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Abstract
Objective The main objective of the study was to assess the influence of different clinical and therapeutic variables on the oncological outcomes of patients with endometrial cancer relapse. In particular, we evaluated the impact of cytoreductive surgery with the achievement of complete gross resection.
Methods This is a multicenter retrospective cohort study conducted in three centers in Italy and including all patients with first relapse of endometrial cancer from January 2010 to December 2021.
Results Data from 331 women with recurrent endometrial cancer were analyzed. Secondary cytoreductive surgery was performed in 56.2% of cases (186 patients). Complete gross resection was achieved in 178 patients (95.7%). Complete gross resection conferred a statistically significant survival benefit both for post-relapse survival and post-relapse free survival (3 years post-relapse survival: 75.4% vs 56.4%, p<0.001; 3 years post-relapse free survival: 32.6% vs 26.5%, p=0.027). At multivariate Cox regression analysis, age ≥75 years, Eastern Cooperative Oncology Group Performance Status ≥2, the advanced-metastatic risk group, complete gross resection, and multiple site relapses were identified as independent significant predictors for post-relapse survival; regarding post-relapse free survival, only age ≥75, the high and advanced-metastatic risk groups, and complete gross resection confirmed their statistical significance.
Conclusions Secondary cytoreductive surgery with achievement of complete gross resection was confirmed to be an independent positive predictor for survival in patients with recurrent endometrial cancer and should be considered a valid primary treatment in the therapeutic decision-making process.
- endometrial neoplasms
- neoplasm recurrence, local
- cytoreduction surgical procedures
Data availability statement
Data are available upon reasonale 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 centers if such is requested.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
Treatment of endometrial cancer recurrences is strongly influenced by the number, type, location of the disease, and previously performed treatments. The prognostic relevance of secondary cytoreductive surgery has been demonstrated in studies with relatively small and not statistically powered populations.
WHAT THIS STUDY ADDS
This study adds data supporting the therapeutic value of secondary cytoreductive surgery when complete gross resection can be achieved. When adjusted for other variables, the survival advantage given by complete gross resection was confirmed for both post-relapse survival and post-relapse disease-free survival.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
Surgical cytoreduction with the aim of complete gross resection should be considered a valid primary treatment in the therapeutic decision-making process for recurrent endometrial cancer.
INTRODUCTION
Endometrial cancer is the most frequent gynecological cancer, with incidence and mortality rates steadily increasing.1 2 Although diagnosis is usually made at an early stage and 5-year survival rates are excellent,1 a non-negligible proportion of patients develop relapse with poor survival outcomes.3–6 The risk of endometrial cancer recurrence strongly depends on the presence of specific factors such as substantial lymph-vascular space invasion, International Federation of Gynecology and Obstetrics (FIGO) stage, histological subtype, and tumor grade.7 8 Relapses can be classified as locoregional (20–50%), lymphatic (12–20%), hematogenous/parenchymal (lung, liver, bone) (17–32%), peritoneal (11–14%), and mixed (22–24%).4–6 9
Previous therapy, location, number of metastases, and patients’ clinical characteristics affect the therapeutic strategy, which varies between surgery, chemotherapy, radiotherapy, and hormonal therapy, alone or in combination. Although recent data showed a positive correlation between survival and optimal debulking, the role of non-exenterative cytoreductive surgery for recurrent disease has not been extensively explored.4 10–16
In this study, we investigated the role of debulking surgery and of clinicopathological variables in survival outcomes of patients with first endometrial cancer recurrence and, more specifically, the role of secondary cytoreductive surgery with the achievement of complete gross resection.
METHODS
This is a multicenter retrospective cohort study including three Italian centers. Participating centers were Fondazione Policlinico Universitario A. Gemelli, IRCCS, Rome; Gemelli Molise Hospital, Campobasso; and the University of Parma. After approval of the Institutional Review Board of Fondazione Policlinico Universitario A. Gemelli,(DIPUSVSP-PD-03–228), the medical records of patients with endometrial cancer undergoing surgery as primary treatment, from January 2010 to December 2021, were retrospectively retrieved. An informed consent was signed by all women for their data to be collected and analyzed for scientific purposes.
Patients’ Clinical and Surgical Data
The main inclusion criterion was histological or radiological diagnosis of endometrial cancer recurrence (first recurrence). Patients who did not undergo surgery as primary treatment, with concomitant primary cancers and lacking relevant clinical or pathological data, were excluded. Non-epithelial histologies were excluded. Demographic, surgical and post-operative variables were retrieved from our prospective electronic database (REDCAP). Based on the histopathological characteristics of the tumor at diagnosis, each patient was categorized into one of five prognostic risk groups indicated in the European Society of Gynaecological Oncology/European Society for Radiotherapy and Oncology/European Society of Pathology (ESGO/ESTRO/ESP) guidelines.17 Relapses were classified as single or multiple based on the number of relapse sites found at radiological assessment (CT, MRI or positron emission tomography), and according to their spreading pathway (loco-regional, lymphatic, hematogenous/parenchymal or peritoneal). If multiple spreading pathways were detected, relapses were classified as mixed.
Patients were referred to different secondary treatments following a multidisciplinary tumor board involving experienced surgeons, oncologists, radiotherapists, radiologists and other specialists (thoracic, general surgeons or urologists). After evaluation of clinical conditions, type and pattern of recurrence and treatments performed, patients received the treatment deemed most appropriate to their case (among surgery, chemotherapy, radiotherapy, hormone therapy or immunotherapy). Due to the recent introduction of the latter, not all patients examined by the study could benefit from the same treatment options. Complete cytoreduction was defined as the absence of macroscopic residual disease (complete gross resection), whereas patients with residual tumor (RT) >0 were defined as not-optimally debulked.
Considering the achievement of complete gross resection as the optimal outcome of debulking surgery, patients with RT >0 and patients referred for secondary treatment other than surgery were pooled together for survival outcomes analysis. Cancer-specific post-relapse survival was calculated from the date of first relapse to the date of death from disease or last follow-up. Post-relapse disease-free survival was calculated from the date of first relapse to the date of second relapse or last follow-up in case of no further relapses.
The primary endpoint of the study was to assess the influence of debulking surgery and of clinicopathological variables on post-relapse survival. The secondary endpoint was the evaluation of the influence of debulking surgery and of clinicopathological variables on post-relapse disease-free survival.
The RECORD (REporting of studies Conducted using Observational Routinely collected health Data) checklist for observational cohort studies was observed.
Statistical Analysis
Assuming a 3-year post-relapse survival of about 50%,5 14–16 165 events are expected in a sample size of 331 patients allowing to include eight covariates in the regression model respecting a rule of at least 20 events per variable. Descriptive statistics were used to describe patients’ clinical, surgical and pathological characteristics. Absolute frequency and percentage were adopted for qualitative variables. Survival analysis was performed using the Kaplan-Meier method. Cox regression analysis was used to ascertain the effects of independent variables on post-relapse and post-relapse free survival.
Multivariable Cox regression analysis was then performed using a backward stepwise (likelihood ratio) model. Variables with a p value <0.100 were included in the multivariable model. A p value <0.050 was considered statistically significant (two-tailed test). Statistical analyses were performed using Statistical Package for Social Science (SPSS) version 29.0 (International Business Machines (IBM), Armonk, NY) software for Macintosh.
RESULTS
A total of 331 patients with recurrent endometrial cancer were evaluated. The patients’ clinical and histopathological characteristics are described in Table 1. Eighteen percent of the population was over 75 years old, 19.3% had an Eastern Cooperative Oncology Group-Performance Status (ECOG-PS) ≥2, and 75.8% had an age-adjusted Charlson Comorbidity Index >2. Prognostic risk groups at initial diagnosis were distributed as follows: 20.2% were low-risk patients, 18.7% intermediate, 14.5% high-intermediate, 38.1% high-risk, and 8.5% were patients with advanced metastatic disease. Relapse characteristics are shown in Table 1. Two-hundred and three patients (61.3%) had a single site relapse, while 128 (38.7%) had multiple site metastasis.
Clinical and histological characteristics of the study population and first relapse details
Regarding the relapse pathway at pre-operative radiological examinations, 39.9% of patients showed loco-regional disease, 20.5% had lymph node recurrence, 17.8% had hematogenous recurrence, 8.8% had peritoneal spread, and 13.0% were mixed. Debulking surgery was considered for 56.2% of patients, while chemotherapy was performed in 27.2% of patients. In the group of patients who underwent debulking surgery, complete gross resection was achieved in 95.7% of cases (Table 1). One hundred and forty-eight patients of 186 (79.6%) received adjuvant chemotherapy post-debulking surgery, while 12 patients (6.4%) did not undergo any adjuvant treatment due to poor post-operative conditions, severe post-operative complications, or they refused chemotherapy. The remaining patients underwent radiotherapy/brachytherapy or hormonal therapy (Table 1).
Survival Analysis
Median follow-up was 65 months. Online supplemental figure S1 shows the survival curves according to the treatment performed (secondary cytoreductive surgery with complete gross resection vs debulking surgery with RT >0 vs other secondary treatments such as chemotherapy, radiotherapy, palliative care). A significantly better post-relapse survival was found for patients with complete gross resection compared with patients with RT >0 and patients undergoing other secondary treatment (p=0.007 and p<0.001, respectively). No differences were found between patients undergoing secondary cytoreductive surgery with RT >0 and other secondary treatment (p=0.48). Figures 1 and 2 show the Kaplan-Meier plots for post-relapse and post-relapse disease-free survival according to complete gross resection, highlighting the survival benefit given by the achievement of no residual disease (3 years post-relapse survival: 75.4% vs 56.4%, p<0.001; 3 years post-relapse free survival: 32.6% vs 26.5%, p=0.027).
Supplemental material
Post-relapse survival according to complete gross resection. CGR, complete gross resection; NR, not reached; RT, residual tumor.
Post-relapse free survival according to complete gross resection. CGR, complete gross resection; NR, not reached; RT, residual tumor.
Further stratifying the population on both residual tumor (complete gross resection vs RT >0 or other secondary treatment) and single or multiple sites metastases, Kaplan-Meier curves showed that achieving complete gross resection conferred a statistically significant post-relapse survival benefit in patients both with single site metastases (3 years post-relapse survival: 84.8% vs 49.7%, p<0.001) and multiple site metastases (3 years post-relapse survival: 92.5% vs 39.4%, p<0.001) (Online supplemental figure S2).
Supplemental material
At univariate Cox regression analysis for post-relapse survival (Table 2), the following factors showed statistical significance: age ≥75 years old (HR 3.35, 95% CI 2.21 to 5.06, p<0.001), BMI ≥30 (HR 1.59, 95% CI 1.06 to 2.39, p=0.023), ECOG-PS ≥2 (HR 2.52, 95% CI 1.65 to 3.86, p<0.001), Charlson Comorbidity Index >2 (HR 2.69, 95% CI 1.46 to 4.96, p=0.001), advanced-metastatic risk group at initial diagnosis (HR 2.51, 95% CI 1.13 to 5.56, p=0.025), adjuvant chemotherapy at first diagnosis (HR 2.25, 95% CI 1.12 to 4.52, p=0.022), the achievement of complete gross resection at secondary cytoreductive surgery (HR 0.50, 95% CI 0.33 to 0.76, p=0.001), and the multiple sites relapses (HR 2.44, 95% CI 1.62 to 3.67, p<0.001). When analyzed by multivariate analysis (Table 2) age ≥75 years, ECOG PS ≥2, advanced-metastatic risk group, complete gross resection, and multiple site relapses maintained their statistical significance (age ≥75 years old: HR 2.81, 95% CI 1.82 to 4.33, p<0.001; ECOG PS ≥2: HR 1.91, 95% CI 1.24 to 2.96, p=0.004; advanced-metastatic risk group: HR 3.23, 95% CI 1.42 to 7.35, p=0.005; complete gross resection: HR 0.54, 95% CI 0.35 to 0.84, p=0.006; and multiple site relapse: HR 2.52, 95% CI 1.66 to 3.82, p<0.001).
Risk factors for post-relapse survival: univariate and multivariate analysis
Concerning post-relapse disease-free survival (Table 3), age ≥75 (HR 1.57, 95% CI 1.12 to 2.22, p=0.009), high-risk group (HR 1.66, 95% CI 1.09 to 2.48, p=0.018), advanced-metastatic risk group (HR 2.04, 95% CI 1.13 to 3.69, p=0.018), adjuvant chemotherapy at first diagnosis (OR 1.70, 95% CI 1.02 to 2.85, p=0.043), and complete gross resection (HR 0.74, 95% CI 0.56 to 0.98, p=0.038) were found to be statistically significant factors at univariate analysis. At multivariate analysis only age ≥75, the high and advanced-metastatic risk groups, and complete gross resection confirmed their statistical significance (age ≥75 years: HR 1.53, 95% CI 1.09 to 2.15, p=0.013; high-risk group: OR 1.54, 95% CI 1.01 to 2.35, p=0.045; advanced-metastatic risk group: HR 2.12, 95% CI 1.17 to 3.86, p=0.014; and complete gross resection: HR 0.75, 95% CI 0.56 to 0.99, p=0.041).
Risk factors for post-relapse free survival: univariate and multivariate analysis
Analyzing the study population per center, we found a significant difference in survival between patients treated in a high-volume cancer center (Rome, patients included: 258) compared with patients coming from the other two smaller centers (Gemelli Molise, patients included: 35; University of Parma, patients included: 38) (log-rank p<0.001) (Online supplemental figure S3). These two groups differed significantly in terms of age ≥75 (Rome 13.6%, minor centers 34.2%, p<0.001), BMI ≥30 (32.2% vs 52.1%, p=0.002), relapse pattern (p=0.035), rate of patients with multiple sites of metastasis (34.9% vs 52.1%, p=0.008), and proportion of debulking surgery (62% vs 35.6%, p<0.001) (Online supplemental table S1).
Supplemental material
Supplemental material
DISCUSSION
Summary of Main Results
Secondary cytoreductive surgery with the achievement of complete gross resection was confirmed as a significant independent positive predictor of improved post-relapse and post-relapse disease-free survival in patients with endometrial cancer recurrence, while age ≥75, ECOG-PS ≥2, the advanced-risk group, and the presence of multiple sites of metastasis were found to be relevant negative predictors for post-relapse survival. In addition, stratifying the population on the number of relapse sites and the treatment performed, complete gross resection conferred a statistically significant post-relapse survival benefit for patients both with single and multiple-site recurrence. Patients treated in a high-volume cancer center were more likely to receive debulking surgery and showed better survival outcomes; however, the small sample size of the minor hubs and differences in population characteristics do not allow us to draw reliable statistical conclusions.
Results in the Context of Published Literature
Patients with endometrial relapsing disease represent a heterogeneous group with different characteristics. We recently proposed a treatment algorithm that considers the number and site of recurrence and the adjuvant treatment received at first diagnosis, and surgery represents a viable option for both locoregional, abdominal, and extra-abdominal disease.18 Surgical resection has usually been limited to patients with vaginal apex recurrences within a previously irradiated pelvic field19 20; however, given the demonstrated survival benefit of secondary cytoreductive surgery in recurrent ovarian cancer21 22 and the poor response rate to standard chemotherapy of recurrent endometrial cancer, surgical cytoreduction has progressively gained interest in this context as well.
Several studies have investigated the role of secondary cytoreductive surgery in recurrent endometrial cancer, although all in retrospective settings.
Bristow et al14 first showed a statistically significant post-relapse survival benefit in patients subjected to surgery compared with non-surgically treated patients (28 vs 13 months). Specifically looking at surgically treated patients, they confirmed the survival advantage only for patients with complete surgical resection. Shikama et al15 confirmed these results in a population of 112 patients, reporting a median post-relapse survival of 81 months for completely resected patients compared with those with any size of residual tumor (23 months) or non-surgically treated (21 months).
The pivotal relevance of secondary cytoreductive surgery in post-relapse survival was then confirmed in multivariable models in two subsequent retrospective studies,5 16 both for post-relapse survival and progression-free survival.16 Other identified factors were age >70, <12 months to initial recurrence, serous histology, advanced stage, adjuvant therapy after initial surgery, increased size of tumor at recurrence, extra-pelvic recurrence, and the lymphatic pattern of recurrence.5 16 Our results substantially confirm these findings, adding consistent data to the body of literature. However, the criteria defining the optimal cytoreduction are not yet established and vary from complete gross resection23–25 to less than 126 27 or 2 cm.28
A meta-analysis by Barlin et al,29 including 14 retrospective cohorts with advanced and recurrent endometrial cancer (672 patients), found that complete cytoreduction to no gross residual disease was associated with superior overall survival (each 10% increase improving survival by 9.3 months, p=0.04), while the survival benefit for patients undergoing optimal surgical cytoreduction, ranging from ≤2 cm to no gross evidence of disease, was not statistically significant.
Translating the results obtained in ovarian cancer, which more widely demonstrated a marked improvement in survival with the progressive reduction of residual cancer,30–32 our results confirmed significantly longer post-relapse and post-relapse free survival intervals for patients benefiting from complete gross resection (p<0.001 and p=0.027, respectively).
Debulking surgery often includes several surgical procedures and is burdened by non-negligible rates of post-operative complications and mortality,16 27 thus it should be reserved for those patients where a complete gross resection is achievable. However, valid pre-operative selection criteria are still lacking. By reviewing the studies that evaluated possible predictors of optimal debulking, the only recurring factor was the presence of a single site relapse.26–28 However, other authors found no predictive factors for residual tumor status, undermining previous findings14 24 and leaving the issue open.
Strengths and Weaknesses
This is currently the largest study examining survival predictors and the specific role of secondary cytoreductive surgery in endometrial cancer relapse, and the one with the highest number of patients undergoing secondary cytoreductive surgery and complete gross resection.5 9 14 16 There are several limitations to our study, primarily its retrospective nature that may have led to a bias in the selection of patients undergoing surgery. Indeed, patients undergoing cytoreductive surgery may have a more indolent and localized disease, with an inherently better prognosis. However, multivariate analysis confirms complete macroscopic resection among positive prognostic factors. Another limit was that we could not assess the impact of some relevant factors such as molecular classification because, given the long study period, this was missing for most of the cohort.
Implications for Practice and Future Research
Surgical debulking with complete gross resection appears to be a viable option for endometrial cancer recurrence; however, there are no consistent data on which patients may benefit from it. Moreover, the treatment landscape of recurrent endometrial cancer is expanding due to the availability of data on molecular characterization and the immune environment that have paved the way for new therapeutic options; several clinical studies with immune checkpoints and poly-ADP ribose polymerase inhibitors are currently ongoing.33
Future studies are needed to help clinicians select patients for surgical treatment and to specifically evaluate the impact of secondary cytoreductive surgery in different molecular classes.
In the light of the recent revolutionary studies on immunotherapy,34 35 the impact of the latter compared with surgery or whether these may have a synergistic effect remains to be assessed.
CONCLUSION
Secondary cytoreductive surgery with the achievement of complete gross resection was confirmed as an independent positive prognostic factor in patients with endometrial cancer recurrence, conferring a significant survival advantage both in terms of post-relapse and post-relapse disease-free survival. Surgical cytoreduction with the goal of complete gross resection should be considered as a valid primary option in the therapeutic decision-making algorithm of endometrial cancer recurrence.
Data availability statement
Data are available upon reasonale 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 centers if such is requested.
Ethics statements
Patient consent for publication
References
Supplementary materials
Supplementary Data
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Footnotes
Twitter @frafanfani
Contributors VV: conceptualization, data curation, formal analysis, methodology, writing - original draft. AR: conceptualization, data curation, formal analysis, methodology, writing - original draft. VAC: data curation, methodology. AG: data curation. SR: data curation. RB: writing - review and editing, supervision. FC: writing - review and editing, supervision, validation. GS: project administration, supervision, validation. FF: project administration, writing - review and editing, supervision, validation, guarantor.
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.
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.