The evidence supporting the use of external beam radiation therapy (EBRT) is provided by seven randomised control trials: PORTEC-1,rr PORTEC-2,r GOG 99,r Aalders et al.,r MRC ASTEC,r NCIC CTG EN.5r and Sorbe 2011r.
The meta-analysis by Kong et al. of five of these trials (n=3628) found the addition of adjuvant EBRT (with or without vaginal brachytherapy) reduced the risk of locoregional recurrence for high risk stage I endometrial carcinoma (hazard ratio [HR], 0.36; 95% CI: 0.25 to 0.52).r 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.
©J Natl Cancer Inst 2012r
The PORTEC-1 trial was a phase III multicentre international randomised trial involving 715 patients with stage IB, grade 2 or 3 tumours and FIGO 2007 stage IC grade 1 or 2 cancers. This trial compared post-operative radiation therapy (RT) to no further treatment (NFT). All patients underwent total abdominal hysterectomy with bilateral salpingo-oophorectomy (TAH-BSO) without lymphadenectomy. At 10 years with a median follow-up of 52 months, the five year actuarial locoregional recurrence rate in the RT arm was 4% vs 14% in the NFT arm (p < 0.001). Survival rates were similar between the two arms; 81% (RT arm) vs 85% (NFT arm). At 15 years, 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 NFT arms, respectively.r
EBRT remains indicated only for the 15% of high intermediate risk (HIR) patients (grade 3 with deep invasion and/or lymphovascular space invasion, and/or lymphovascular space invasion (LVSI), serous or clear cell histology) or advanced staged patients. 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 endometrial cancer patients.rr
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.rrr
Role of vault brachytherapy
Recently, the role of adjuvant pelvic RT has been the subject of debate. There has also been an increased interest in using vaginal brachytherapy (VBT) alone in patients with pathologically negative lymph nodes. Both the GOG 99 (surgically staged) and PORTEC-1 (most not surgically staged) trials revealed most initial recurrences for patients with 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 PORTEC-2 trial also confirmed EBRT could be safely substituted by VBT. VBT reduced gastrointestinal treatment toxicities and provided better quality of life in patients with FIGO 2007 stage I-IIA (grade 1 and 2) disease.rr
Role of chemotherapy
The updated analysis of the multicentre randomised phase 3 trial PORTEC-3 with a median follow-up of 72.6 months for 660 patients has been published.r It demonstrates a significantly improved overall survival and failure-free survival with chemoradiation therapy (CRT) compared to RT alone for high risk endometrial carcinoma; 5 year overall survival 81.4% versus 76.1% (p = 0.034), and 5 year failure-free survival 76.5% versus 69.1% (p = 0.016), respectively. ‘High-risk’ disease was classified as FIGO 2009 stage I, endometrioid grade 3 with deep myometrial invasion or LVSI, or both; stage II or III disease; or stage I-III disease with serous or clear cell histology. In the RT arm patients received RT alone (48.6 Gy in 1.8 Gy fractions given 5 days per week), with brachytherapy boost given if glandular or stromal cervical involvement was present (to equivalent of 14 Gy in 2 Gy fractions). The CRT arm consisted of 2 cycles of cisplatin 50 mg/m2 given concurrently with radiation therapy (day 1 and 22), followed by 4 cycles of carboplatin AUC5 and paclitaxel 175 mg/m2. There was no significant difference in rates of grade 3 adverse events between the two arms at 5 years, and only one grade 4 adverse event in the CRT group (ileus or obstruction).
Patients with stage III disease and serous carcinoma histology were shown to receive the largest benefit from CRT vs RT alone, whereas the benefit for patients with stage I or II disease was small (absolute improvement of 2% in 5 year overall survival and 4% in failure-free survival). For serous carcinoma there was a significant improvement in overall survival (absolute improvement 19%; HR 0.48 (95% CI: 0.24-0.96)) and failure-free survival (absolute improvement 12%; 0.42 (0.22-0.80)). However, absolute numbers are small and it is not clear if this benefit is equivalent for all stages of disease. For those with stage III disease, 5 year overall survival was 78.5% vs 68.5% (p = 0.043) and 5 year failure-free survival was 70.9% vs 58.4% (p = 0.011). This treatment schedule should be discussed with patients, especially those with stage III and/or serous cancers, as part of a shared decision making process.rr
Figure 1: PORTEC-3 trial Kaplan-Meier survival curves for overall survival (A) and failure-free survival (B) in all patients.
© The Lancet 2019r
Figure 2: PORTEC-3 trial Kaplan-Meier survival curves for overall survival (A) and failure-free survival (B) among patients with stage III endometrial cancer, and overall survival (C) and failure-free survival (D) for patients with serous cancer.
© The Lancet 2019r
The randomised control trial GOG 249, in which 601 patients with stage I to II endometrial carcinoma received either EBRT of 45-50.4 Gy over 5 weeks or VBT and three cycles of carboplatin-paclitaxel chemotherapy, was designed as a non-inferiority trial. It did not demonstrate a progression-free survival advantage by replacing pelvic RT with systemic therapy and vaginal cuff brachytherapy.r With EBRT, pelvic control was better and acute toxicity was demonstrated to be lower. The authors concluded that pelvic EBRT remains the standard of care for these patients.
GOG 258 is another recently published randomised phase 3 trial which assessed whether 6 cycles of platinum-based chemotherapy plus RT offers longer relapse-free survival than six cycles of combination chemotherapy alone for patients with stage III or IVA endometrial cancer.r This study, with 736 patients and a median follow-up period of 47 months, was also designed as a non-inferiority trial and did not show supporting evidence for use of CRT over chemotherapy alone in this advanced-disease cohort. The relapse-free survival at 60 months was 59% for the CRT group vs 58% for the chemotherapy only group. There was a significantly lower incidence of vaginal (2% vs 7%), pelvic and para-aortic nodal recurrence (11 vs 20%) in the CRT group, however the distant recurrence rate was higher (27% vs 21%). There was no significant difference in rates of grade 3-5 adverse events between the two groups. The authors note, sequencing of chemotherapy and/or RT remains the greatest issue for this cohort of patients. Creutzberg et al. note the 5-year relapse-free survival rates were similar to those seen in the RT arm of the PORTEC-3 trial. However, comparison of outcomes between the CRT arms between the two trials (using the same schedule) shows a lower 5-year failure free survival in GOG 258 for stage III disease (58% vs 69%).r
The role of sequential adjuvant chemotherapy and radiation therapy was evaluated in a pooled anaylsis of two randomised trials by Hogberg et al.r In stage I-III endometrial cancer with high risk features, sequential adjuvant chemotherapy and RT resulted in better progression-free survival than radiation therapy alone (HR 0.63; 95% CI: 0.44 to 0.89). However, Kuoppala et al. found the addition of chemotherapy did not improve progression-free survival or overall survival compared to radiation therapy alone.r
The role of adjuvant chemotherapy irrespective of RT has been assessed in a 2011 Cochrane meta-analysis by Johnson et al.r Five randomised control trials 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 al. 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 RT. There is limited evidence that it is associated with increased toxicity.r
The role of adjuvant chemotherapy either alone or in combination with adjuvant radiation therapy also remains to be determined.