In PORTEC-1 (postoperative radiation therapy in endometrial carcinoma) trial, patients with stage I (G1 with outer-half myometrial invasion, i.e., >50 % myometrial invasion, G2 with any invasion, or grade 3 with superficial myometrial invasion, i.e., <50 % myometrial invasion) were randomized to pelvic EBRT (46 Gy) or no further treatment after surgery (total abdominal hysterectomy and bilateral salpingo-oophorectomy without lymphadenectomy). At a median follow-up of 52 months, 5-year locoregional recurrence rates were 4 % in the radiotherapy group and 14 % in the control group (p < 0 · 001), while the 5-year overall survival rates were similar in the two groups: 81 % (radiotherapy) and 85 % (controls), p = 0 · 31. Most (73 %) of the local recurrences were restricted to the vagina. The overall incidence of distant metastases was similar in both groups: 8 % in the radiotherapy group and 7 % in the control group. Treatment-related complications occurred in 25 % of radiotherapy patients and in 6 % of controls (p < 0 · 0001). It was concluded from this trial that postoperative EBRT for stage I patients (with high-risk features for locoregional relapse) reduced locoregional recurrence but has no impact on overall survival (OS) [8, 9]. Additionally, EBRT increased treatment-related morbidity [9].

In the GOG 99 (Gynecologic Oncology Group) trial, adjuvant whole pelvic EBRT (50.4 Gy) for stage IB, IC, and II (occult) patients had a substantial positive impact on 2-year cumulative recurrence (12 % in the observation group and 3 % in the EBRT group; p = 0.007). The treatment difference was particularly evident among the high-intermediate-risk group subgroup (2 years in cumulative recurrence was 26 % in the observation arm versus 6 % in the RT arm). Thus adjuvant radiation resulted in 58 % reduction in the hazard for any relapse in high-intermediate-risk group. The estimated 4-year OS did not differ between the observation and the EBRT groups (86 % versus 92 %; p = 0.56) [5].

In the ASTEC/EN.5 trial, patients with high-intermediate and high risk (including stages IA and IB grade 3, IC of all grades, and serous or clear cell histology) were randomized to receive postoperative adjuvant EBRT (40–46 Gy) or observation. At a median follow-up of 58 months, the overall survival with EBRT was no better than observation with a hazard ratio 1 · 05 (95 % CI 0 · 75–1 · 48; p = 0 · 77). Despite randomizing high-risk group women, the isolated locoregional recurrence rate in ASTEC/EN.5 (5-year cumulative incidence 6 · 1 % in observation versus 3 · 2 % in external beam radiotherapy arm) is similar or lower than that seen in other trials recruiting low-risk/intermediate-risk women. Only 35 % (42 of 120) of the total recurrences were isolated local recurrence, and the small reduction in isolated local recurrence (absolute difference of 2.9 %) did not translate into an effect on overall or recurrence-free survival [10]. The ASTEC/EN.5 findings suggested that brachytherapy might be an effective strategy for local control with less toxicity compared to EBRT, and this formed the basis of PORTEC-2 trial.

In PORTEC-2 trial, patients with high-intermediate risk (age >60 years and stage IC G1 or G2 disease, stage IB grade 3 disease, or any age and stage IIA disease) were randomized to receive pelvic EBRT (46 Gy) or VBT (21 Gy high-dose rate or 30 Gy low-dose rate). Five-year locoregional recurrence rate (EBRT versus VBT = 2.1 % versus 5.1 %; p = 0.17), OS (79.6 % versus 84.8 %; p = 0.57), or disease-free survival (DFS, 78.1 % versus 82.7 %; p = 0.74) did not differ between the two groups. This trial concluded that VBT is effective in ensuring vaginal control and a better quality of life, with fewer gastrointestinal toxic effects (12.6 %) than with EBRT (53.8 %) [11, 12].

The updated systematic review and meta-analysis confirms that adjuvant EBRT reduces locoregional recurrence but does not improve CSS (cancer-specific survival) or OS in stage I endometrial carcinoma. EBRT is associated with statistically significantly increased morbidity and a reduction in quality of life [13]. Despite the inclusion of differing risk profiles of patients, the rates of death from disease were similar in women participating in the PORTEC-1, PORTEC-2, and ASTEC/EN.5. These unsatisfying outcomes are the rationale for the adjuvant systemic therapy in early-stage endometrial cancer with high-risk factors.

Thus it can be seen that adjuvant radiation therapy in early-stage endometrial cancer reduces locoregional recurrence rates but has no impact on overall survival. This is at least partly attributable to the excellent outcome of majority of early-stage patients such that any benefits are incremental and hard to prove and one of the reasons why there are continuing questions about the role and place of this modality in the management of these patients. This has also stimulated continuing interest in exploring systemic therapy options in order to impact survival outcomes.

Hirai et al. assessed the efficacy of adjuvant chemotherapy in stage I endometrial cancer; 251 primary surgically treated stage I patients were studied [14]. Of 54 patients with lymphovascular space invasion, 10-year survival rate in patients who had surgery followed by adjuvant chemotherapy (n = 23) was 86 %, while in patients who had surgery alone (n = 31), it was 59 %. This difference in outcome was statistically significant (p = 0.02). This trial also indicated that lymphovascular space invasion is the most significant prognostic factor in both 5- and 10-year survival rates (p = 0.001 at both times), and stage/depth of invasion is significant for the 10-year survival rate (p = 0.04).

A retrospective analysis of 170 cases with endometrioid histology, FIGO stage I or II, was done by Akoi et al. Non-endometrioid histologic subtypes such as serous and clear cell subtypes were excluded. Surgery was followed by adjuvant postoperative chemotherapy, consisting of intravenous cisplatin (70 mg/m²), doxorubicin (40 mg/m²), and cyclophosphamide (500 mg/ m²) (CAP) given every 4 weeks for three courses in 41 patients. No whole pelvic or vaginal radiation was given in these patients. To select a high-risk subgroup that might benefit from adjuvant systemic therapy in patients with FIGO stage I or II, the investigators divided early-stage patients into low-risk group and high-risk group based on four prognostic factors (LVSI, tumor grade, cervical invasion, and depth of myometrial invasion). Five-year disease-free survival and overall survival in the low-risk group (with 0 or 1 prognostic factor) were 97.4 % and 100 %, respectively. In the high-risk group, disease-free survival and overall survival rates were significantly lower as compared to the low-risk group (P < 0.001). Among high-risk patients, the 5-year DFS and OS were 88.5 % and 95.2 % in 26 patients treated with adjuvant chemotherapy and 50.0 % and 62.5 % in eight cases who underwent only surgery (p = 0.0150 and p = 0.0226, respectively). This trial concluded that the high-risk group of patients should be treated with postoperative adjuvant CAP to decrease distant failure and improve prognosis [15]. The relatively small number of patients and the retrospective nature of this study limit the power of these conclusions.

Kodama et al. conducted a retrospective study in 167 patients with surgically staged IB–II and IIIA (positive peritoneal cytology only) to assess the efficacy of adjuvant chemotherapy [16]. Of these, 58 patients (34.7 %) underwent combination chemotherapy comprising cyclophosphamide-epirubicin-cisplatin or paclitaxel-pirarubicin-carboplatin. Adjuvant chemotherapy was administered to 14 of 23 patients with histologic grade 3 tumors. The 5-year OS rate for these patients was 92.3 %, significantly higher than that in patients who had not received chemotherapy (50.0 %). The authors concluded that histologic grade 3 is an independent prognostic factor in patients with endometrial cancer and adjuvant chemotherapy might improve survival in these patients.

The abovementioned studies suggest that adjuvant chemotherapy might improve survival in early-stage endometrial cancer patients with high-risk factors. However, these studies lack a well-designed control arm, trials subdivided early-stage patients in different ways, and the numbers of patients included are small. Because of this heterogeneity, it is difficult to confidently recommend adjuvant chemotherapy in early-stage patients.

In a Finnish trial, patients with stages IA–IB G3 (n = 28) or IC–IIIA grades 1–3 (n = 128) were randomized to receive pelvic EBRT (56 Gy) or chemoradiotherapy [EBRT combined with three courses of cisplatin (50 mg/m²)-epirubicin (60 mg/m²)-cyclophosphamide (500 mg/m²)]. The first cycle was given immediately after the surgery. The second one was carried out during the pause in radiotherapy and the last within 2 weeks after the completion of the second radiation course. The disease-specific 5-year OS was 84.7 % in the EBRT group versus 82.1 % in the CTRT group (p = 0.148). The median disease-free survival was 18 (range 9–36) months with EBRT and 25 (range 12–49) months with CTRT (p = 0.134), respectively. The addition of CT failed to improve OS or the recurrence rate, but the patients in RT group lived a median of 23 months as compared to 37 months in CTRT group (p = 0.148). Chemotherapy was reasonably well tolerated. Grade 3/4 leucopenia was seen in 50 % patients but only 6.2 % of the patients had grade 3 infection. While designing this trial, it was presumed that the 5-year survival rate in the radiation-only group would be 60 %, and the study was powered to detect a 20 % difference in the 5-year survival in favor of the chemotherapy group (i.e., from 60 % to 80 %). In fact, the 5-year disease-free survival in the radiotherapy-only group was 25 % better than expected (84.7 %). Thus this trial was underpowered for the actual survival differences between the arms and a smaller, but clinically meaningful, benefit of adjuvant chemotherapy cannot be ruled out [17].

The EORTC 55991 trial included stage I–IIIC patients and compared EBRT with or without VBT plus cisplatin-based multi-agent chemotherapy versus EBRT with or without VBT. Several CT regimens were allowed – CAP, AP, or paclitaxel plus carboplatin for a total of four cycles. RT was given before CT in the sequential radiotherapy and chemotherapy arm. The 5-year PFS and OS were better for the combined radiotherapy plus chemotherapy arm (HR = 0.62, 95 % CI = 0.40–0.97, p = 0.03, and HR = 0.65, 95 %CI = 0.40–1.06, p = 0.08, respectively). Despite the fact that 27 % of the patients who were randomized to CT-RT arm did not received chemotherapy, radiotherapy plus chemotherapy was still found to be better than RT alone as adjuvant therapy for patients with high-risk early endometrial cancer [18]. Similar trial (ILIADE-III) was performed by the Gynecologic Oncology Group at the Mario Negri Gynecologic Oncology group (MaNGO) which compared pelvic RT with combined radiotherapy plus chemotherapy in stage IIB and IIIA–C disease. In this trial chemotherapy was given before radiation therapy and consisted of three courses of cisplatin (50 mg/m²) and doxorubicin (60 mg/m²) at 3-week interval. Since neither trial was large enough to show a statistically significant benefit, the results were combined for a total of 534 patients randomized to receive pelvic radiotherapy with or without chemotherapy. In the combined analysis, the estimate of risk for relapse or death was similar but with narrower confidence limits (HR 0.63, CI 0.44–0.89; p = 0.009). Overall survival approached statistical significance (HR 0.69, CI 0.46–1.03; p = 0.07). Combined modality seems better from these trials, but these studies had few limitations – the eligibility criteria allowed inclusion of patients with several risk levels of the disease, different CT regimens were used, and lymphadenectomy was optional and performed in a fraction of the patients [18].

These studies suggest that addition of adjuvant chemotherapy to radiation therapy improves progression-free survival in early-stage endometrial cancer with high-risk features.

In the Japanese Gynecologic Oncology Group (JGOG) randomized trial, stage IC–IIIC patients with deep (≥50 %) myometrial invasion and <75 years of age received adjuvant pelvic RT (45–50 Gy EBRT) or cyclophosphamide (333 mg/m²)-doxorubicin (40 mg/m²)-cisplatin (50 mg/m²) for three or more courses. The majority (77.4 %) of patients had stage IC or II lesions. The 5-year PFS in the EBRT and chemotherapy groups was 83.5 % and 81.8 %, while the 5-year OS was 85.3 % and 86.7 %, respectively. These rates were not significantly different in intermediate-risk group defined as stage IC patients under 70 years old with G1/2 endometrioid adenocarcinoma. However, among 120 patients in high-intermediate-risk group defined as stage IC in patients over 70 years old or with G3 endometrioid adenocarcinoma or stage II or IIIA (positive cytology), the chemotherapy group had a significantly higher 5-year PFS rate (83.8 % versus 66.2 %, log-rank test p = 0.024, hazard ratio 0.44) and higher 5-year OS rate (89.7 % versus 73.6 %, log-rank test p = 0.006, hazard ratio 0.24). Moreover, adverse effects were not significantly increased in the CAP arm when compared with those in the EBRT arm. The authors concluded that adjuvant platinum-based combination chemotherapy is a suitable alternative to radiotherapy for intermediate-risk endometrial cancer. In patients with high-intermediate-risk endometrial cancers, the adjuvant chemotherapy improved the prognosis significantly compared to pelvic radiation. The above results were derived from post hoc analysis, and hence the validity is limited [19]. Demonstration of a true advantage of chemotherapy requires a large-scale randomized controlled trial with stratification for risk factors prior to randomization.