Treatment optimization of pelvic external beam radiation and/or vaginal brachytherapy for patients with stage I to II high-risk Endometrioid adenocarcinoma: a retrospective multi-institutional analysis

Endometrial cancer (EC) is a common gynecological cancer across China, among which endometrioid adenocarcinoma accounts for most [1]. Surgery is the radical curative method. Adjuvant radiotherapy is recommended for specific patient subgroups. The radiation modality consists of pelvic external beam radiotherapy (EBRT) to the pelvis and vaginal brachytherapy (VBT) to the vaginal cuff to clear up microscopic disease in the locoregional area.

The choice of adjuvant radiotherapy modality is risk-based. In 2016, the European Society for Medical Oncology, European Society for Radiotherapy & Oncology and European Society of Gynaecological Oncology (ESMO-ESGO-ESTRO) consensus was devised and classified endometrial cancer into four risk groups according to FIGO stage, depth of myometrial invasion, differentiation grade, tumor type and lymphovascular invasion (LVSI) [2]. Patients with low-risk endometrial cancer have a low recurrence rate and are managed by surgery alone [3]. For patients with intermediate- to high-risk factors, several trials [4‐6] have compared treatment with EBRT to no further therapy and concluded that EBRT significantly reduced the local-regional recurrence rate among these patients. For patients with intermediate or high-intermediate risk factors, prospective randomized studies of slightly different patient populations [7‐9] have demonstrated that VBT provides a comparable reduction in vaginal recurrence to pelvic radiation and that pelvic recurrence rates are low among patients treated with vaginal cuff brachytherapy. VBT is recommended for this patient risk group.

High-risk endometrial cancer is characterized by an increased risk of pelvic recurrence and distant metastases that contribute to the inferior outcomes of this group. However, due to the small number of high-risk patients in previous prospective studies, the optimal mode of radiotherapy for this group of patients remains controversial.

The present study aimed to compare the oncologic outcomes of EBRT, EBRT + VBT and VBT alone for high-risk patients with stage I to II endometrioid adenocarcinoma treated at multiple radiation oncology centers across China.

For stage I to II high-risk endometrioid adenocarcinoma, we reported that compared with VBT alone, adjuvant pelvic external radiation, including EBRT or EBRT combined with VBT, significantly improved the DFS, LRFS and DMFS with good compliance and safety. Overall survival was significantly prolonged in the EBRT + VBT group. There was no significant difference in survival outcomes between the EBRT and EBRT + VBT modalities.

The indication and modality of adjuvant radiotherapy is risk-based. For patients with intermediate or high-intermediate risk factors, prospective trials comparing postoperative EBRT to no adjuvant therapy showed that postoperative radiotherapy increased the local-regional control rate [4‐6]. However, it did not translate into survival benefits. The PORTEC-2 trial [7, 8] directly compared EBRT with vaginal brachytherapy and concluded that VBT was no less effective than EBRT in terms of locoregional control rate and survival outcome. Aalders’ randomized trial [9] found that, compared to VBT, combined EBRT and VBT reduced locoregional recurrences but did not reduce distant metastases or improve survival. Vaginal brachytherapy alone is currently recommended for intermediate- or high-intermediate-risk cases (FIGO stage IA and Grade 3 disease or FIGO stage IB and Grade 1/2 disease).

The use of vaginal brachytherapy alone in the high-risk subset is still under debate. Prospective trials, such as the PORTEC-1 and PORTEC-2 trials, specifically excluded patients with stage IB (FIGO 2009) Grade 3 endometrial cancer, while other studies only included a small number of higher-risk patients. Data from SEER analyses found that among patients with FIGO stage IB and Grade 3 disease who underwent lymph node dissection, all three radiotherapy modalities (EBRT, EBRT + VBT and VBT alone) were superior to no adjuvant treatment, without significant differences among the radiation modalities [10]. Another research from SEER database concluded VBT (with or without EBRT) might confer a cancer-specific survival benefit in stage IB Grade 3 patients. Regional treatment with EBRT and lymph node dissection were critically important in high-grade stage II disease [11]. However, a 2018 published research from SEER database demonstrated there was no difference in disease specific survival when VBT alone was compared with EBRT alone or both for Grade 2–3 stage II disease [12].

In this research, we explored the optimal adjuvant radiotherapy mode for patients with high-risk endometrioid adenocarcinoma after total hysterectomy and bilateral salpingo-oophorectomy and mostly lymphadenectomy (87.2%). In terms of survival, DFS, LRFS and DMFS were significantly higher in patients treated with pelvic external radiation than in those treated with VBT alone. Overall survival was significantly improved in the EBRT + VBT group. Previous studies have shown that, compared with VBT alone, adjuvant external irradiation could reduce the pelvic recurrence rate [13] while controlling vaginal stump relapse. However, in patients with low- or intermediate-risk factors, the locoregional recurrence rate was low due to the low degree of malignancy. Other trials demonstrated that the 5-year locoregional recurrence rate was 6.1% in the ASTEC observation group [4], 6.9% in the Aalder VBT group [9] and 5.1% in the PORTEC2 VBT group [8]. Therefore, substitution of VBT with EBRT + VBT or EBRT could not significantly reduce the locoregional recurrence rate; even if it was reduced, it could not translate into survival benefits [8, 9, 13]. With the upgrade of stage and differentiation, the failure rate of local, regional and distant areas increased. For patients receiving 46 Gy of pelvic radiation in the PORTECT1 trial [14], the actuarial 5-year rates of locoregional relapse were 1 to 3% for IC, Grade 1–2, compared with 14% for stage IC, Grade 3 patients. The five-year distant metastasis rates were 20% for stage IB and Grade 3 tumors and 31% for stage IC and Grade 3 tumors (FIGO 1988). Due to a high degree of malignancy, high-risk patients had high local, pelvic and distant failure rates. Therefore, external irradiation could effectively reduce pelvic and vaginal failure rates and indirectly play a role in reducing distant recurrence, ultimately benefiting survival. In our research, patients in VBT group had older age, higher grade, which were known as potential risk factors on survival and might influence the outcome. A propensity-matched analysis based on stage, grade and age was performed, and results still showed an improved survival towards EBRT.

In this study, we reported that survival was not significantly different for combined EBRT and VBT compared to EBRT alone. VBT was effective in vaginal stump recurrence control, while pelvic radiation offered the possibility of treating the vaginal area in addition to the pelvic lymphatic drainage area. Among deeply myometrial invasive Grade 3 patients (stage IB, G3) after pelvic radiation, the vaginal recurrence rate was only 5% [14]. Among cervical involvement patients (stage II), there was no suggestion that the addition of a vaginal cuff brachytherapy boost to pelvic radiation was beneficial for pelvic control (84% vs. 95%, p = 0.43) or survival [15]. Analysis from SEER demonstrated a non-significant survival difference between combined EBRT and VBT or EBRT alone in stage IB, G3 or stage II patients [11]. Therefore, for high-risk patients, the local-regional control rate of EBRT alone was acceptable. A VBT boost seemed to be unable to improve the pelvic and vaginal control rate or overall survival. However, whether external irradiation should be combined with internal irradiation is still under debate.

Regarding failure mode, the results showed that the locoregional recurrence rate of patients with pelvic irradiation, was significantly lower and that the distant failure rate tended to be lower than that of VBT alone, which emphasized the importance of EBRT in high-risk populations. In addition, distant metastasis was the main cause of failure in this study, which was similar to other studies [16, 17]. Chemotherapy might eliminate systemic micro-metastases, especially distant metastases and benefit survival. Currently, studies had been conducted to evaluate the efficacy of chemotherapy for patients with high-risk endometrial cancer by replacing pelvic radiation or using it as sequential or concurrent adjuvant therapy [18‐21]. The PORTECT3 trial [22] showed for early stage high-risk patients (stage IB patients with Grade 3 or LVSI and stage II patients), chemoradiotherapy didn’t significantly improve 5-year failure-free survival compared to radiotherapy alone. GOG-0249 [23] was designed to study the impact on recurrence-free survival of substitution of VBT with chemotherapy for EBRT among patients with high-risk stage I to II endometrial cancer. However, superiority of VBT with chemotherapy compared to EBRT was not demonstrated. In our research, chemotherapy did not significantly improve survival. Anyway, risk factors such as LVSI and deep myometrial invasion still warranted attention.

In terms of toxicity, acute toxicity was well tolerated in all patients, with only one patient representing a Grade 4 acute response. No adverse reactions of Grade 3 or above were found in the follow-up period after treatment. Currently, many studies are combining molecular targeted therapy with clinicopathological risk factors, which can distinguish patients who require less or more intensified adjuvant treatment [24, 25]. However, more evidence is needed, and randomized trials are necessary.

Some of the limitations were as follows. As a retrospective study, some details about pathology and chemotherapy were not complete. As a muti-center study, clinical and pathology records and treatment standards might not be unified across institutions. Statistically speaking, the number of patients in the three groups were not equally distribute, which might affect the efficiency of statistical calculation. However, this was the largest retrospective multicenter research focusing on selection of EBRT with/or VBT in stage I-II high risk endometrioid adenocarcinoma patients.

For patients with FIGO (2009) stage I to II endometrioid adenocarcinoma, adjuvant radiotherapy including pelvic external radiation significantly improved DFS, LRFS and DMFS with good compliance and safety. Survival outcomes were not significantly different between the EBRT and EBRT + VBT modalities. Further validation of these findings is necessary in the future.