What is the recommended management approach for a patient with stage II endometrial cancer, particularly those with high-risk features such as deep myometrial invasion, grade 3 histology, or serous/clear cell histology, in terms of External Beam Radiation Therapy (EBRT) and chemotherapy?

Management of Stage II Endometrial Cancer and High-Risk Features

No, not all patients meeting PORTEC inclusion criteria require concurrent EBRT with chemotherapy plus adjuvant chemotherapy—the treatment approach depends on specific risk stratification, with intermediate-risk disease managed with vaginal brachytherapy alone, while only high-risk disease (including stage II, stage I grade 3 with deep invasion, and serous/clear cell histology) requires combined chemoradiotherapy. 1, 2

Risk-Stratified Treatment Algorithm

Intermediate-Risk Disease (Does NOT Require Chemoradiation)

• Stage I endometrioid, grade 1-2, ≥50% myometrial invasion, LVSI negative: Vaginal brachytherapy alone is sufficient, providing equivalent survival to EBRT with superior quality of life 3
• This represents the PORTEC-2 population, where VBT alone achieved excellent outcomes without the toxicity of pelvic radiation 3

High-Intermediate Risk (May Not Require Chemotherapy)

• Stage I with surgical nodal staging, node negative: VBT for grade 1-2 with negative LVSI; limited field EBRT for grade 3 or unequivocally positive LVSI 3
• Chemotherapy is not routinely indicated for this group unless additional high-risk features are present 2

High-Risk Disease (REQUIRES Combined Chemoradiotherapy)

Stage II disease specifically requires combined modality treatment because cervical stromal invasion increases both locoregional and distant recurrence risk 1. The GOG 249 trial demonstrated that stage II patients had 9% pelvic/para-aortic recurrence with VBT plus chemotherapy versus 4% with EBRT, indicating inadequate pelvic control without radiation 4, 5.

Other high-risk features requiring chemoradiation include:

• Stage I grade 3 with ≥50% myometrial invasion and no surgical nodal staging 2
• Stage I-II serous or clear cell histology 4, 1
• Stage III disease (any histology) 2
• p53-abnormal tumors by molecular classification 1, 2

Standard Chemoradiotherapy Protocol

The established regimen consists of:

Concurrent Phase

• Pelvic EBRT 48.6 Gy in 1.8 Gy fractions 1, 2
• Concurrent cisplatin 50 mg/m² on days 1 and 29 1, 2
• Vaginal brachytherapy boost may be added for stage II or concern for vaginal involvement 1

Adjuvant Phase

• Four cycles of carboplatin (AUC 5-6) plus paclitaxel (175 mg/m²) every 3 weeks 1, 2
• Administered following completion of radiotherapy 1

Evidence Supporting Combined Modality Treatment

PORTEC-3 trial demonstrated superiority of chemoradiation for high-risk disease:

• 5-year recurrence-free survival: 75.5% with chemoradiation versus 68.6% with RT alone (HR 0.63,95% CI 0.44-0.89) 4, 1
• 5-year overall survival: 81.8% versus 76.7% (HR 0.70,95% CI 0.51-0.97) 2
• Stage II disease was specifically included in this trial and showed benefit 1

GOG 249 trial showed inadequacy of chemotherapy alone for stage II:

• Pelvic/para-aortic recurrence: 9% with VBT/chemotherapy versus 4% with EBRT 4, 5
• No difference in overall survival or distant recurrence 4, 5
• This demonstrates that stage II requires radiation for pelvic control 1

Molecular Classification Refinement

When molecular profiling is available, treatment should be modified:

• p53-abnormal tumors: Greatest benefit from chemoradiation with 23% absolute RFS improvement—strongly recommend combined therapy even for lower stage disease 1, 2
• POLE-ultramutated tumors: Excellent prognosis without intensive treatment; may not require chemoradiation even with stage II disease 1, 2
• MMR-deficient/NSMP tumors: Follow standard risk-based algorithms as outlined above 2

Critical Pitfalls to Avoid

Common errors in management:

• Treating stage II with VBT alone: Inadequate pelvic control demonstrated by 9% pelvic recurrence rate in GOG 249 4, 5
• Omitting chemotherapy for stage II: Stage II shares similar high-risk features with stage III, including increased frequency of deep invasion and grade 3 histology 1
• Using chemotherapy alone without radiation for stage II: Sequential chemotherapy alone shows inadequate pelvic control compared to combined chemoradiotherapy 1
• Overtreating intermediate-risk disease: VBT alone is sufficient for stage I grade 1-2 with deep invasion and negative LVSI—EBRT adds toxicity without survival benefit 3

Toxicity Considerations

Expected adverse events with chemoradiation:

• Grade 3 or worse adverse events: 60% with chemoradiation versus 12% with RT alone 2
• Most grade 3 events are hematological (45%) 2
• Persistent sensory neuropathy: 6% at 5 years 2
• Gastrointestinal toxicity: 32% grade 3/4 6
• Grade 3/4 neutropenia: 45% 6

These toxicity rates are acceptable given the survival benefit in truly high-risk disease, but underscore the importance of accurate risk stratification to avoid overtreatment of intermediate-risk patients 2, 3.