Endometrial cancer remains the most common gynaecologic malignancy in women with 319,600 new cases and 34,700 deaths worldwide and incidence of endometrial cancer in the developed world is on the rise [1]. Majority of patients present early and have an excellent prognosis with 5-year survival rates ranging from 85-90% for Stage I and 80% for Stage II disease [2]. However, patients with Stage III disease have a much poorer outcome with 5-year survival decreasing to 50-65%, with more than half the total number of deaths arising from advanced disease [2,3]. Adjuvant management of Stage III endometrial cancer following surgery remains controversial. The optimal management of this group of patients has yet to be defined. External beam pelvic radiation therapy (EBRT) is indicated to maximize pelvic control, but there is no prospective data to suggest that it improves overall survival. Historically, adjuvant radiotherapy to the whole abdomen and pelvis was found to decrease recurrence [4], however these small and mostly retrospective series also found that the majority of them relapsed distally, paving the way for chemotherapy trials [5].

Systemic chemotherapy has been shown to improve survival outcomes in stage III and IV endometrial cancer compared to whole abdominal irradiation in a prospective phase III randomized controlled trial by the Gynaecologic Oncology Group (GOG) [6]. However, patients who received chemotherapy had a higher pelvic relapse rate (18%). In view of these findings, there has been significant interest in integrating both chemotherapy and radiation therapy in the treatment of this group of patients in order to optimize both local and distant disease control. Several authors have reported that the combined modality of treatment for women with endometrial cancer yielded superior outcomes compared to single modality treatment. This includes 2 phase III randomized trials, the NSGO/EORTC and the MaNGO-ILIADE III [7]. These two studies investigated the role of adjuvant sequential chemotherapy followed by radiation versus radiation alone in 540 women with operated endometrial cancer [7]. The pooled analysis of these two trials demonstrated that the combined modality treatment improves progression-free survival (HR 0.63; p = 0.009) but not overall survival (HR 0.69; p = 0.07). Majority of patients in this study had early stage cancer, with only 19% of patients with Stage III disease. This study, like many other studies, included heterogenous patient population with various disease stages and histological subtypes [7].

Since 2006, sequential chemotherapy followed by radiation (C-RT) has been the standard of care for women with Stage III endometrial cancer following comprehensive surgical staging in our institution. Prior to 2006, our patients were treated with single-modality radiation (RT) treatment only. In this single-institution retrosepctive review, we aim to determine if the outcomes of surgical Stage III (FIGO 1988) endometrial cancer patients treated with adjuvant C-RT were better than those treated with RT only. We have limited our study to patients with exclusively endometrioid adenocarcinoma histology, as these tumours may be biologically different from the non-endometrioid tumours [8].

Institutional Review Board approval was obtained from Singhealth and a single-institution retrospective analysis was performed on patients diagnosed with Stage III uterine cancer in KK Women’s and Children’s Hospital (KKH) between January 2000 to December 2010. The gynaecology oncology database in KKH was utilized to identify patients with surgical Stage III disease. Only pure endometrioid adenocarcinoma was included in the analysis. All histology specimens were reviewed by two pathologists. Casenotes were reviewed and information was extracted and recorded using Microsoft Excel. The standard surveillance practice in our hospital was to review patients every 3 months for the first 3 years, then every 6 months for the next 2 years and annually thereafter.

Statistical analysis was performed using IBM SPSS Statistics software package (Version 19). Various statistical methods such as ANOVA, Pearson Chi-square test were used to compare differences between the groups analyzed. Significant p-value was taken as < 0.05. The Kaplan-Meier model and Log Rank tests were used to compare unit variables among the 2 groups and graphs were plotted to compare the disease-free survival (DFS), cancer-specific survival (CSS) and overall survival (OS). Cox proportion hazard model was used for multivariate analysis.

To date, our study is amongst the largest reported institutional series of patients with Stage III endometrioid endometrial cancer. This study primarily evaluates treatment outcomes of patients treated with sequential chemotherapy and radiation and those patients who received single modality radiation treatment. We have limited our study to patients with surgical Stage III endometrial cancer with endometrioid adenocarcinoma histology only.

In this study, C-RT had good tolerability but failed to improve the 5-year DFS, CSS and OS over single-modality RT. Although there was a trend towards improved OS and CSS in the C-RT group, our patients who received RT did not under-perform; in fact they had excellent survival outcomes with a 5-year DFS of 75.9% and OS of 77.2% that are comparable to other series of Stage III endometrial cancer treated with radiation that reported 5-year DFS and OS rates ranging between 67-76% [9-11].

However, the two treatment groups in our study were imbalanced with regard to tumour grade; more patients in the C-RT group had grade 3 tumours. Klopp et al. reported that grade 3 endometrioid tumours were independent predictors of adverse survival [10] which may confer an unfavourable outcome in the C-RT group. The prognostic significance of tumour grade in Stage III endometrioid endometrial cancer is however far from clear. In contrast to the findings by Klopp et al., grade 3 disease was not an independent predictor of inferior survival in our study and in the study by Lee et al. [11].

The lack of survival benefits with combined modality treatment in our study is consistent with the findings of Secord and colleagues [12]. Their large retrospective series of women with Stage IIIC endometrial cancer failed to demonstrate a survival benefit in women treated with chemotherapy and radiation compared to radiation alone. These findings, however, contradict that of several prospective and retrospective studies which have reported the superiority of the multimodality treatment over single modality radiation treatment in endometrial cancer [6,7,13]. However, many of these studies involved heterogenous patient groups. Investigators often studied patients with Stage III disease together with either high-risk early stage (Stage I and II) disease [7] or with Stage IV disease [6,13], despite their very different prognoses. The extent of surgical staging also varies, for example, less than 30% of patients in the NSGO/EORTC and the MaNGO-ILIADE III study underwent pelvic lymphadenectomy [7]. Moreover, endometrioid and non-endometrioid subtypes are often included in the same studies [7,13,14] despite their marked molecular differences according to study findings by the Cancer Genome Atlas Research Network (TCGA) [8]. Papillary serous endometrial cancers share genomic features with ovarian high grade serous cancers with the propensity for peritoneal spread [15]. It is thus postulated that these cancers are more likely to benefit from chemotherapy than the endometrioid cancers though the benefit of chemotherapy in this subtype still remains unclear. In subgroup analyses of two large randomized studies, the NSGO 9501/EORTC 5591 and MaNGO-ILIADE III trials suggested that the benefit of adjuvant chemotherapy was limited to patients with endometrioid tumours rather than the serous or clear cell tumours (HR 0.83; 95% CI 0.42-1.64; p = 0.59) [7]. The recently published PORTEC-3 study reported that the non-endometrioid tumours derived similar failure free-survival benefit from chemo-radiation when compared to the endometrioid tumours [16]. However, as these analyses were unplanned small subgroup analyses, no definite conclusions can be drawn on the efficacy of adjuvant chemotherapy for serous or clear cell cancers.

For studies limited to the endometrioid endometrial cancers with patient population more akin to our study, the MaNGO-ILIADE III is a phase III randomized study of patients with Stage IIB and III endometrioid adenocarcinoma endometrial cancer. Patients were randomized to receive shorter courses of chemotherapy comprising of three cycles of cisplatin and doxorubicin chemotherapy followed by radiation treatment or radiation alone. The study showed that the combined treatment failed to improve the progression-free survival (HR 0.61; p = 0.10) or the OS (HR 0.74; p = 0.41) [7]. However, the study only managed to recruit 157 of the planned 300 subjects thus making the interpretation of the study results difficult. A retrospective series by Lee LJ and colleagues of 66 patients with Stage IIIC endometrioid endometrial cancer, reported that the combined chemotherapy and radiation therapy independently predicts for improved DFS and OS (HR 0.12, 95% CI 0.03-0.49; p < 0.01; HR 0.20, 95% CI 0.05-0.75, p = 0.02) compared to radiation [11]. The combined treatments involved heterogenous treatment regimens and the decision to add chemotherapy to radiation was at the discretion of the treating clinician. At our institution, combined treatment is routinely offered since 2006 thereby minimizing the patient selection bias of selecting out the fitter patients for the combined treatment and the consequent improved outcomes in patients treated with this modality.

We performed a sub-analysis of survival and treatment outcomes for patients with Stage IIIA and IIIC disease as patients with adnexal involvement may have different treatment or survival outcomes compared to those with nodal involvement. We found that only the CSS differed between the Stage IIIA and IIIC patients, with no differences in OS and DFS (Table 2). In our study, no particular subgroup of Stage III patients (IIIA/IIIB/IIIC) appeared to benefit from the addition of chemotherapy to radiation (Table 3). This is consistent with the results of the Korean KROG 13-17 study by Yoon et al., which concluded that there was no survival benefit in Stage IIIC1 and IIIC2 cancers with either treatment modality [17]. Conflicting results from Lum et al. suggests survival benefit from use of adjuvant chemo-radiation for Stage IIIA patients, however they included non-endometrioid histology subtypes in their retrospective study, which may account for the differing results [14]. Our results also showed that high grade tumours (Grade 3) did not preferentially benefit from the addition of chemotherapy.

In this study, advancing age independently predicts for inferior OS; women above the age of 60 had a 42.5 fold increased risk of death compared to their younger counterparts and presence of residual disease after full surgical staging also independently negatively predicts for poorer OS and CSS, which is consistent with the majority of reports [11]. Grade 3 disease, tumour size, myometrial invasion, lymphovascular invasion, positive peritoneal cytology and nodal involvements did not independently predict for DFS, CSS or OS.

In summary, in our single institution retrospective study of Asian women with surgical Stage III endometrioid endometrial cancer, there was a trend towards C-RT having better OS and CSS over RT alone but this did not reach statistical significance. The lack of statistically significant OS benefit is consistent with the findings of other large randomized studies. Combination chemotherapy and radiation treatment in Stage III endometrial cancers at best only improved the DFS compared with radiotherapy [7,16,17]. The added toxicities of these additional treatment modalities to improve cancer control need to be weighed against the lack of OS improvements. It is clear that not all patients with Stage III endometrial cancer will benefit from adjuvant combination treatment. Future clinical trials should integrate molecular classifiers to enable the risk stratification and study of adjuvant treatment efficacy. The Cancer Genome Atlas Network Research (TCGA) identified four prognostic subgroups based on the POLE mutation, p53 and MSI status [8]. Molecular classifiers such as ProMISE (Protective Molecular Risk Classifier for Endometrial Cancer) and the classifier developed by the Leiden/Translational Research in Postoperative Radiation Therapy for Endometrial Cancer (TransPORTEC) team that are based on the TCGA study show great potential as tools to stratify patient risk in early stage endometrial cancers [22,23]. The development of molecular classifiers for advanced endometrial cancers are urgently required and we eagerly await future results.

This study was approved by the Institutional Review Board (IRB) of Singhealth, Singapore under approval number 2014/837/B. Due to its retrospective nature, approval for waiver of informed consent was sought and permitted during the analysis of data for this study.

The authors would like to express gratitude to all those who supported us during the analysis and writing of this manuscript. We would also like to thank all editors and reviewers who provided valuable feedback during the revision of the manuscript.

All authors have no conflict of interest to declare.