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Original research
Trends over time in the incidence and use of hormonal therapy in endometrial cancer: a population-based study in the Netherlands
  1. Willem Jan van Weelden1,
  2. Reini Bretveld2,3,
  3. Andrea Romano4,5,
  4. Stephan van Erp1,
  5. Sam Engels1,
  6. Roy Lalisang5,6,
  7. Johanna Pijnenborg1 and
  8. Maaike van der Aa2
  1. 1 Department of Obstetrics and Gynaecology, Radboudumc, Nijmegen, Gelderland, The Netherlands
  2. 2 Netherland Comprehensive Cancer Organisation (IKNL), Utrecht, Utrecht, The Netherlands
  3. 3 Medisch Spectrum Twente, Enschede, Overijssel, The Netherlands
  4. 4 Department of Obstetrics and Gynaecology, Maastricht University Medical Center+, Maastricht, Limburg, The Netherlands
  5. 5 GROW-School of Oncology and Developmental Biology, Maastricht University Medical Center+, Maastricht, Netherlands
  6. 6 Department of Medical Oncology, Maastricht University Medical Centre+, Maastricht, Limburg, The Netherlands
  1. Correspondence to Dr Willem Jan van Weelden, Department of Obstetrics and Gynaecology, Radboudumc, Nijmegen, Gelderland, Netherlands; willemjan.vanweelden{at}radboudumc.nl

Abstract

Introduction According to current guidelines, hormonal therapy may be applied in endometrioid type endometrial cancer as an alternative to surgery for fertility preservation and in medically unfit patients. Since it is unknown how often hormonal therapy is applied, the objective of this study was to investigate trends over time in hormonal therapy use in the background of the overall incidence of endometrial cancer.

Methods All patients with endometrial cancer (n=48 222) registered in the Netherlands Cancer Registry in the period 1989–2018 were included. European age-standardized incidence rates with corresponding estimated annual percentage change were calculated to describe trends in the incidence of endometrial cancer. The use of hormonal therapy was analyzed in the three periods 1989–1998, 1999–2008, and 2009–2018 for the following sub-groups: primary and adjuvant therapy, International Federation of Gynecology and Oncology (FIGO) stage I–II and III–IV, and by age group.

Results The European age-standardized incidence rate of endometrioid endometrial cancer peaked in 2004 with a significant increase from 1989 to 2004 (annual percentage change 0.55; 95% CI 0.10 to 0.99, p=0.020) and a subsequent decrease from 2005 to 2018 (annual percentage change −1.79; 95% CI −2.28 to −1.31, p<0.001). The incidence rate of non-endometrioid type endometrial cancer increased significantly in the study period. Hormonal therapy was used in 1482 (3.5%) patients with endometrioid endometrial cancer. Among patients with FIGO stage I aged ≤40 years, hormonal therapy increased from 0% in 1989–1998 to 27% in 2009–2018. Primary hormonal treatment increased from 175 patients (5.5%) to 329 patients (7.8%) in those aged ≥75 years. Adjuvant hormonal treatment was mostly used in advanced stage endometrial cancer.

Conclusions The use of primary hormonal therapy in endometrioid type endometrial cancer increased over time in patients aged ≤40 years and among elderly patients. The observed trends in the current use of hormonal therapy support the need to study the effect of hormonal treatment in elderly patients and as adjuvant treatment in advanced stage endometrial cancer.

  • endometrial neoplasms
  • obesity
  • morbid

Data availability statement

Data are available upon reasonable request. A dataset from the Netherlands Cancer Registry was used for this research. Any requests regarding access to the dataset can be made to the corresponding author.

https://doi.org/10.1136/ijgc-2021-002444

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    HIGHLIGHTS

    • Standardized incidence rates of endometrioid endometrial cancer decreased in the last 15 years

    • Hormonal therapy is currently applied to 27% of women aged ≤40 years with stage I endometrial cancer

    • The use of hormonal therapy as an alternative to surgery has risen to 7.8% in elderly patients

    Introduction

    Worldwide, endometrial cancer is the sixth most common cancer type in women.1 An estimated 382 000 women per year are diagnosed with endometrial cancer and the incidence is still increasing in many countries.1 2 The rising incidence is often attributed to the obesity epidemic and the resulting increase in endometrioid type endometrial cancer. Yet, several recent studies have reported an increase in non-endometrioid type endometrial cancer.3–7 Endometrioid endometrial cancer is the most common histologic subtype and its development is largely mediated by estrogens.8 Fat cells are a major source of estrogens in post-menopausal women, explaining the relevance of obesity as a risk factor for endometrioid type endometrial cancer.9 10 In contrast, non-endometrioid type endometrial cancers are assumed to develop independent of estrogens.11

    The standard treatment for endometrial cancer consists of hysterectomy and bilateral salpingo-oophorectomy. Adjuvant radiotherapy and/or chemotherapy may be considered based on high-risk factors in the surgical specimen.12 13 Hormonal therapy is an alternative treatment for young patients with grade 1 stage I endometrial cancer who wish to preserve fertility, and for patients who cannot undergo surgery due to morbidities or other reasons. Hormonal therapy, mostly in the form of progestins, has a response rate of 75% in fertility preservation.14 15 The efficacy of hormonal therapy for medically unfit patients has not been properly investigated as available studies only included patients with grade 1 stage I endometrioid type endometrial cancer.16 17 If high-risk factors are present pre-operatively, surgery also includes pelvic and para-aortic lymph node dissection and, if extrauterine disease is present, adjuvant treatment often consists of chemoradiotherapy. In cases where no curative treatment options are available, palliative treatment with chemotherapy or hormonal therapy may be given. The response rate to chemotherapy and hormones in this setting is 50–60% and 20–40%, respectively.18–20 The response to hormones in all groups is suboptimal compared with surgery, despite application of predictive markers like low tumor grade and estrogen and progesterone receptor expression.18 19 More efforts are needed to optimize existing markers and identify new potential biomarkers to improve selection of hormonal treatment for individual women. In addition, it is unclear how often hormonal therapy is used and how the application of endometrial cancer treatment has evolved over time. In this nationwide population-based study, we investigate the trends over time in primary and adjuvant hormonal therapy use in endometrioid type endometrial cancer in relation to trends in the incidence of endometrial cancer.

    Methods

    Data Collection

    Anonymized population-based data of all patients with endometrial cancer in the period 1989–2018 were identified from the nationwide Netherlands Cancer Registry which is based on the notification of newly diagnosed malignancies by the automated nationwide pathological archive (PALGA). Completeness of the Netherlands Cancer Registry is at least 95%.21 Patients with endometrial sarcomas and stromal sarcomas were excluded.

    Information on patient characteristics including age, year of diagnosis, histology and tumor grade, International Federation of Gynecology and Obstetrics (FIGO) tumor stage and treatment were extracted from the Registry database by two authors (RB, MvdA). Other members of the research team had no access to identifiable information from the Registry. All commonly used hormonal drugs (medroxyprogesterone acetate, megestrol acetate, tamoxifen, and aromatase inhibitors) were coded as hormonal therapy. The levenorgestrel delivering intrauterine device (Mirena) was not included in the Registry. In cases where chemotherapy, radiotherapy, or hormonal treatment was applied without surgery, it was defined as primary treatment. If chemotherapy, radiotherapy, or hormonal therapy was started after surgery, it was considered adjuvant treatment.

    The surgical FIGO criteria 2009 were used to assign the stage of the patient and to group patients into early (FIGO stage I–II) and advanced stage (FIGO III–IV) endometrial cancer.22 Patients treated with primary hormonal therapy were classified according to clinical FIGO stage as the surgical stage was lacking. Cases with undocumented stage were classified as having early-stage endometrial cancer. Tumor grade was classified as low (grade 1–2) or high (grade 3). Age was categorized into four groups: ≤40, 41–59, 60–74, and ≥75 years: patients aged ≤40 years with stage I endometrioid type endometrial cancer were assumed to use hormonal therapy for fertility preservation. Patients aged ≥75 years were considered to use hormonal therapy due to co-morbidities that precluded them from standard surgical treatment. Histology was coded according to the International Classification of Disease for Oncology (ICD-O).

    This study was performed in accordance with the Declaration of Helsinki. Since only anonymized data were used for the analyses in this research, no informed consent was required. The internal review board of the Netherlands Cancer Registry approved the study (reference number K18.212).

    Statistical Analyses

    The annual incidence of endometrial cancer and its subtypes were analyzed as European age-standardized incidence rates. The rates were calculated per 100 000 person-years, using the annual mid-year population size obtained from Statistics Netherlands. Consequently, rates were age-standardized to the European standard population. This is the rate that would have been found if the population of the Netherlands had the same age composition as a hypothetical European population. The rates are calculated by applying the age-specific rates to a theoretical European standard population expressed per 100 000 persons per year. Changes were evaluated by calculating the estimated annual percentage change (EAPC) with the corresponding 95% confidence interval (95% CI) by fitting a regression line to the natural logarithm of the rates, using the calendar year as regressor variable (y=ax+ b, where y=ln(rate) and x=calendar year), then EAPC=100 × (eaa−1). The trends in incidence were compared between the periods 1989–2004 and 2005–2018, based on a previous study in which stabilization in the incidence of endometrioid endometrial cancer was observed from 2004 onwards.3

    To describe trends in baseline characteristics and treatment, three 10-year time periods were considered: 1989–1998, 1999–2008, and 2009–2018. These time periods were selected to accurately describe trends in therapy while limiting the influence of annual fluctuations in application of hormonal therapy. The baseline characteristics were analyzed using the analysis of variance (ANOVA) test with Tukey’s honestly significant difference (HSD) post-hoc test for continuous variables and χ2 test for discrete variables. Separate comparisons between different time periods were performed according to the pre-specified age groups and according to early and advanced stage endometrioid type endometrial cancer. The trends in application of adjuvant chemotherapy and adjuvant hormonal therapy were compared in advanced stage endometrioid type endometrial cancer. Trends over time in treatment were compared between different time periods using the Cochran–Armitage trend test. Separate analyses were performed without undocumented stage cases. For all statistical analyses, a two-sided p value of <0.05 was considered statistically significant. Statistical analyses were performed with Statistical Analysis Software version 9.4 (SAS institute, Cary, North Carolina, USA).

    Results

    Trends in Endometrial Cancer Incidence

    A total of 48 222 women were diagnosed with endometrial cancer between 1989 and 2018. Of these, 42 622 were diagnosed with endometrioid type endometrial cancer, 5223 were diagnosed with non-endometrioid type endometrial cancer, and 377 were diagnosed with unspecified type endometrial cancer. As shown in Figure 1, the highest standardized incidence rates for endometrial cancer were observed in 2004 and 2005 (17.5 and 17.4/100.000 person-years, respectively) with a significant increase in 1989–2004 followed by a significant decrease in 2005–2018. The standardized incidence rate of endometrioid endometrial cancer showed a similar pattern with a significant increase from 1989 to 2004 (EAPC 0.55; 95% CI 0.10 to 0.99, p=0.020), followed by a significant decrease in the period 2005–2018 (EAPC −1.79; 95% CI −2.28 to −1.31, p<0.001). The standardized incidence rate of non-endometrioid endometrial cancer increased significantly from 1989 to 2018 (estimated annual percentage change 4.81; 95% CI 4.35 to 5.27, p<0.001). Tumors of unspecified histology remained uncommon throughout the study period.

    Figure 1
    Figure 1

    Trends in annual European age-standardized incidence rate of endometrial cancer in total and by histologic subtype. EC, endometrial cancer; EEC, endometrioid endometrial cancer; NEEC, non-endometrioid endometrial cancer; EAPC: estimated annual percentage change.

    Characteristics of Cohort with Endometrioid Type Endometrial cancer

    The overall median age at diagnosis was 66.0 years (range 24–10.2) (Table 1). The proportion of cases with early stage was 88.3% during the study period. In total, 4.5% of cases had undocumented stage and were included in the early-stage group. The proportion of patients aged ≥75 years varied between 25.1% and 26.5%. The group of patients diagnosed at age ≤40 years was consistently <1%. There was a significant increase in low-grade endometrioid tumors from 75.9% to 81.7% and a small but significant decrease in surgical treatment from 93.9% to 92.0% over time.

    View this table:
    Table 1

    Characteristics of endometrioid type endometrial cancer cohort

    Primary and adjuvant treatment with chemotherapy increased significantly. The use of primary radiotherapy remained stable around 1% while adjuvant radiotherapy decreased significantly. Combined treatment with hormonal therapy and radiotherapy or hormonal therapy and chemotherapy was applied to 0.3% and combined hormonal and chemotherapy was used in 0.08% of cases.

    Trends in Hormonal Therapy

    In total, 1482 patients (3.5% of all endometrioid cancers) were treated with hormonal therapy: 998 (2.3%) patients received primary hormonal treatment and 484 patients (1.1%) were treated with adjuvant hormonal treatment (Table 1). The application of primary hormonal therapy remained stable in the period 1989–2008 and showed a significant increase in 2009–2018. The use of adjuvant hormonal therapy decreased significantly.

    Primary Hormonal Therapy

    The mean (SD) age of patients treated with primary hormonal therapy was 78.2 (13.1) years. Application of primary hormonal therapy increased significantly among patients aged ≤40 and ≥75 years (Figure 2).

    Figure 2
    Figure 2

    Trends in primary hormonal therapy according to age in the endometrioid endometrial cancer population.

    For the subset of patients aged ≤40 years with FIGO stage I endometrioid cancers, the use of primary hormonal therapy increased from no patients in 1989–1998 to five patients (5.4% of cases with FIGO stage I diagnosed ≤40 years) in 1999–2008 and to 27 patients (27%) in 2009–2018 (p<0.001). Among patients aged ≥75 years, primary hormonal therapy increased from 175 patients (5.5% of all endometrioid cancers diagnosed ≥75 years) in 1989–1998 to 329 patients (7.8%) in 2009–2018. This increase was significant for patients with early stage endometrioid cancers (Figure 3). The increase was most pronounced in 2009–2018. In the same time frame, surgery decreased from 86.0% in 1989–1998 and 85.3% in 1999–2008 to 81.1% in 2009–2018 among patients aged ≥75 years (p<0.001). Observed trends were similar for analyses with known stage only.

    Figure 3
    Figure 3

    Trends in primary hormonal therapy according to stage among patients with endometrioid endometrial cancer aged ≥75 years.

    Systemic Therapy in the Adjuvant Setting

    The mean age of patients treated with adjuvant hormonal therapy was 70.0 years (SD 12.1). Application of adjuvant hormonal therapy for endometrioid cancers decreased significantly between 1989–1998 and 1999–2008 (Figure 4A). In 1999–2018, adjuvant hormonal therapy was used in 0.2–0.3% of patients with early stage and 5.3–5.5% of patients with advanced stage endometrioid cancers. As shown in Figure 4B, hormonal therapy was the most often applied systemic therapy for advanced stage endometrioid cancers in the adjuvant setting in 1989–1998. In the subsequent periods, chemotherapy use increased significantly. The largest increase in application of chemotherapy was observed in 2009–2018. Separate analyses among cases with known stage showed similar results.

    Figure 4
    Figure 4

    Trends in adjuvant systemic therapy. (A) Trends in hormonal treatment according to early and advanced stage endometrioid endometrial cancer. (B) Trends in adjuvant hormonal treatment and chemotherapy in advanced stage endometrioid endometrial cancer.

    Discussion

    Summary of Main Results

    In this population-based study, we demonstrate a decline in the incidence rate of endometrioid cancer and endometrioid type endometrial cancer in the period 2005–2018. In contrast, the incidence rate of non-endometrioid endometrial cancer increased. The application of primary hormonal therapy among patients aged ≤40 years with FIGO stage I endometrioid type endometrial cancers has risen. Additionally, a growing number of elderly patients with endometrioid type cancer received primary hormonal therapy. Adjuvant hormonal therapy use remained unchanged in 1998–2018 while adjuvant chemotherapy was increasingly applied in advanced stage endometrioid type endometrial cancer.

    Results in the Context of Published Literature

    The trends in incidence rates observed in this study are in line with recent trends found in Denmark and the USA.6 7 Observed trends might be explained by the added diagnostic possibilities, allowing for better pathological differentiation between histologic subtypes. Also, estrogen-related risk factors, including obesity, have recently been shown to be relevant for both sub-types.23 Unlike other studies, endometrioid type incidence rates decreased in recent years for unclear reasons.3–5 We hypothesize that this could be related to increased awareness of post-menopausal bleeding, leading to adequate prevention of endometrioid type endometrial cancer. Among the endometrioid subtype, primary hormonal therapy is increasingly applied as an alternative to standard surgical treatment. For young patients with FIGO stage I, this is probably related to increased application of fertility preservation therapy, as also reported by Ruiz et al.24 This is in line with several studies in which hormonal therapy was shown to be a safe alternative to surgery in a select group of young patients with endometrial cancer.13 24–26

    Primary hormonal therapy is most often applied to patients aged ≥75 years. This might be explained by the fact that patients with endometrial cancer are at an increasingly older age and have higher body mass indices, reflecting a population with more co-morbidity in which surgery is not always feasible. This was confirmed by our observation of a decline in surgical treatment in elderly patients. Other studies have also shown increasing age and body mass index in patients with endometrial cancer, and have found that older patients have more co-morbidities and are precluded from surgical treatment more often.27–30

    The decrease in adjuvant radiotherapy correspond with publication of studies which showed that radiotherapy can be omitted in low-risk cases without affecting outcome.31 Around the same time, increasing evidence for the use of chemotherapy was observed, especially in advanced stage disease.32 33 These trends are reflected in actual application of adjuvant treatments in this cohort. Adjuvant hormonal therapy decreased as several studies showed no benefit of adjuvant hormonal treatment in early-stage endometrial cancer.34 35 In contrast, adjuvant hormonal treatment in advanced stage endometrial cancer has not been properly investigated.36 Nonetheless, a small group of patients with advanced stage disease is still treated with hormones.

    Strengths and Weaknesses

    The strengths of this study include the population-based design, in which all patients with endometrial cancer were registered in the NCR over a period of 30 years, and the resulting large database of patients with endometriod type endometrial cancer who used hormonal therapy. Furthermore, the female population of the Netherlands is similar to other European countries in terms of obesity and diabetes mellitus.37 38 Obesity is even more prevalent in the USA and Australia.39 40 The observed trends can therefore also be expected in other high-income countries.

    There are also limitations to be addressed. First, assumptions were made for the reason of applying hormonal therapy as this is not noted in the Netherlands Cancer Registry. The assumption was made that patients aged ≤40 years with stage I endometrioid type cancer were treated with hormonal therapy for fertility preservation. Because hormonal therapy is still regarded as an alternative and temporary treatment until childbearing is complete, it is unlikely that young patients with FIGO stage I would use hormonal therapy for other reasons than fertility preservation.13 Similarly, since surgery is the standard treatment in patients aged ≥75 years, we assumed that the application of hormonal therapy in this age group was indicative of patients who were unfit for surgery, in line with guideline recommendations.13 26 In a recent study, older age and high co-morbidity score were the most important reasons for application of non-surgical treatment, supporting the assumptions made in our study.41 Second, the Mirena intrauterine device was not included in the Cancer Registry. This might have resulted in an underestimation of the actual number of cases with hormonal therapy. Yet oral progestins such as medroxyprogesterone acetate and megestrol acetate are still the preferred route of administration because of high efficacy and more clinical experience.26 42 43 The Mirena intrauterine device can currently be considered as additive to oral progestins in cases of limited or absent response.43 44 Furthermore, the definition of adjuvant treatment implies that tumor resection is complete. Since completeness of tumor resection was only registered from 2018 onwards, we had to assume that tumor resection was complete in cases with post-operative treatment. In 2018, most patients had a complete tumor resection, indicating that adjuvant treatment was correctly defined in this study. In addition, patients with undocumented stage were defined as having early-stage endometrial cancer. In the Netherlands Cancer Registry, a selection of cases had tumor stage missing because no staging procedure was performed in low-grade, early-stage endometrial cancer. In reality, these patients had stage I and were regarded as such in this study. Since the application of hormonal therapy is especially frequent among patients without surgical staging procedure, cases with undocumented stage were not excluded. Finally, hormonal therapy is also frequently applied in patients with recurrent endometrial cancer in a palliative setting. Unfortunately, recurrences are not yet registered and therefore we were unable to investigate hormonal therapy use in this group.

    Implications for Practice and Future Research

    The increasing use of hormonal therapy both in young women who wish to preserve fertility and in older women who cannot undergo surgery provides a strong incentive to optimize the effect of hormonal therapy. This is especially relevant considering that body weight is still increasing in many countries, also among children and adolescents.45 46 As a result, more endometrial cancer cases and use of hormonal therapy can be expected. In the USA, where the prevalence of obesity is higher than in Europe, increasing endometrial cancer incidence rates are already being observed in young women.47

    This study is the first to show that hormonal therapy is currently a frequently applied treatment in older patients. To our knowledge, there is no previous study in which the response to primary hormonal treatment was specifically studied in inoperable patients, although a first clinical trial is currently underway (NCT01686126, www.clinicaltrials.gov). Interestingly, in patients with advanced stage endometrial cancer, a number of studies have investigated the effect of targeted drugs.48–50 In contrast, research into hormonal therapy is minimal. Considering that hormonal therapy has limited side effects and low costs, further research on identifying the group of patients with optimal benefit from hormonal therapy is warranted.18 Once this sub-group is recognized, the selection for systemic palliative treatment can be individualized based on the presence of predictive biomarkers.

    Conclusions

    In this study we show a recent decrease in the incidence of endometrioid type endometrial cancer while the incidence rate of non-endometrioid type endometrial cancer continues to increase. The use of hormonal therapy as primary treatment in endometrioid type endometrial cancer has increased in recent years. As expected, hormonal treatment use rose among patients aged ≤40 years. In addition, the application of primary hormonal therapy in elderly patients has risen substantially despite limited supporting data. The use of adjuvant hormonal therapy stabilized and is mainly prescribed in advanced stage endometrial cancer. The increased use of hormonal therapy supports the need for prospective data on efficacy in the primary setting for elderly patients and in the adjuvant setting.

    Data availability statement

    Data are available upon reasonable request. A dataset from the Netherlands Cancer Registry was used for this research. Any requests regarding access to the dataset can be made to the corresponding author.

    Ethics statements

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    Footnotes

    • Contributors Conceptualization: WW, JP, MvdA. Methodology: RB, MvdA. Software: RB. Validation: WW, RB, JP, MvdA. Formal analysis: WW, RB. Investigation: WW, RB, AR, RL, JP, MvdA. Data curation: RB. Writing – original draft: WW, SvE, SE, JP, MvdA. Writing – review and editing: WW, RB, AR, RL, JP, MvdA. Visualization: WW, JP. Supervision: MvdA, JP.

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.