 |
115.474 postmenopausale Frauen insgesamt. Durchschnittsalter bei Einschluss: 57 Jahre. Mittelwert des Alters bei Diagnose: 65 Jahre. Interventionsarm: 50.894 Frauen. Kontrollarm: 64.580 Frauen.
|
Hormontherapie (HRT). |
Keine Hormontherapie. |
Endometriumkarzinom-Risiko. |
Hormontherapie erhöht das Endometrium-karzinom-Risiko in Abhängigkeit vom Hormontherapie-Regime. Effektschätzer: Östrogenmono-Therapie: HR 2,52, 95 % CI: 1,77–3,57); Tibolon: HR 2,96, 95 % CI: 1,67 –5,26). Kombinations-HRT: HR 1,41, 95 % CI: 1,08–1,83). |
Unterschiedliche Hormontherapie-Regimes in einer Studie analysiert. Kohortenstudie mit dramatischen Effekten. |
|
Beral 2005 |
Retrospektive Kohortenstudie LoE 2 |
716.738 postmenopausale Frauen insgesamt. Interventionsarm: 320.953 Frauen. Davon mit kontinuierlich-kombinierter Hormontherapie: Kontrollarm: 395.785 Frauen. |
Hormontherapie (HRT) |
Keine Hormontherapie. |
Endometriumkarzinom-Inzidenz während 3,4 Jahren Beobachtungs-zeitraum. |
Unterschiedliche Endometrium-karzinom-Inzidenz, je nach Hormontherapie-Regime. Effektschätzer: RR 0,71 (95 % CI: 0,56–0,90 für kontinuierlich-kombinierte Hormontherapie; RR 1,79 (1,43–2,25) für Tibolon; RR 1,45 (1,02–2,06); p = 0,04) für Östrogen-Mono-Therapie; RR 1,05 (0,91–1,22) für zyklische, kombinierte Hormontherapie. |
Hohe Aussagekraft durch Größe der Kohorte gegeben; Verminderung der Aussagekraft durch die Verschreibung der Hormontherapie durch Hausärzte, die im Gegensatz zu Gynäkologen keine endokrinologische Expertise aufweisen. Kohortenstudie mit dramatischen Effekten. |
|
Ettinger 2008 |
Randomisiert-kontrollierte Studie LoE 3 (Sekundäranalyse einer Studie mit ursprünglich anderer Zielgröße) |
3.519 postmenopausale Frauen mit intaktem Uterus und Osteoporose. Durchschnittsalter: 68 Jahre. Interventionsarm: 1.746 Frauen. Drop-out-Rate: n = 333. Kontrollarm: 1.773 Frauen. Drop-out-Rate: n = 240. |
Tibolon 1,25 mg/Tag. |
Placebo. |
Osteoporosebedingte Frakturen; Endometriumeffekte. |
Tibolon erhöht die Endometriumdicke, die Rate an vaginalen Blutungen und eventuell das Endometrium-karzinom-Risiko. Effektschätzer: Effektgröße für Endometrium-karzinom nicht angegeben; 4 versus 0 Fälle von Endometrium-karzinom im Tibolonarm versus Kontrollarm (p = 0,06). |
Keine Power für Endometrium-karzinom; nicht geeignet. |
3.1.8 EvT 3.13
|
Referenz |
Studientyp/ |
Untersuchte Population |
Intervention |
Kontrolle |
Untersuchte Endpunkte |
Hauptergebnisse |
Methodische Bemerkungen |
|
Dossus 2010 |
Prospektive multizentrische Kohortenstudie innerhalb der EPIC-Studie (European Prospective Investigation into Cancer and Nutrition [EPIC]-Studie: http://epic.iarc.fr) LoE 3 |
302.618 Frauen. 1.017 Endometrium-karzinom-Fälle: Davon waren 161 prämenopausal ( 55 Jahre) und 193 perimeno-pausal/unbekannt (zwischen 46–55 Jahren). |
Keine. |
Keine. |
Risikofaktoren für Endometriumkarzinom. |
Späte Menarche, frühe Menopause, Anwendung oraler Kontrazeptiva, höhere Geburtenrate und ein kürzerer Abstand zur letzten vollausgetragenen Schwangerschaft reduzieren das Endometrium-karzinom-Risiko. Effektschätzer: HR 0,66 für 5–9 Jahre und HR 0,57 für > 10 Jahre. |
Hohe Aussagekraft über Assoziation von Endometrium-karzinom mit reproduktiven Faktoren durch hohe Fallzahl der internationalen Population. |
|
Setiawan 2012 |
Gepoolte Analyse von 17 Studien (4 retrospektive Kohortenstudien, 13 Fall-Kontroll-Studien) LoE 3 |
25.233 Frauen mit intaktem Uterus insgesamt.
8.671 Endometrium-karzinom-Fälle. 16.562 Kontrollen. |
Keine. |
Durchschnitts-bevölkerung. |
Alter bei letzter Geburt. |
Alter bei letzter Geburt beeinflusst das Endometrium-karzinom-Risiko. Effektschätzer: OR 0,87 (95 % CI: 0,85–0,90) pro 5 Jahre Alterssteigerung bei Geburt des letzten Kindes. |
Hohe Qualität durch große Kohorte und internationale Population; Angaben zu Publication Bias. Random-effects-Modell wurde verwendet. |
|
Karageorgi 2010 |
Kohortenstudie auf Basis der prospektiven Nurses’ Health Study Cohort 1976–2004; http://www.nurseshealthstudy.org/) LoE 3 |
121.700 Frauen, davon 778 Endometrium-karzinom-Fälle (in einem Follow-up-Zeitraum von 28 Jahren), bei 1.850,078 Personenjahren. |
Keine. |
Keine. |
Einfluss von reproduktiven Faktoren auf das Endometriumkarzinom-Risiko. |
Reproduktive Faktoren, wie z. B. Alter bei Menarche, Alter bei Menopause, Alter bei Geburt des ersten Kindes, beeinflussen das Endometrium-karzinom-Risiko. Effektschätzer: RR 0,62 (0,46; 0,85) für ≥ 15 Jahre Menarchealter; RR 1,49 (1,11; 2,01) für Menopausenalter ≥ 55 Jahre. |
Hohe Qualität durch große Kohorte. |
3.1.8 EvT 3.14
|
Referenz |
Studientyp/ |
Untersuchte Population |
Intervention |
Kontrolle |
Untersuchte Endpunkte |
Hauptergebnisse |
Methodische Bemerkungen |
|
Friberg 2007 |
Metaanalyse von 16 Beobachtungs-studien (3 Kohorten- und 13 Fall-Kontroll-Studien) LoE 3 |
96.003 Frauen insgesamt. Interventionsarm: 7.596 Endometrium-karzinom-Fälle. Kontrollarm: n.a. |
Keine. Diabetes war das Kriterium für Fälle. |
Keine. Kein Diabetes. |
Endometriumkarzinom. |
Diabetes ist mit erhöhtem Endometrium-karzinom-Risiko assoziiert. Effektschätzer: RR 2,10: 95 % CI: 1,75–2,53. |
Keine Beurteilung der Studienqualität; keine Beurteilung bzgl. Publication Bias. |
|
Barone 2008 |
Metaanalyse von 23 Beobachtungs-studien; 4 ausgewertet bzgl. Endometrium-karzinom-Risiko. LoE 3 |
Interventionsarm: 429 Endometriumkar-zinom-Patientinnen mit präexistentem Diabetes.
Kontrollarm: 2.900 Endometrium-karzinom-Patientinnen ohne präexistenten Diabetes. |
Diabetes. |
Kein Diabetes. |
Endometriumkarzinom-Risiko, Krebsmortalität. |
Diabetes ist mit Endometrium-karzinom assoziiert und mit einer erhöhten Gesamtmortalität bei Krebspatienten. Effektschätzer: HR, 1,76; 95 % CI: 1,34–2,31 für Endometrium-karzinom-Risiko. |
Endometrium-karzinom-Risiko als Subgruppe; Endpunkt „All-cause mortality“. Random-effects-Modell: DerSimonian/Laird-Methode. Angaben zu Publication Bias vorhanden. |
|
Huang 2014 |
Metaanalyse von 16 prospektiven Kohortenstudien, davon nur 1 zum Endometrium-karzinom LoE 4 |
891.426 Frauen und Männer; unterteilt in Asiaten und Nicht-Asiaten, Frauen und Männer gemischt, nicht alle Teilnehmer haben den oralen Glukosetoleranz-Test erhalten. |
Prädiabetes. |
Normoglykämie. |
Krebs. |
Prädiabetes ist mit einem erhöhten Risiko für Krebs, allen voran Leber-, Magen-/ Effektschätzer: RR 1,15: 95 % CI: 1,06, 1,23. |
Angaben zu Publication Bias vorhanden. |
|
Zhang 2013 |
Metaanalyse von prospektiven Kohortenstudien; 21 Studien, davon 15 Studien bzgl. Endometrium-karzinom-Inzidenz und 6 Studien bzgl. Endometrium-karzinom-Letalität LoE 3 |
n.a. Nur die jeweiligen Kohortengrößen der Studien sind angegeben. |
Diabetes. |
Kein Diabetes. |
Inzidenz und Letalität von Endometriumkarzinom. |
Diabetes ist mit einem erhöhten Risiko für Endometrium-karzinom assoziiert, nicht aber mit einer erhöhten Letalität. Effektschätzer: RR 1,81; 95 % CI: 1,38–2,37 für Endometrium-karzinom-Risiko. |
Trennung der Aussagen zu Inzidenz und Letalität erlaubt differenzierte Aussage; Angaben zu Publication Bias vorhanden. Random-effects-Modell: DerSimonian/Laird-Methode. |
|
Liao 2014 |
Metaanalyse von 29 (17 prospektive, 12 retrospektive) Kohortenstudien LoE 3 |
Keine summarische Angabe der Anzahl der Personen; Angaben zu Personen in allen Einzelstudien Eingeschlossene Studien: 23 Studien zur Endometrium-karzinom-Inzidenz, 5 zur endometrium-karzinom-spezifischen Mortalität, 1 Studie zu beiden Endpunkten. |
Diabetes. |
Kein Diabetes. |
Krebsspezifische Endometriumkarzinom-Mortalität, Endometriumkarzinom-Inzidenz. |
Diabetes ist mit einem erhöhten Risiko für Endometrium-karzinom assoziiert, in dieser Metaanalyse auch mit einer erhöhten krebsspezifischen Endometrium-karzinom-Mortalität, allerdings bei uneinheitlicher Studienlage. Effektschätzer: RR 1,89 (95 % CI: 1,46–2,45) für Endometrium-karzinom-Risiko. |
Hohe methodische Qualität mit Angaben zu Publication Bias. |
|
Luo 2014 |
Prospektive Kohortenstudie LoE 3 |
88.107 Frauen insgesamt, davon 1.241 Frauen mit Endometrium-karzinom. |
Diabetes. |
Kein Diabetes. |
Endometriumkarzinom-Inzidenz. |
Diabetes ist mit einem erhöhten Endometrium-karzinom-Risiko assoziiert, wobei dieses Risiko nach Adjustierung für BMI nicht mehr signifikant ist. Effektschätzer: HR 1,44: 95 % CI: 1,13–1,85 für Endometrium-karzinom-Risiko. |
Subanalyse innerhalb der WHI-Kohorte (ClinicialTrials.gov Identifier: NCT000000611); daher Endometrium-karzinom-Risiko nur einer von vielen Endpunkten. |
|
Gnagnarella 2008 |
Metaanalyse von Beobachtungs-studien; 39 Studien, davon 5 Studien (1 Fall-Kontroll-, 4 Kohortenstudien) zum Endometrium-karzinom-Risiko bzgl. Glycaemic Load und Glycaemic Index LoE 3 |
2.569 Endometrium-karzinom-Fälle.
|
Glycaemic Load; Glycaemic Index. |
Keine. |
Endometriumkarzinom-Risiko. Risiko für kolorektale Karzinome. |
Glycaemic Load und Glycaemic Index sind mit Endometrium-karzinom-Risiko assoziiert. Effektschätzer: für Glycaemic Load und Glycaemic Index: RR 1,36: 95 % CI: 1,14, 1,62 und RR 1,22; 95 % CI: 1,01, 1,49. |
Keine Angabe zu Studienqualität; keine Angabe zu Publication Bias. |
|
Mulholland 2008 |
Metaanalyse von 4 prospektiven Beobachtungs-studien und 1 Fall-Kontroll-Studie LoE 3 |
Summarische Angaben sind nur in den Einzelstudien zu finden (Table 1). |
Analyse von Glycaemic Index, Glycaemic Load. |
n.a. |
Endometriumkarzinom-Risiko, Ovarialkarzinom-Risiko. |
Eine hohe Glycaemic Load, nicht aber ein hoher Glycaemic Index sind mit einem erhöhten Endometrium-karzinom-Risiko assoziiert. Effektschätzer: RR 1,20; 95 % CI: 1,06–1,37) für hohe Glycaemic Load. |
Keine Angabe zu Studienqualität; Angaben zu Publication Bias vorhanden; Random-effects-Modell wurde verwendet. |
|
Choi 2012 |
Metaanalyse von Kohortenstudien; 36 Studien, davon 5 zum Endometrium-karzinom-Risiko LoE 3 |
60.811 Personen (Frauen und Männer) insgesamt. 3.200 Endo-metriumkarzinom-Fälle. Weitere summarische Angaben zur Population in den Einzelstudien. |
Messung von Glycaemic Index und Glycaemic Load. |
n.a. |
Inzidenz von diversen Krebsarten, auch Endometriumkarzinom. |
Eine erhöhte Glycaemic Load ist mit einem erhöhten Endometrium-karzinom-Risiko assoziiert. Effektschätzer: Glycaemic Load/Risiko: RR 1,21; 95 % Glycaemic Index 1,07. |
Endometrium-karzinom-Risiko nur in einer Subgruppe analysiert; keine Angaben zu Studienqualität, jedoch Angabe zu Publication Bias; keine Details zu Einzelstudien angegeben. |
|
Nagle 2013 |
Fall-Kontroll-Studie (eigene Daten) und Metaanalyse von 6 prospektiven Kohortenstudien und 2 Fall-Kontroll-Studien LoE 3 |
2.726 Fälle aus Fall-Kontroll-Studien und Metaanalyse von 8 weiteren Studien mit 5.569 Fällen. Interventionsarm: 1.290 Frauen (Fall-Kontroll-Studien); 5.569 Frauen (Metaanalyse). Kontrollarm: 1.436 Frauen. |
Messung von Glycaemic Index und Glycaemic Load. |
Aufnahme von Nahrungsmitteln mit einem geringen Glycaemic Index und somit einer niedrigen Glycaemic Load. |
Endometriumkarzinom-Risiko. |
Erhöhte Glycaemic Load, aber nicht Glycaemic Index ist mit einem erhöhten Endometrium-karzinom-Risiko assoziiert. Effektschätzer: OR 1,43: 95 % CI: 1,11–1,83 für hohen Glycaemic Index und OR 1,15: 95 % CI: 0,90–1,48 für hohe Glycaemic Load. |
Analyse bzgl. Publication Bias durchgeführt; Angaben zu exkludierten Studien vorhanden; keine Analyse der Studienqualität der metaanalysierten Studien; Random-effects-Modell wurde verwendet. |
|
Fearnley 2010 |
Fall-Kontroll-Studie LoE 4 |
554 Frauen mit neu diagnostiziertem Endometrium-karzinom (Alter: Interventionsarm: 156 Frauen. Kontrollarm: 398 Frauen. |
PCOS. |
Kein PCOS. |
Endometriumkarzinom-Risiko. |
PCOS erhöht das Endometrium-karzinom-Risiko. Effektschätzer: OR 4,0, 95 % CI: 1,7–9,3. |
Die Diagnose PCOS wurde nach Angaben der Frauen im Rahmen von Telefoninterviews erhoben; daher eingeschränkte Beurteilbarkeit hinsichtlich der Diagnose PCOS. |
|
Gottschau 2015 |
Prospektive Kohortenstudie LoE 3 |
12.070 Frauen mit PCOS, davon 279 Endometrium-karzinom-Fälle.
|
Frauen mit PCOS. |
Durchschnitts-bevölkerung. |
Endometriumkarzinom-Risiko. |
PCOS ist mit einem um das Vierfache erhöhten Endometrium-karzinom-Risiko assoziiert. Effektschätzer: SIR 3,9: 95 % CI: 2,2–6,3. |
Landesweite Registerstudie; hohe Aussagekraft durch systematische Erhebung der Diagnosen Endometrium-karzinom und PCOS. |
|
Chittenden 2009 |
Systematischer Review LoE 4 |
4.056 Frauen insgesamt (in 4 Studien, die den Zusammenhang von PCOS und Endometrium-karzinom-Risiko untersuchten). Interventionsarm: Kontrollarm: |
PCOS. |
Kein PCOS. |
Inzidenz gynäkologischer Malignome. |
PCOS ist mit einem erhöhten Endometrium-karzinom-Risiko assoziiert. Effektschätzer: Dreifach erhöhtes Endometrium-karzinom-Risiko bei Patientinnen mit PCOS (OR 2,70, 95 % CI: 1,00–7,29): Ergebnisse von 4 Fall-Kontroll-Studien. |
Keine Angaben zu Studienqualität und Publication Bias, Einschluss nur von Fall-Kontroll-Studien. |
|
Haoula 2012 |
Metaanalyse von Beobachtungs-studien; 5 Studien (4 Fall-Kontroll-, 1 retrospektive Querschnittsstudie) LoE 3 |
4.605 Frauen insgesamt. Interventionsarm: 88 Frauen mit PCOS, davon 47 mit einem Endometrium-karzinom. Kontrollarm: 4.517 Frauen ohne PCOS, davon 773 mit einem Endometrium-karzinom. |
PCOS. |
Kein PCOS. |
Endometriumkarzinom-Risiko. |
PCOS ist mit einem erhöhten Endometrium-karzinom-Risiko assoziiert. Effektschätzer: OR 2,89: 95 % CI: 1,52–5,48.
|
Angabe zu Publication Bias vorhanden. Eingeschlossene Studien waren hauptsächlich Fall-Kontroll-Studien. |
|
Barry 2014 |
Metaanalyse von 11 Beobachtungs-studien; 5 Studien davon zum Endometrium-karzinom. LoE 3 |
Interventionsarm: 919 Frauen mit PCOS; 61 davon mit Endometriumkarzinom. Kontrollarm: 72.054 Frauen ohne PCOS, davon 1.072 mit Endometrium-karzinom. |
PCOS. |
Kein PCOS. |
Endometriumkarzinom, Ovarialkarzinom, Mammakarzinom. |
PCOS ist mit Endometriumkarzinom assoziiert (5 Studien), nicht jedoch mit Ovarialkarzinom oder Mammakar-zinom. Effektschätzer: OR 2,79; 95 % CI: 1,31–5,95. |
Qualität der Studien angegeben; Publication Bias angegeben. Random-effects-Modell: Mantel-Haenszel-Methode. |
3.1.8 EvT 3.15
|
Referenz |
Studientyp/ |
Untersuchte Population |
Intervention |
Kontrolle |
Untersuchte Endpunkte |
Hauptergebnisse |
Methodische Bemerkungen |
|
Crosbie 2010 |
Metaanalyse von Beobachtungs-studien; 24 Studien, davon 9 Studien zum Einfluss der Hormontherapie auf das BMI-assoziierte Endometrium-karzinom-Risiko LoE 3 |
17.710 Fälle insgesamt. Angaben zu Interventions-/ |
Hormontherapie (HRT). |
Keine Hormontherapie. |
Endometriumkarzinom-Risiko in Abhängigkeit von BMI und Hormontherapie-Einnahme. |
Ein erhöhter BMI ist mit einem Endometrium-karzinom-Risiko assoziiert und beeinflusst dieses unter Hormontherapie. Effektschätzer: BMI/Risiko: RR 1,60 (95 % CI: 1,52–1,68) pro 5 kg/m2-Schritt BMI. |
Keine systematische Analyse der Studienqualität; Angaben zu Publication Bias vorhanden; Random-effects-Modell verwendet. |
|
Ward 2013 |
Retrospektive Kohortenstudie LoE 3 |
165.876 Frauen, die sich einer Hysterektomie unterzogen haben, davon wurde bei 6.905 Frauen der BMI gemessen: 1.891 Endometrium-karzinom-Fälle. |
Hysterektomie; Messen des BMI. |
Keine. |
Endometriumkarzinom-Risiko in Abhängigkeit von BMI. |
BMI ist linear mit Endometrium-karzinom-Risiko assoziiert. Effektschätzer: OR 1,11; 95 % CI: 1,09–1,13 für jeden BMI-Schritt (1 Einheit). |
Nur Frauen mit Hysterektomie untersucht, daher keine Aussage zum Endometrium-karzinom-Risiko bzgl. BMI für die Gesamtpopulation möglich. |
|
Renehan 2008 |
Metaanalyse von 141 prospektiven Kohortenstudien LoE 3 |
Frauen und Männer (Table 1). 17.084 Endometrium-karzinom-Fälle. 3. 044 538 Kontrollen.
|
Erhöhter BMI. |
BMI im Normbereich. |
Krebsinzidenz, auch Endometriumkarzinom, in Abhängigkeit von BMI. |
Ein hoher BMI erhöht das Endometrium-karzinom-Risiko. Effektschätzer: RR 1,59 pro 5 kg/m2 BMI. „In women, we recorded strong associations between a 5 kg/m² increase in BMI and endometrial (1,59, p < 0,0001) […] cancer[s].“ |
Angaben zu Publication Bias vorhanden; Random-effects-Modell wurde verwendet. |
|
Dobbins 2013 |
Metaanalyse von Beobachtungs-studien; 98 Studien, davon 16 Studien zu Endometrium-karzinom-Risiko LoE 3 |
Genaue Angaben zu Interventions-/ |
Adipositas. |
Normalgewicht. |
Krebsinzidenz in Abhängigkeit von Adipositas. |
Adipositas (BMI > 35) erhöht das Endometrium-karzinom-Risiko. Effektschätzer: RR 1,85 für Adipositas.
|
Endometrium-karzinom als Subgruppe analysiert; keine Angaben zu Absolutzahlen der analysierten Studien zum Endpunkt Endometrium-karzinom; keine Angaben zu Publication Bias; keine Beurteilung der Studienqualität. |
|
Bergström 2001 |
Metaanalyse von Beobachtungs-studien; 27 Studien, davon 14 Studien zu Endometrium-karzinom-Inzidenz; 4 davon meta-analysiert. LoE 3 |
Studien zu Nieren-, Endometrium-, kolorektalem, Prostata-, Gallenblasen- und postmenopausalem Mammakarzinom in Europa. Davon 14 Studien zum Endometrium-karzinom mit 14.230 neuen Fällen pro Jahr. Summarische Angaben zur Population: Table IV und V in der Studie. |
Adipositas. |
Normalgewicht. |
Krebsinzidenz in Abhängigkeit von Adipositas. |
Adipositas ist ein Risikofaktor für Endometrium-karzinom (14 Studien). Effektschätzer: 39 % der Endometrium-karzinome sind bedingt durch Adipositas (14.230 neue Fälle pro Jahr; s. Table V in der Studie). Der durchschnittl. Zuwachs der RR für Endometrium-karzinom lag bei 1,10 per Einheit, bezogen auf steigenden BMI (95 % CI: 1,07–1,12). |
------------------------------ |
|
Reeves 2011 |
Prospektive Kohortenstudie (mit Daten aus der WHI-Studie: ClinicialTrials.gov Identifier: NCT000000611) LoE 3 |
86.937 postmeno-pausale Frauen mit intaktem Uterus insgesamt. Interventionsarm: 806 Endometrium-karzinom-Fälle. Kontrollarm: 86.131 Kontrollen. |
Adipositas. |
Normalgewicht. |
Endometriumkarzinom-Inzidenz in Abhängigkeit von Übergewicht. |
Hoher BMI und erhöhte WHR (Waist-to-Hip-Ratio) sind Risikofaktoren für Endometrium-karzinom. Effektschätzer: HR 1,80: 95 % CI: 1,44–2,27 für BMI ≥ 30 versus < 25. |
------------------------------ |
3.1.8 EvT 3.16
|
Referenz |
Studientyp/ |
Untersuchte Population |
Intervention |
Kontrolle |
Untersuchte Endpunkte |
Hauptergebnisse |
Methodische Bemerkungen |
|
Win 2015 |
Systematischer Review und Metaanalyse von 16 Beobachtungs-studien LoE 3 |
Interventionsarm: 3.871 Frauen. Kontrollarm: 49.475 Frauen. |
Verwandte ersten Grades in der Familienanamnesemit Endometrium-karzinom, kolorektalem Karzinom, Mammakarzinom, Ovarial- und Zervixkarzinom. |
Keine positive Familienanamnese für die genannten Tumorentitäten. |
Endometriumkarzinom-Risiko in Abhängigkeit der Familienanamnese. |
Eine positive Familienanamnese für Endometrium-karzinom oder Kolonkarzinom erhöht das Endometrium-karzinom-Risiko. Effektschätzer: Gepoolter RR 1,82 (1,65–1,98) für Endometrium-karzinom bei betroffener Verwandter ersten Grades. |
Angabe zu Publication Bias vorhanden; Random-effects- und Fixed-effects-Modell wurden verwendet; Heterogenität zwischen den Studien und zwischen und in den Gruppen berechnet (mit I2-Statistik). |
3.2 EvT 3.17
|
Referenz |
Studientyp/ |
Untersuchte Population |
Intervention |
Kontrolle |
Untersuchte Endpunkte |
Hauptergebnisse |
Methodische Bemerkungen |
|
Keum 2014 |
Metaanalyse von 20 Beobachtungs-studien (10 Kohorten-, 10 Fall-Kontroll-Studien) LoE 3 |
Exakte summarische Angaben sind nur in den Einzelstudien zu finden.
|
Freizeitaktivität. Lineare und nicht-lineare Dosis-Wirkungs-Metaanalyse. |
Keine/Geringere Freizeitaktivität. |
Endometriumkarzinom-Risiko in Abhängigkeit von Freizeitaktivität. |
Es existiert eine Dosis-Wirkungs-Beziehung zwischen Freizeitaktivität und Endometrium-karzinom-Risiko: „An increase in leisure-time physical activity may continue to decrease EC risk, within the range of 0–50 MET-hour/week or 0–15 hour/week.“ Effektschätzer: RR 0,98: 95 % CI: 0,95–1,00 pro 3 Aktivitätsstunden/ |
Angaben zu Studienqualität vorhanden; Angaben zu Publication Bias vorhanden; Random-effects-Modell verwendet. |
|
Gierach 2009 |
Prospektive Kohortenstudie (innerhalb der NIH-AARP Diet and Health Study: www.dietandhealth.cancer.gov ) LoE 3 |
1. Befragung (1995–1996) zu körperlicher Aktivität von 109.621 Frauen ohne Krebs-geschehen in der Vorgeschichte; Alter: 50–71 Jahre. 2. Befragung (1996–1997) von Interventionsarm: 1.052 Fälle. Kontrollarm: n.a. |
Körperliche Aktivität. |
Geringere körperliche Aktivität. |
Endometriumkarzinom-Inzidenz. |
Körperliche Aktivität korreliert invers mit dem Endometrium-karzinom-Risiko, insbesondere bei übergewichtigen Frauen. Effektschätzer: RR 0,77: 95 % CI: 0,63-0,95 für 5 x / Woche körperliche Aktivität. |
------------------------------ |
|
Moore 2010 |
Metaanalyse von prospektiven Kohortenstudien: 9 Kohortenstudien untersuchten den Einfluss von Freizeitaktivitäten, 5 den von beruflich bedingter Aktivität. 1 zusätzliche Studie (NIH-AARP Diet and Health Study mit 69.648 Frauen: www.dietandhealth.cancer.gov) LoE 3 |
2.663 Fälle (aus 3.463). Exakte Angaben zur Population sind nur in den Einzelstudien zu finden.
|
Körperliche Aktivität. |
Geringe körperliche Aktivität. |
Endometriumkarzinom-Risiko. |
Endometrium-karzinom-Risiko korreliert invers mit körperlicher Aktivität: „The totality of evidence now convincingly indicates that physical activity prevents or reduces risk of endometrial cancer.” Effektschätzer: 0,73; 95 % CI: 0,58–0,93 für hohes Aktivitätsniveau. |
Random-effects-Modell wurde verwendet. Keine Angaben zu Publication Bias. |
|
Voskuil 2007 |
Metaanalyse von Kohorten- und Fall-Kontroll-Studien; 20 Studien, davon 7 Studien mit gepoolten Analyse LoE 3 |
Summarische Angaben nur in den Einzelstudien. |
Körperliche Aktivität. |
Geringe körperliche Aktivität. |
Endometriumkarzinom-Risiko. |
Physische Aktivität korreliert invers mit Endometrium-karzinom-Risiko. Effektschätzer: OR, 0,77; 95 % CI: 0,70–0,85 für starke körperliche Aktivität. |
Angaben zur Studienqualität vorhanden; Angaben zu Publication Bias vorhanden. |
|
Schmid/ |
Metaanalyse von 43 Beobachtungs-studien (21 prospektiven Kohorten- und 22 Fall-Kontroll-Studien) LoE 3 |
68.936 Frauen und Männer insgesamt. Die summarischen Angaben finden sich in den Studien/Table 1. Eingeschlossene Studien: n = 8 zum Endometrium-karzinom-Risiko.
|
Hoher TV-Konsum. |
Geringer TV-Konsum. |
Risiko für Kolorektales-Karzinom, Endometriumkarzinom, Lungen-Karzinom und weitere Entitäten. |
Dauer des TV-Konsums und die Zeit, die mit anderen sitzenden Tätigkeiten verbracht wird, ist mit Endometrium-karzinom-Risiko assoziiert. Effektschätzer: Für Endometrium-karzinom: RR 1,66 (95 % CI: 1,21–2,28 für hohes Niveau an TV-Konsum. |
Angaben zu Publication Bias vorhanden; Random-effects-Modell verwendet; keine systematische Analyse der Studienqualität. |
3.2 EvT 3.18
|
Referenz |
Studientyp/ |
Untersuchte Population |
Intervention |
Kontrolle |
Untersuchte Endpunkte |
Hauptergebnisse |
Methodische Bemerkungen |
|
Soini 2014 |
Retrospektive Kohortenstudie LoE 2 (Vollerhebung, finnlandweit) |
93.843 LNG-IUD-Anwenderinnen (LNG-IUD: levonorgestrel-releasing intra-uterine device), davon 2.781 Endometrium-karzinom-Fälle bei 855.324 Frauenjahren. |
LNG-IUD. |
Kein LNG-IUD. |
Endometriumkarzinom-Risiko. |
LNG-IUD-Anwendung war mit einer niedrigeren Endometrium-karzinom-Inzidenz gegenüber Nicht-Anwendung assoziiert. Effektschätzer: 0,50 (95 % CI: 0,35–0,70). |
Hohe Aussagekraft durch populations-basiertes Register. |
|
Felix 2015 |
Metaanalyse von Beobachtungs-studien (18 Studien) LoE 3 |
Interventionsarm: 8.801 Frauen mit Endometrium-karzinom. Kontrollarm: 15.357 Frauen. |
Intrauterinpessar (engl. intrauterine device: IUD). |
Kein Intrauterinpessar. |
Endometriumkarzinom-Inzidenz. |
Anwenderinnen von Intrauterinpessaren haben ein geringeres Endometrium-karzinom-Risiko als Nicht-Anwenderinnen. Hier allen voran Anwenderinnen von inerten IUD, da diese seit den 1980er-Jahren angewendet wurden, was eine passende Latenzzeit für ein Endometrium-karzinom aufzeigt, ebenso scheint das Endometriumkar-zinom-Risiko bei Anwendung von Kupferspiralen verringert zu sein (statistisch hier nicht relevant). Daten für das levonor-gestrelhaltige IUD lagen hier noch nicht ausreichend vor. Effektschätzer: OR 0,81, 95 % CI: 0,74–0,90 für jemals genutzt. |
Keine Angaben zu Publication Bias, keine systematische Analyse der Studienqualität. |
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