Surgery and postoperative radiotherapy versus surgery alone for patients with stage-1 endometrial carcinoma: multicentre randomised trial

Summary

Background

Postoperative radiotherapy for International Federation of Gynaecology and Obstetrics (FIGO) stage-1 endometrial carcinoma is a subject of controversy due to the low relapse rate and the lack of data from randomised trials. We did a multicentre prospective randomised trial to find whether postoperative pelvic radiotherapy improves locoregional control and survival for patients with stage-1 endometrial carcinoma

Methods

Patients with stage-1 endometrial carcinoma (grade 1 with deep [≥50%] myometrial invasion, grade 2 with any invasion, or grade 3 with superficial [<50%] invasion) were enrolled. After total abdominal hysterectomy and bilateral salpingo-oophorectomy, without lymphadenectomy, 715 patients from 19 radiation oncology centres were randomised to pelvic radiotherapy (46 Gy) or no further treatment. The primary study endpoints were locoregional recurrence and death, with treatment-related morbidity and survival after relapse as secondary endpoints.

Findings

Analysis was done according to the intention-to-treat principle. Of the 715 patients, 714 could be evaluated. The median duration of follow-up was 52 months. 5-year actuarial locoregional recurrence rates were 4% in the radiotherapy group and 14% in the control group (p<0·001). Actuarial 5-year overall survival rates were similar in the two groups: 81% (radiotherapy) and 85% (controls), p=0·31. Endometrial-cancer-related death rates were 9% in the radiotherapy group and 6% in the control group (p=0·37). Treatment-related complications occurred in 25% of radiotherapy patients, and in 6% of the controls (p<0·0001). Two-thirds of the complications were grade 1. Grade 3–4 complications were seen in eight patients, of which seven were in the radiotherapy group (2%). 2-year survival after vaginal recurrence was 79%, in contrast to 21% after pelvic recurrence or distant metastases. Survival after relapse was significantly (p=0·02) better for patients in the control group. Multivariate analysis showed that for locoregional recurrence, radiotherapy and age below 60 years were significant favourable prognostic factors.

Interpretation

Postoperative radiotherapy in stage-1 endometrial carcinoma reduces locoregional recurrence but has no impact on overall survival. Radiotherapy increases treatment-related morbidity. Postoperative radiotherapy is not indicated in patients with stage-1 endometrial carcinoma below 60 years and patients with grade-2 tumours with superficial invasion.

Introduction

Endometrial carcinoma is the most common gynaecological cancer, having an incidence in western countries of 15–20 per 100 000 women per year.¹ 75–80% of endometrial cancers are diagnosed at an early stage (International Federation of Gynaecology and Obstetrics [FIGO] stage I). The most significant prognostic factors are tumour stage, histological grade, and depth of myometrial invasion. Others are age, histological type, peritoneal cytology, vascular space invasion, progesterone receptor activity, menopausal stage, and uterine size.2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 Total abdominal hysterectomy and bilateral salpingooophorectomy is the cornerstone of treatment. If risk factors are present, that is, myometrial invasion to 50% or more of the myometrial width and/or grade 2 or 3 histology, pelvic radiotherapy is indicated to reduce the risk of pelvic relapse. The value of postoperative radiotherapy in the treatment of patients with stage-1 endometrial carcinoma is, however, controversial due to a lack of data from randomised studies and the low relapse rate.¹⁴ Patients with stage-1 endometrial carcinoma treated with surgery and postoperative radiotherapy have a 5-year overall survival of 80–90%, a 5-year cancer-specific survival of 90–95%, and locoregional recurrence rates of 4–8%.2, 5, 6, 9, 12, 15, 20 However, patients with grade-3 tumours with deep myometrial invasion have a much higher risk of relapse.2, 5, 7, 19 Only one randomised study has been reported, in which 540 women who had had postoperative vaginal radiotherapy were randomly assigned to additional pelvic radiotherapy or observation.² Although pelvic radiotherapy reduced vaginal and pelvic recurrence (2% vs 7%), more distant metastases were found in the pelvic radiotherapy group (10% vs 5%), and survival was not improved (89% vs 91% at 5-years). Only the subgroup with grade-3 tumours with deep (≥50%) invasion showed both improved local control and survival after additional pelvic radiotherapy.

In retrospective studies of stage-1 endometrial carcinoma treated surgically followed by radiotherapy in case of poor prognostic factors, relapse rates of 15–20% are reported, of which 4–7% are locoregional recurrences and 7–17% distant metastases.5, 6, 9, 12, 15, 16, 17, 18, 19, 20, 21 Most locoregional relapses are in the vagina, mainly in the vaginal vault. In previously unirradiated patients the salvage rate for isolated vaginal relapse is 40–80%.8, 14, 15, 22, 23, 24, 25, 26, 27 The salvage rate of extravaginal pelvic relapse is low, ranging from less than 5% for patients who have received previous pelvic radiotherapy to 20–30% in those not previously irradiated.14, 15, 23, 27, 28 In the Gynaecological Oncology Group (GOG) staging study,⁴ the risk of pelvic node metastases in surgical stage-1 endometrial carcinoma was less than 10%, except for the subgroup with grade-3 tumours, in whom the risk was 18%.

A multicentre prospective randomised trial was initiated to establish the role of postoperative pelvic radiotherapy in FIGO stage-1 endometrial carcinoma, based on the following rationale: the locoregional relapse rate of stage-1 endometrial cancer is low; the efficacy of radiotherapy has never been established in a randomised trial; lymphadenectomy studies4, 29 show an incidence of pelvic lymph node involvement in surgical stage-1 endometrial carcinoma of less than 10%; the salvage rate of vaginal relapses in previously unirradiated patients is high. Patients with grade-1 tumours with deep myometrial invasion, grade-2 tumours with any invasion, or grade-3 tumours with superficial invasion were randomly assigned to either postoperative pelvic radiotherapy or no further treatment. The objectives of the Post Operative Radiation Therapy in Endometrial Carcinoma (PORTEC) study were to compare locoregional control, overall survival, and treatment-related morbidity of patients with stage-1 endometrial carcinoma, treated with postoperative pelvic radiotherapy or surgery alone.