Elsevier

The Lancet

Volume 375, Issue 9717, 6–12 March 2010, Pages 816-823
The Lancet

Articles
Vaginal brachytherapy versus pelvic external beam radiotherapy for patients with endometrial cancer of high-intermediate risk (PORTEC-2): an open-label, non-inferiority, randomised trial

https://doi.org/10.1016/S0140-6736(09)62163-2Get rights and content

Summary

Background

After surgery for intermediate-risk endometrial carcinoma, the vagina is the most frequent site of recurrence. This study established whether vaginal brachytherapy (VBT) is as effective as pelvic external beam radiotherapy (EBRT) in prevention of vaginal recurrence, with fewer adverse effects and improved quality of life.

Methods

In this open-label, non-inferiority, randomised trial undertaken in 19 Dutch radiation oncology centres, 427 patients with stage I or IIA endometrial carcinoma with features of high-intermediate risk were randomly assigned by a computer-generated, biased coin minimisation procedure to pelvic EBRT (46 Gy in 23 fractions; n=214) or VBT (21 Gy high-dose rate in three fractions, or 30 Gy low-dose rate; n=213). All investigators were masked to the assignment of treatment group. The primary endpoint was vaginal recurrence. The predefined non-inferiority margin was an absolute difference of 6% in vaginal recurrence. Analysis was by intention to treat, with competing risk methods. The study is registered, number ISRCTN16228756.

Findings

At median follow-up of 45 months (range 18–78), three vaginal recurrences had been diagnosed after VBT and four after EBRT. Estimated 5-year rates of vaginal recurrence were 1·8% (95% CI 0·6–5·9) for VBT and 1·6% (0·5–4·9) for EBRT (hazard ratio [HR] 0·78, 95% CI 0·17–3·49; p=0·74). 5-year rates of locoregional relapse (vaginal or pelvic recurrence, or both) were 5·1% (2·8–9·6) for VBT and 2·1% (0·8–5·8) for EBRT (HR 2·08, 0·71–6·09; p=0·17). 1·5% (0·5–4·5) versus 0·5% (0·1–3·4) of patients presented with isolated pelvic recurrence (HR 3·10, 0·32–29·9; p=0·30), and rates of distant metastases were similar (8·3% [5·1–13·4] vs 5·7% [3·3–9·9]; HR 1·32, 0·63–2·74; p=0·46). We recorded no differences in overall (84·8% [95% CI 79·3–90·3] vs 79·6% [71·2–88·0]; HR 1·17, 0·69–1·98; p=0·57) or disease-free survival (82·7% [76·9–88·6] vs 78·1% [69·7–86·5]; HR 1·09, 0·66–1·78; p=0·74). Rates of acute grade 1–2 gastrointestinal toxicity were significantly lower in the VBT group than in the EBRT group at completion of radiotherapy (12·6% [27/215] vs 53·8% [112/208]).

Interpretation

VBT is effective in ensuring vaginal control, with fewer gastrointestinal toxic effects than with EBRT. VBT should be the adjuvant treatment of choice for patients with endometrial carcinoma of high-intermediate risk.

Funding

Dutch Cancer Society.

Introduction

Endometrial carcinoma is the most common gynaecological malignant disease in postmenopausal women in developed countries.1 About 80% of patients present with early stage disease (International Federation of Gynecology and Obstetrics [FIGO] stage I, limited to the uterine corpus) and have a favourable prognosis. Surgery consisting of total abdominal hysterectomy and bilateral salpingo-oophorectomy is the basis of treatment.

Both the first Post Operative Radiation Therapy in Endometrial Carcinoma (PORTEC-1) trial2, 3 and the Gynecological Oncology Group (GOG) 99 trial4 compared pelvic external beam radiotherapy (EBRT) with no additional treatment for patients with stage I endometrial carcinoma, and showed that EBRT significantly reduced the rate of locoregional (vaginal or pelvic, or both) recurrence. Both trials defined a so-called group of high-intermediate risk that showed the largest absolute reduction of locoregional recurrence after EBRT. In PORTEC-1, major risk factors for recurrence were invasion in the outer half of the myometrium, grade 3 histology, and age greater than 60 years.2, 3 For patients at high-intermediate risk with two of these three major risk factors, locoregional recurrence at 5 years was reduced from 23% to 5% after EBRT.2, 3 In GOG 99, EBRT provided a 58% hazard reduction of 4-year cumulative recurrence in the group at high-intermediate risk (from 27% to 13%), and reduction of isolated initial local recurrence from 13% to 5%.4 In both trials this reduction was mainly caused by reduction of vaginal recurrence, which accounted for 75% of locoregional recurrence in the group receiving no additional treatment. EBRT did not improve overall survival, and rates of distant metastases were similar. In PORTEC-1, adverse effects were recorded in 26% of patients receiving EBRT, predominantly mild gastrointestinal toxic effects.5

Retrospective studies reported vaginal brachytherapy (VBT) to be very effective in prevention of vaginal recurrence.6, 7, 8, 9, 10 The randomised PORTEC-2 trial was started to investigate whether VBT would be equally effective as EBRT in reduction of vaginal recurrence, with fewer treatment-related toxic effects and improved quality of life. Analysis of quality of life reported by patients in PORTEC-2 during the first 2 years after treatment has shown that those who had received EBRT reported significantly more, clinically relevant gastrointestinal symptoms, especially diarrhoea,11 resulting in restriction of daily activities and decreased social functioning.

This study aimed to compare outcomes and adverse effects after VBT and EBRT, and to establish optimum adjuvant treatment for patients with endometrial carcinoma of high-intermediate risk.

Section snippets

Patient selection and eligibility criteria

The PORTEC-2 trial was a multicentre randomised trial, in which 19 of the 21 Dutch radiation oncology centres participated. The study was undertaken between May 27, 2002, and Sept 25, 2006. Patients were assessed and operated on by their regional gynaecologist. Initial assessment included pelvic examination and endometrial tissue biopsy. Preoperative assessment included chest radiography and haematology and chemistry tests. During surgery a peritoneal cytology specimen was obtained and

Results

Figure 1 shows the trial profile. 427 patients were randomly allocated to EBRT (n=214) or VBT (n=213). Data were frozen for analysis on May 19, 2009, and all patients were entered in the intention-to-treat analysis. Patient and tumour characteristics were well balanced between the groups (table 1). Table 2 shows radiotherapy details.

23 (5%) protocol violations occurred, of which 12 (3%) were major (seven in EBRT group, five in VBT group). 11 patients did not receive the allocated treatment, one

Discussion

The PORTEC-2 trial compared the efficacy and toxicity of EBRT and VBT for endometrial cancer of high-intermediate risk. At a median follow-up of 45 months, very few vaginal recurrences occurred in both treatment groups, showing VBT to be very effective in ensuring of local control. The vaginal recurrence rate after EBRT is very similar to the rate of 2·2% at 5 years in the first PORTEC trial in patients at intermediate risk, showing consistency of this main finding in both trials.2

After

References (23)

Cited by (944)

View all citing articles on Scopus
View full text