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Abstract
Objective To evaluate real-world treatment patterns and clinical outcomes in recurrent/advanced endometrial cancer patients who progressed following prior systemic therapy in clinical practice in Europe.
Design Endometrial Cancer Health Outcomes-Europe (ECHO-EU) is a retrospective patient chart review study.
Setting ECHO-EU is a multicentre study conducted in the UK, Germany, Italy, France and Spain.
Participants Patients with recurrent/advanced endometrial cancer who progressed between 1 July 2016 and 30 June 2019 following prior first-line systemic therapy were eligible and data were collected until last available follow-up through November 2021.
Primary and secondary outcome measures Data collected included patient demographics, clinical and treatment characteristics, and clinical outcomes. Kaplan-Meier analyses were performed since initiation of second-line therapy to estimate time to treatment discontinuation, real-world progression-free survival (rwPFS) and overall survival (OS).
Results A total of 475 patients were included from EU5 countries. Median age was 69 years at advanced endometrial cancer diagnosis, 78.7% had stage IIIB–IV disease, 45.9% had Eastern Cooperative Oncology Group status ≥2 at second-line therapy initiation. In second line, a majority of patients initiated either non-platinum-based chemotherapy (55.6%) or endocrine therapy (16.2%). Physician-reported real-world overall response rate (classified as complete or partial response) to second-line therapy was 34.5%, median rwPFS was 7.4 months (95% CI 6.2 to 8.0) and median OS was 11.0 months (95% CI 9.9 to 12.3).
Conclusions Patients had poor clinical outcomes with a median OS of <1 year and rwPFS of approximately 7 months, highlighting the significant unmet medical need in pretreated recurrent/advanced endometrial cancer patients. Novel therapies with potential to improve PFS and OS over conventional therapies could provide significant clinical benefit.
- chemotherapy
- gynaecological oncology
- gynaecological oncology
- oncology
- gynaecology
Data availability statement
Data are available on reasonable request. In accordance with the journal’s guidelines, we will provide our data for independent analysis by a selected team by the editorial team for the purposes of additional data analysis or for the reproducibility of this study in other centres if such is requested.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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STRENGTHS AND LIMITATIONS OF THIS STUDY
This is a multicountry study with a sufficient follow-up period to evaluate survival outcomes.
This study used data from patient medical charts, often the best and most complete sources of information for documentation of advanced cancer treatments and clinical outcomes, of a random sample of eligible patients selected from all geographic regions of the included five European countries.
Study data are subject to extraction or measurement errors, and given the nature of chart review studies, this study is subject to potential physician and patient selection bias.
The data extracted were limited by information available in patients’ medical charts, and loss to follow-up could have occurred if patients switched practices.
Differences in outcome assessment methodology and frequency are expected across participating physicians and practices in the real-world setting, especially for physician-reported response and progression.
Background
Endometrial cancer is the most common malignancy of the female reproductive tract in developed countries and has increased in incidence in recent decades.1 In 2020, the estimated incident cases of endometrial cancer in Europe were reported to be 130 051, with 29 963 reported deaths.2 Over 70% of patients are initially diagnosed with stage I, which has a 5-year survival rate of >90%. However, among the 10%–13% of women diagnosed with advanced stage III and stage IV disease, 5-year survival is poor (60% and 29%, respectively).3 4 Furthermore, the 3-year recurrence rate for patients with early-stage disease is estimated at 7%, with varying 5-year overall survival (OS) depending on the site of recurrence (17.5%–64.8%).5
Traditionally, endometrial cancer treatment consisted of a combination of surgery, radiotherapy and/or chemotherapy, depending on disease stage and histology. For patients with recurrent or advanced disease who are not candidates for curative surgery or radiation therapy, chemotherapy with carboplatin and paclitaxel or hormonal therapy was recommended by the guideline valid in 2016 as the standard systemic therapies in the front line, while there was no standard of care in later lines.6 Guidelines indicate that the most active second-line chemotherapies are doxorubicin and paclitaxel, and that retreatment with platinum-based chemotherapies can be considered as well.7 However, novel biomarker-directed therapies focusing on DNA mismatch repair (MMR) tumour status are changing the treatment landscape for patients with recurrent or advanced disease in Europe.7–10
Despite the evolving treatment landscape, real-world treatment patterns and clinical outcomes with conventional treatments prior to the approvals of the novel therapies in patients with recurrent/advanced endometrial cancer in Europe are not well documented. The aim of the Endometrial Cancer Health Outcomes-Europe study was to evaluate the treatment patterns and clinical outcomes in recurrent/advanced endometrial cancer patients who progressed following prior first-line systemic therapy from July 2016 to June 2019 in Europe.
Methods
Study design and eligibility criteria
A multicentre, retrospective patient medical chart review study was conducted in the UK, Germany, Italy, France and Spain. A geographically dispersed, random sample of endometrial cancer-treating oncologists (medical, gynaecological or clinical oncologists) were recruited from each country. Oncologists provided data from eligible patients’ medical records and data were deidentified before analyses.
Participating oncologists randomly selected patients for eligibility screening among all their available recurrent/advanced endometrial cancer patients based on the first letter of their first name, as indicated by a random letter generator. Patients were eligible if they were ≥18 years of age, diagnosed with advanced/inoperable endometrial cancer between 1 July 2016 and 31 December 2018 and received at least one systemic therapy after diagnosis and progressed between 1 July 2016 and 30 June 2019. All patients diagnosed with stage I/II endometrial cancer were required to have a recurrence reported to be eligible. Diagnosis of recurrent and advanced endometrial cancer was physician reported based on real-world clinical practice. Patients were excluded if they were enrolled in any EC clinical trial during the study period, or if they had any prior malignancy active within the previous 3 years of diagnosis, except for locally curable cancers that had been cured. All eligible patients were included in the study for analysis.
Data collection and study measures
Patient data were entered by participating oncologists into an electronic case report form via a secure online portal. Data collected included patient demographic data, microsatellite instability (MSI)/MMR testing, clinical characteristics, tumour histology, treatment history and patterns, and clinical outcomes.
Clinical outcomes included real-world overall response rate, real-world progression-free survival (rwPFS) and OS. Results presented here describe results for recurrent/advanced endometrial cancer patients who initiated second-line systemic therapy. Response to second-line therapy was abstracted as reported by the physician from patients’ medical records and was categorised as complete response, partial response, stable disease or progressive disease. The real-world overall response rate consisted of an overall complete or partial response to second-line therapy.
Statistical analyses
Categorical variables were summarised using percentage and count, and continuous variables with mean and SD or median and IQR, as appropriate. The time-to-event variables were summarised using Kaplan-Meier methods and reported as median values and estimated probabilities at specific time points. Clinical outcomes were assessed across all patients and separately by therapy groups (platinum-based chemotherapy, taxane monotherapy, non-platinum chemotherapy (excluding taxane monotherapy) and endocrine therapy).
The rwPFS was estimated from the date of initiation of second-line therapy until the earliest date of any progression during second-line therapy or death. If the patient progressed but did not report a date of progression or death, then time to event was measured until start of third-line therapy (if available), else to the end of second-line therapy. Patients with no progression or death events were censored at start of third-line therapy (if available), at end of second-line therapy (if available), else at last follow-up. Patients with unknown progression status and missing discontinuation status on second-line therapy were excluded from the rwPFS analysis.
OS was estimated from the date of initiation of second-line therapy until date of death, with patients censored at date of last available patient follow-up/visit, if reported alive at the time of data extraction.
Analyses were conducted by using Statistical Analysis Software V.9.4.
Patient and public involvement
Patients/the public were not involved in the design of this chart review study.
Results
Physician characteristics
A total of 103 physicians participated across all countries. Physicians were primarily medical oncologists (89.3%), and 76.7% had been practising for more than 10 years. Almost all physicians practised in an urban setting (96.1%), and 92.2% were part of a hospital practice. Most physicians primarily practised at an academic hospital (75.7%), followed by community hospital (22.3%) and private office (2.9%).
Demographic and clinical characteristics of recurrent/advanced endometrial cancer patients initiating second-line therapy
Our study included 475 eligible recurrent/advanced endometrial cancer patients who experienced disease progression between 1 July 2016 and 30 June 2019, and had initiated a second-line therapy—including 101 from the UK, 96 from France, 88 from Germany, 100 from Italy and 90 from Spain. At advanced endometrial cancer diagnosis, overall median age was 69 years and 96.6% of patients were White/Caucasian, with median age and race similar across therapy groups. Race and ethnicity data were not collected in France due to legal restrictions. The most prevalent comorbidity was diabetes (35.6%). More than half of the patients (57.7%) had endometrioid carcinoma histology, and 78.7% had stage IIIB–IV disease at initial diagnosis. A majority of patients (51.1%–77.9%) had endometrioid histology across therapy groups. At initiation of second-line therapy, 45.9% had poor Eastern Cooperative Oncology Group performance status of ≥2 (table 1).
Patient demographics and clinical characteristics
Of the 475 patients, MSI/MMR testing was conducted in 166 (34.9%) using PCR and/or immunohistochemistry (IHC). Among the 166 patients with known MSI/MMR status, 74.7% had non-MSI-high (non-MSI-H)/MMR proficient (pMMR) tumours, 14.5% had MSI-H/MMR deficient (dMMR) tumours and 10.8% had discordant results (patients received both PCR and IHC tests, who had non-MSI-H and dMMR tumour, or MSI-H and pMMR tumour). Median follow-up from aEC diagnosis was just over 2 years overall, including 29.5 months for patients who received a platinum-based chemotherapy, 32 months for patients who received endocrine therapy, 24 months for patients who received non-platinum chemotherapy and 25 months for patients who received taxane monotherapy.
Treatment patterns in recurrent/advanced endometrial cancer patients initiating second-line therapy
A total of 168 (35.4%) patients received a primary surgery following initial endometrial cancer diagnosis, and 64 (13.5%) received adjuvant/neoadjuvant therapy, primarily consisting of carboplatin and paclitaxel. As first-line systemic therapy after the diagnosis of recurrent/advanced endometrial cancer, 94.7% of the 475 patients received chemotherapy, primarily with carboplatin and paclitaxel combination (online supplemental table S1).
Supplemental material
In second line, 55.6% of the overall cohort initiated non-platinum chemotherapy (n=264, excluding taxane monotherapy), 18.1% initiated a platinum-based chemotherapy (n=86), 16.2% initiated endocrine therapy (n=77), 6.5% initiated taxane monotherapy (n=31) and 3.6% initiated other therapies (n=17). The most common chemotherapy and endocrine therapy were doxorubicin or doxorubicin liposomal monotherapy (n=171, 36.0%) and medroxyprogesterone acetate (n=28, 5.9%), respectively. Among the 86 patients who received a platinum-based therapy in second line, about 81.4% (n=70) had received a prior platinum-based therapy in an adjuvant/neoadjuvant or in first-line setting (online supplemental table S1).
A total of 429 (90.3%) patients discontinued second-line therapy by last follow-up. Median time to treatment discontinuation was 4.9 months (95% CI 4.5 to 5.3)] from initiation of second-line therapy (figure 1). The median time to treatment discontinuation ranged between 3.7 months (taxane monotherapy) and 8.5 months (endocrine therapy) across therapy groups. The most common reasons for second-line treatment discontinuation were disease progression (n=244; 56.9%), maximum clinical benefit achieved (n=72; 16.8%), and completion of planned regimen (n=68; 15.9%). Among the 429 patients who discontinued second-line therapy, only 14.9% (n=64) of patients initiated a third-line. The most common third-line therapy initiated was paclitaxel (n=11; 17.2%), followed by doxorubicin liposomal (n=9; 14.1%) and megestrol acetate (n=7; 10.9%).
Kaplan-Meier plot of time to treatment discontinuation on second-line therapy in recurrent or aEC patients. aEC, advanced endometrial cancer; 2LOT, second line of therapy.
Clinical outcomes in recurrent/advanced endometrial cancer patients initiating second-line therapy
Physician-reported real-world overall response rate in patients initiating second-line therapy was 34.5% (CR, 6.9%; PR, 27.6%) overall, and was 32.2% in the non-platinum chemotherapy group, 38.4% in the platinum-based chemotherapy group, 31.2% in the endocrine therapy group and 22.6% in the taxane monotherapy group.
The overall median OS since the initiation of second-line therapy was 11.0 months (95% CI 9.9 to 12.3) (figure 2). The estimated probabilities of survival at 12 and 24 months since the initiation of second-line therapy were 45.9% (95%CI 41.5% to 50.8%) and 29.9% (95% CI 25.7% to 34.7%), respectively. The median OS was 9.9 months (95% CI 8.5 to 11.1) in the non-platinum chemotherapy group, 12.0 months (95% CI 11.0 to 32.5) in the platinum-based chemotherapy group, 13.7 months (95% CI 9.8 to 30.8) in the endocrine therapy group, and 8.1 months (95% CI 4.5 to 14.5) in the taxane monotherapy group.
Kaplan-Meier plot of overall survival (OS) on second-line therapy in recurrent or aEC patients. aEC, advanced endometrial cancer; 2LOT, second line of therapy.
For 2.1% of patients, progression status was unknown and dates of initiation of a third-line therapy and of permanent discontinuation of second-line therapy were not recorded; these patients were excluded from the rwPFS analyses, and therefore, 465 remaining patients were included. The overall median rwPFS on second-line therapy was 7.4 months (95% CI 6.2 to 8.0) (figure 3). The overall estimated probabilities of rwPFS at 6 and 12 months on second-line therapy were 56.5% (95% CI 52.1% to 61.3%) and 29.4% (95% CI 25.2% to 34.3%), respectively. The median rwPFS was 6.1 months (95% CI 5.5 to 7.6) in the non-platinum chemotherapy group, 8.0 months (95% CI 7.4 to 9.7) in the platinum-based chemotherapy group, 7.4 months (95% CI 4.7 to 15.2) in the endocrine therapy group, and 4.0 months (95% CI 2.9 to 9.2) in the taxane monotherapy group.
Kaplan-Meier plot of real-world progression-free survival (rwPFS) on second-line therapy in recurrent or aEC patients. aEC, advanced endometrial cancer; 2LOT, second line of therapy.
Discussion
Summary of main results
Our real-world, retrospective, multicountry observational study conducted in Europe provides comprehensive findings on treatment patterns and real-world clinical outcomes of conventional systemic therapies in recurrent/advanced endometrial cancer patients who progressed following prior systemic therapy between 2016 and 2019. Geographically dispersed physicians from 5 countries provided data on nearly 500 eligible patients.
Historically, MSI/MMR testing has not been well adopted in European clinical practice, as indicated by the lack of literature available in this population of recurrent/advanced endometrial cancer patients in Europe. Our study shows an overall low prevalence of MSI/MMR testing (34.9%) in these patients in Europe. However, in 2021, dostarlimab and pembrolizumab were approved for adult patients with recurrent/advanced dMMR/MSI-H endometrial cancer that has progressed on or following prior treatment with a platinum-containing regimen, and pembrolizumab in combination with lenvatinib for the treatment of recurrent/advanced endometrial cancer in adults who have disease progression on or following prior treatment with a platinum-containing therapy in any setting, regardless of MMR status and who are not candidates for curative surgery or radiation therapy.7 10 Guidelines were updated in 2022 to include these newly approved regimens for patients whose disease progressed following prior chemotherapy, and again in 2023 to include the use of pembrolizumab in combination with carboplatin and paclitaxel for first-line treatment regardless of MMR status.11 Thus, utilisation of MSI/MMR testing is expected to increase after 2021 since the availability of these recently approved novel therapies.
More than 94% of patients in our study initiated first line of systemic therapy with chemotherapy (primarily carboplatin and paclitaxel combination therapy). Our study also found that 41 different regimens were initiated as second-line therapy, indicating a lack of consensus among physicians on the standard of care for second line. The real-world treatment patterns observed in our study were consistent with the clinical practice guidelines at the time.6
In our study, about one-third of patients achieved a response to second-line treatment, a majority of whom had a partial rather than complete response. The overall patient cohort in our study showed a median OS of 11.0 months and rwPFS of 7.4 months from initiation of second-line therapy, and outcomes were similar across therapy groups, indicating a transient effect of conventional regimens in pretreated patients in Europe. In addition, about three out of four patients who received a platinum-based therapy in second line had been previously treated with platinum-based therapy in adjuvant, neoadjuvant or first-line settings; outcomes for platinum-rechallenged patients (results previously reported) were consistent with those of the general platinum-treated subgroup.12
Results in the context of published literature
While no real-world evidence studies are available on advanced endometrial cancer patients across the five European countries included in our study, a real-world observational study conducted in England found a median OS of 10.3 months and median time-to-next-treatment of 7.7 months in patients diagnosed with recurrent/advanced endometrial cancer between 1 January 2013 and 31 December 2018 who were immune checkpoint inhibitor-eligible and progressed and received second-line therapy.13 The poor survival outcomes found in this study were similar to those found in our study and highlight the challenges in achieving desirable survival outcomes for this patient population in real-world clinical settings in Europe. In a retrospective study conducted in the USA in non-MSI-H/pMMR recurrent/advanced endometrial cancer patients who progressed following prior systemic therapy, median OS was 10 months and rwPFS was 5 months. While these findings are numerically not unlike those from our current study, note that our current study included all eligible patients regardless of MSI/MMR tumour status.14
Data from clinical trials also provide some understanding on the effectiveness of various treatment regimens in this population. The phase III Study 309/KEYNOTE-775 randomised trial assessed outcomes in recurrent/metastatic/advanced endometrial cancer patients who progressed after a prior platinum-based therapy.9 In Study 309, previously treated patients randomised to physician’s choice of chemotherapy (doxorubicin or paclitaxel) had a median OS of 11.4 months and median PFS of 3.8 months. While these outcomes help us to contextualise the results of our study, direct comparisons to the clinical trial cannot be drawn because data has not been adjusted for baseline differences between the two populations. The outcomes evaluated in the clinical trial as well as our real-world study results corroborate the challenges in achieving optimal outcomes for recurrent/advanced endometrial cancer patients with conventional therapies and highlight the unmet need for adoption of novel therapies in European clinical settings.
Strengths and weaknesses
Our study has several limitations. First, study results are subject to extraction or measurement errors. Multiple efforts before and after data extraction were made to ensure data accuracy and consistency and to minimise errors. Second, the data extracted were limited by information available in patients’ medical charts, and loss to follow-up could have occurred if patients switched practices. Third, given the nature of chart review studies which require physician consent to participate, this study is subject to potential physician and patient selection bias. Data collection for our study was limited to patients who were included; no information was collected on patients who were not eligible or included in the study. We made efforts to include a broad physician sample and a random patient selection method to minimise the potential selection bias and improve generalisability of the results across Europe. Lastly, differences in outcome assessment methodology and frequency are expected across participating physicians and practices in the real-world setting, especially for physician-reported response and progression.
Our study also has several strengths. First, it integrated data from five European countries with a random sample of eligible patients selected from all geographic regions of the participating countries. The study sample represented a large and broad patient population regardless of demographics and clinical characteristics, supporting the generalisability of our study results. Second, patient medical charts are often the best and most complete sources of information for documentation of advanced cancer treatments and clinical outcomes. Third, the study period allowed for sufficient follow-up for the collection of subsequent lines of therapy and evaluation of survival outcomes.
Implications for practice and future research
Overall, data suggest a significant unmet medical need in pretreated recurrent/advanced endometrial cancer patients in Europe and opportunity to improve clinical outcomes. Adoption of novel therapies approved since 2021 could potentially help improve clinical outcomes in the previously treated advanced endometrial cancer patient population.
Conclusion
Our study provides real-world treatment patterns and clinical outcomes in recurrent/advanced endometrial cancer patients in Europe who progressed following prior systemic therapy from mid-2016 to mid-2019, prior to the availability of novel therapies approved since 2021 in this patient population. Patients initiated second-line therapy with over 40 different chemotherapy or endocrine therapy regimens and had high rates of treatment discontinuation and poor clinical outcomes with median OS of less than 1 year and median rwPFS of 7.4 months. The adoption of testing in routine practice may enhance treatment options for these patients and potentially lead to better clinical outcomes.
Data availability statement
Data are available on reasonable request. In accordance with the journal’s guidelines, we will provide our data for independent analysis by a selected team by the editorial team for the purposes of additional data analysis or for the reproducibility of this study in other centres if such is requested.
Ethics statements
Patient consent for publication
Ethics approval
This study involves human participants but this study was determined to not fall under the realm of the respective ethics committee/institutional review board oversight in each country: Sächsische Landesärztekammer (Germany), Hospital De La Santa Creu I Sant Pau (Spain), National Health Service Health Research Authority (UK; IRAS ID 302562), and Agenzia Italiana del Farmaco (Italy). In France, this study was carried out under méthodologie de référence 004 (MR-004), and thus, did not require any further approval. Participants gave informed consent to participate in the study before taking part.
Acknowledgments
Interim results from our study have been published previously at the meetings of the American Association for Cancer Research, 8 April 2022–13 April 2022, New Orleans, LA, USA, American Society of Clinical Oncology, 3 June 2022–7 June 2022, Chicago, IL, USA, and Society of Gynecologic Oncology, 25 March 2023–28 March 2023, Tampa, FL, USA. Study conceptualisation and design support was provided by Shelby Corman from OPEN Health, and by Chizoba Nwankwo and Shrividya Iyer from Eisai. Data analysis support provided by Yoscar Ogando from OPEN Health. Medical writing and editorial support provided by Rishi Verma from OPEN Health.
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
Contributors SSK (manuscript guarantor) and YQ oversaw the development of this manuscript as well as the design, management and statistical analysis for the study. VG and NM assisted in the study design and management and oversaw data collection. JZ and VSP contributed to the conception and design of the study and approved all other study aspects. CM provided insight for the interpretation of data.
Funding This study was funded by Merck Sharp & Dohme LLC (a subsidiary of Merck & Co., Inc., Rahway, New Jersey, USA) and Eisai (Nutley, New Jersey, USA).
Competing interests Authors report the following conflicts of interest: SSK, employment with OPEN Health which received consulting fees from Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, New Jersey, USA (MSD); YQ, former employment with OPEN Health which received consulting fees from MSD, and stock with AstraZeneca; JZ, employment with Eisai; VSP, employment with MSD and stock with Merck & Co., Inc., Rahway, NJ, USA; VG and NM, employment with M3 EU; CM, honoraria from AstraZeneca, GlaxoSmithKline, MSD, consulting fees from GlaxoSmithKline, MSD, Novartis, PharmaMar, Roche, and Seagen, and advisory board participation with GlaxoSmithKline and Karypharma.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.