The evidence supporting the use of external beam radiotherapy is provided by seven randomized control trials (PORTEC-1rr, PORTEC-2r, GOG99r, Aalders et alr, MRC ASTECr/NCIC CTG EN.5r and Sorbe 2011r).
The meta-analysis by Kong et alr of five of these trials (n=3628) found the addition of adjuvant external beam radiotherapy (with or without vaginal brachytherapy) reduced the risk of locoregional recurrence for high risk Stage 1 endometrial carcinoma (hazard ratio [HR], 0.36; 95% CI, 0.25 to 0.52). This did not translate to an overall survival benefit (HR, 0.99; 95% CI, 0.82 to 1.20) or endometrial cancer-related survival benefit (HR, 0.96; 95% CI, 0.72 to 1.28). High risk data within the analysis was limited, though a benefit of EBRT for high risk women could not be excluded.
© Kong et al 2012r
The PORTEC-1 trial, a Phase III multicentre international randomized trial involving 715 patients with Stage IB, Grade 2 or 3 tumours and FIGO 2007 Stage IC Grade 1 or 2 cancers compared post-operative radiotherapy to no further treatment. All patients underwent TAHBSO without lymphadenectomy. At 10 years with a median follow-up of 52 months, the five year actuarial locoregional recurrence rate was 4% (RT arm) versus 14% (no further treatment arm) (p<0.001). Survival rates were similar between the two arms (81% vs. 85%).
At 15 yearsr, with a median follow up of 13.3 years, the 15 year actuarial locoregional recurrence (LRR) rates were 6% vs 15.5% (p<0.001) and the overall survival was 52% vs 60% (p=0.014) for EBRT and the no additional treatment arms, respectively.
© Creutzberg et al 2011r
EBRT remains indicated only for the 15% of high intermediate risk patients (Grade 3 with deep invasion and/or lymphvascular space invasion, and/or lymphvascular space invasion (LVSI), serous or clear cell histology) or advanced stages. Omitting EBRT for those patients has been shown to result in significantly lower pelvic control rates and may even affect survival. The use of high risk and HIR factors for decisions on adjuvant treatment underlines the critical importance of complete and reproducible pathology evaluation in the treatment of EC patients.r
Role of lymphadenectomy
The role of lymphadenectomy or lymph node sampling in high risk disease is the subject of debate. Lymphadenectomy may guide tailoring of adjuvant treatment and treatment fields by identifying patients with more advanced disease, though there is no demonstrated long term disease specific survival advantage.rr
Role of vault brachytherapy
Recently, the role of adjuvant pelvic RT has been the subject of debate. There has also been and increased interest in using vaginal brachytherapy alone in patients with pathologically negative lymph nodes. Both the GOG 99 (surgically staged) and PORTEC1 (most not surgically staged) trials revealed that most of the initial recurrences for patients with initial uterine confined tumours were limited to the vagina (75% in the control group), prompting an increase in the use of vaginal brachytherapy alone as adjuvant treatment, in select patient subgroups.r
Results from the PORTEC2 trial also confirmed that EBRT could be safely substituted by vaginal brachytherapy (VBT), with VBT reducing GI treatment toxicities and providing better QOL in patients with FIGO (2007) Stage I-IIA (grade 1 and 2) disease.rr
Role of chemotherapy
The role of adjuvant chemoradiotherapy is being examined in three, as yet, unreported randomized control trials. PORTEC-3 and GOG-0249 investigate the use of adjuvant chemotherapy in the high risk group of patients, whilst the GOG-0258 trial investigates the use in advanced stage disease. These trials have completed accrual and results are eagerly awaited. GOG-0249 has been reported in abstract at SGO in 2014.r Early results indicate that there is no advantage to replacing pelvic RT with systemic chemotherapy and vaginal cuff brachytherapy.
The role of sequential adjuvant chemotherapy and radiotherapy was evaluated in a pooled anaylsis of two randomized trials by Hogberg et al.r In Stage I-III endometrial cancer with high risk features, sequential adjuvant chemotherapy and radiotherapy resulted in better progression-free survival than radiotherapy alone (HR 0.63; 95% CI, 0.44 to 0.89). However, Kuoppala et alr found that the addition of chemotherapy did not improve progression-free survival or overall survival compared to radiotherapy alone.
The role of adjuvant chemotherapy irrespective of radiotherapy has been assessed in a 2011 Cochrane meta-analysis by Johnson et al.r Five RCTs compared no additional treatment with additional chemotherapy in the adjuvant setting. Post-operative platinum based chemotherapy was associated with a small benefit in progression free survival and overall survival (HR 0.74 for overall survival).
A second Cochrane analysis by Galaal et alr in 2014 focusing on advanced endometrial cancer (FIGO Stage III/IV) reported moderate quality evidence that chemotherapy increases survival time after primary surgery by approximately 25% relative to radiotherapy. There is limited evidence that it is associated with increased toxicity.
The role of adjuvant chemotherapy either alone or in combination with adjuvant radiotherapy also remains to be determined.