Adjuvant Radiotherapy in High-Risk Endometrial Cancer
For high-risk endometrial cancer (stage I grade 3 with ≥50% myometrial invasion, stage II-III, or non-endometrioid histologies), combined chemotherapy and radiotherapy is the preferred adjuvant treatment, providing superior failure-free survival and cancer-specific survival compared to radiotherapy alone. 1, 2
Risk-Stratified Treatment Approach
High-Risk Endometrioid Disease (Stage I Grade 3, ≥50% Myometrial Invasion)
Combined modality therapy with chemotherapy plus radiotherapy reduces the risk of relapse or death by 36% (HR 0.64,95% CI 0.41-0.99; P=0.04) compared to radiotherapy alone. 1, 3 Cancer-specific survival is significantly improved with combined treatment (HR 0.55,95% CI 0.35-0.88; P=0.01). 1, 3
The standard regimen consists of:
- Pelvic external beam radiotherapy (48.6 Gy in 1.8 Gy fractions) with concurrent cisplatin 50 mg/m² for 2 cycles, followed by 4 cycles of carboplatin AUC5 and paclitaxel 175 mg/m². 2
- Alternative: Carboplatin/paclitaxel for 3-6 cycles with radiotherapy. 3
High-Intermediate Risk Disease
For patients with stage I grade 3 with <50% myometrial invasion, or grade 1-2 with unequivocally positive LVSI and deep invasion:
If surgical nodal staging performed and node-negative:
- Adjuvant vaginal brachytherapy is recommended to decrease vaginal recurrence. 1
- Observation is an acceptable alternative. 1
If no surgical nodal staging:
- Pelvic external beam radiotherapy is recommended for LVSI unequivocally positive to decrease pelvic recurrence. 1
- Vaginal brachytherapy alone for grade 3 with negative LVSI. 1
Stage II Disease
- Stage IIA: Treat according to stage I risk stratification. 1
- Stage IIB (cervical stromal invasion): Pelvic external beam radiotherapy with or without vaginal brachytherapy boost is recommended. 1, 4
Stage III Disease
Combined chemotherapy and radiotherapy is strongly recommended for stage III disease, as it provides both improved locoregional control and reduced distant metastases. 1 The PORTEC-3 trial demonstrated 5-year failure-free survival of 75.5% with chemoradiotherapy versus 68.6% with radiotherapy alone (HR 0.71,95% CI 0.53-0.95; P=0.022). 2
Non-Endometrioid Histologies (Serous, Clear Cell, Carcinosarcoma)
These aggressive histologies require combined chemotherapy and radiotherapy regardless of stage, given significantly higher recurrence rates than endometrioid types. 3, 5 Standard treatment includes 6 cycles of carboplatin/paclitaxel with pelvic radiotherapy. 3
Radiotherapy Alone: Limited Role
Pelvic external beam radiotherapy alone significantly reduces locoregional recurrence but does NOT improve overall survival in intermediate-risk disease. 1, 6, 7 Three large randomized trials (PORTEC-1, GOG-99, ASTEC) consistently demonstrated this finding. 1
For intermediate-risk disease (stage I grade 1-2 with ≥50% myometrial invasion, LVSI negative), vaginal brachytherapy alone is superior to pelvic external beam radiotherapy, providing equivalent local control with better quality of life and less toxicity. 1, 3, 4 The PORTEC-2 trial definitively established this approach. 3, 4
Chemotherapy Considerations
Platinum-based chemotherapy should be strongly considered in stage I grade 3 with adverse risk factors including advanced age, lymphovascular space invasion, and high tumor volume. 1, 3
Historical trials comparing chemotherapy alone versus radiotherapy alone (Japanese JGOG-2033, Italian Maggi trial) showed no difference in overall survival or progression-free survival. 1 However, these trials preceded the era of combined modality therapy.
Critical Pitfalls to Avoid
Common errors include:
- Overtreatment with pelvic external beam radiotherapy when vaginal brachytherapy suffices for intermediate-risk disease. 3
- Undertreatment of high-risk disease with radiotherapy alone when combined modality therapy is indicated. 3, 2
- Failing to recognize that grade 3 histology or positive LVSI warrants more aggressive adjuvant treatment. 3
- Using progestins in adjuvant treatment—this does NOT improve survival and is NOT recommended (Level I evidence). 1, 3, 8
Toxicity Considerations
Grade 3 or worse adverse events occur in 60% of patients receiving chemoradiotherapy versus 12% with radiotherapy alone. 2 Persistent grade 2 or worse neuropathy occurs in 8% at 3 years with chemoradiotherapy versus 1% with radiotherapy alone. 2 These toxicity profiles must be weighed against the survival benefits, particularly in elderly or frail patients.
Evidence Strength
The recommendation for combined modality therapy in high-risk disease is based on two randomized trials (NSGO-EC-9501/EORTC-55991 and MaNGO ILIADE-III) and the PORTEC-3 trial, representing the highest quality evidence available. 1, 2 The PORTEC-3 trial, published in 2018, is the most recent and definitive study, though it showed improved failure-free survival but not overall survival at 5 years. 2