What is the role of adjuvant radiation therapy (RT) in the treatment of endometrial cancer?

Adjuvant Radiation Therapy in Endometrial Cancer

Adjuvant radiation therapy in endometrial cancer should be tailored based on disease stage, histologic grade, depth of myometrial invasion, and lymphovascular space invasion, with vaginal brachytherapy alone recommended for most patients with uterine-confined disease and combined modality treatment for advanced stages. 1

Risk Stratification for Adjuvant Therapy

Low-Risk Disease

• Patients with grade 1-2 endometrioid tumors with no invasion or <50% myometrial invasion and no other high-risk features can safely be observed after hysterectomy without adjuvant therapy 1, 2
• No evidence supports routine use of adjuvant treatment for patients with disease confined to the uterus 1

Intermediate-Risk Disease

• For patients with intermediate-risk disease (stage I endometrioid, grade 1-2, ≥50% myometrial invasion, LVSI negative), adjuvant vaginal brachytherapy is recommended 1, 2
• PORTEC-2 trial demonstrated that vaginal brachytherapy alone provides equivalent vaginal and pelvic control rates compared to external beam radiation therapy (EBRT) with less toxicity 1

High-Intermediate Risk Disease

• High-intermediate risk patients (defined by GOG-99 and PORTEC-1 trials as having combinations of age, deep myometrial invasion, grade 3 histology, and LVSI) benefit from adjuvant radiation 1
• Vaginal brachytherapy is preferred over EBRT for most high-intermediate risk patients due to similar efficacy with reduced toxicity 1, 2
• GOG-249 trial showed no superiority of vaginal brachytherapy plus chemotherapy over pelvic radiation alone in high-intermediate and high-risk early-stage disease 3

High-Risk Disease

• For high-risk stage I disease (grade 3 with ≥50% myometrial invasion), adjuvant EBRT with limited fields is recommended to decrease locoregional recurrence 1
• For patients with high-risk histologies (serous, clear cell, carcinosarcoma) or stage II disease, adjuvant radiation therapy is recommended 1
• For surgically staged node-negative patients, options include adjuvant EBRT or vaginal brachytherapy 1

Advanced Stage Disease (Stage III-IV)

• For stage III-IV disease, systemic therapy forms the mainstay of treatment, often combined with EBRT and/or vaginal brachytherapy 1
• Combined modality adjuvant therapy (chemotherapy plus radiation) provides better therapeutic benefit compared to single-modality therapy for stage III disease 1
• In a retrospective review of stage IIIC endometrial cancer, patients receiving adjuvant chemotherapy alone had a 2.2-fold increased risk of recurrence and 4.0-fold increased risk of death compared to those receiving adjuvant RT or RT plus chemotherapy 1
• PORTEC-3 trial showed improved 5-year overall survival with chemoradiotherapy versus radiotherapy alone (81.4% vs 76.1%) for high-risk endometrial cancer 1
• Patients with serous cancers and stage III disease benefited most from the addition of systemic therapy to radiation in the PORTEC-3 trial 1

Radiation Techniques and Considerations

External Beam Radiation Therapy (EBRT)

• Pelvic EBRT (45-50.4 Gy in 25-28 fractions) is used for patients with high-risk features 4
• EBRT significantly reduces locoregional recurrence but has not consistently shown overall survival benefit in early-stage disease 1
• Intensity-modulated RT with daily image guidance is recommended to reduce toxicity 4

Vaginal Brachytherapy

• Provides excellent vaginal control with minimal toxicity 1
• Can be used alone for intermediate and high-intermediate risk disease 2
• May be considered following EBRT, though evidence for this approach is limited 1

Combined Modality Approaches

• The RTOG 9708 phase II trial demonstrated excellent local-regional control with combined chemoradiation (cisplatin/paclitaxel) for high-risk endometrial cancer 5
• At 4 years follow-up, pelvic and regional recurrence rates were only 2% each, with overall survival of 85% 5
• For stage III patients, 4-year survival and disease-free survival rates were 77% and 72%, respectively 5

Impact of Surgical Staging on Adjuvant Therapy

• Sentinel lymph node mapping is now recommended over complete pelvic lymphadenectomy for surgical nodal staging 4
• Patients with isolated tumor cells should be treated as node-negative with adjuvant therapy based on uterine risk factors 4
• Patients with micrometastases should be treated as node-positive 4

Emerging Role of Molecular Classification

• Molecular classification of endometrial cancer (POLE ultra-mutated, microsatellite instable hypermutated, copy-number-low, and copy-number-high) has stronger prognostic impact than traditional histopathological characteristics 6
• Molecular tumor profiling should be increasingly considered when making recommendations for adjuvant therapy 4

Common Pitfalls and Caveats

• Whole abdominal radiation therapy is considered inferior to chemotherapy and too toxic; it is no longer recommended 1
• Overtreatment of low-risk patients with unnecessary radiation should be avoided 1, 2
• Undertreatment of high-risk patients with vaginal brachytherapy alone when EBRT is indicated may lead to increased pelvic recurrence 1
• PORTEC-1 and PORTEC-2 specifically excluded patients with stage IC, grade 3 endometrial carcinoma; thus, the use of adjuvant brachytherapy alone in this highest-risk subset remains undetermined 1
• Adjuvant therapy decisions should consider both locoregional and distant metastatic risk 1