Should all patients with high-risk endometrial cancer, including those with stage 1 grade 3 disease, lymphovascular space invasion (LVSI), and deep myometrial invasion, receive concurrent external beam radiation therapy (EBRT) followed by adjuvant chemotherapy, similar to those with stage 3, serous, or p53 positive tumors?

Treatment Recommendations for High-Risk Endometrial Cancer Based on PORTEC-3 Inclusion Criteria

Not all patients meeting PORTEC-3 inclusion criteria require concurrent chemoradiotherapy followed by adjuvant chemotherapy—treatment should be stratified based on specific risk features, with the most aggressive combined modality therapy reserved for stage III disease, serous histology, and p53-abnormal tumors. 1, 2

Risk Stratification Within PORTEC-3 Eligible Patients

The PORTEC-3 trial included a heterogeneous population, and subsequent analysis revealed differential benefit based on disease characteristics:

Highest Priority for Combined Chemoradiotherapy

Stage III disease and serous carcinomas demonstrate the most substantial survival benefit from combined chemoradiotherapy and should routinely receive this treatment. 1, 3 The updated PORTEC-3 analysis showed 5-year overall survival of 81.4% with chemoradiotherapy versus 76.1% with radiotherapy alone (HR 0.70,95% CI 0.51-0.97, p=0.034), with the greatest benefit observed in these high-risk subgroups. 3

• P53-abnormal tumors show a 23% absolute recurrence-free survival improvement with chemotherapy, making combined modality treatment essential for this molecular subtype. 1, 2
• Serous carcinomas require aggressive treatment regardless of stage due to inherently aggressive biology. 2

Stage I Grade 3 Endometrioid Disease: Nuanced Approach Required

For stage I grade 3 endometrioid tumors with deep myometrial invasion, treatment depends critically on nodal staging status and LVSI:

If surgical nodal staging was performed and nodes are negative:

• Adjuvant EBRT with limited fields is recommended to decrease locoregional recurrence (Level I evidence, Strength B). 4
• Adjuvant brachytherapy may be considered as an alternative (Level III evidence, Strength B). 4
• Adjuvant systemic chemotherapy remains under investigation in this specific subset (Level II evidence, Strength C). 4

If no surgical nodal staging was performed:

• Adjuvant EBRT is generally recommended for pelvic control. 4
• There is greater evidence to support combined chemotherapy plus EBRT than either treatment modality alone (Level II evidence, Strength B). 4
• Sequential adjuvant chemotherapy may be considered to improve progression-free survival and cancer-specific survival (Level II evidence, Strength C). 4

The Critical Role of LVSI

Substantial LVSI is the strongest independent prognostic factor for distant metastasis (HR 4.5, CI 2.4-8.5) and should trigger consideration of combined chemoradiotherapy, particularly in grade 3 tumors. 5

• In grade 3 endometrioid tumors with LVSI, adjuvant chemotherapy with or without radiation improved progression-free survival compared to observation or radiation alone (HR 0.25 for CHEMO+/-RAD vs RAD; 95% CI: 0.12-0.52). 6
• Focal LVSI alone does not carry the same risk as substantial LVSI and may not require intensified treatment. 5

Molecular Classification Refines Treatment Decisions

When molecular profiling is available, treatment intensity should be adjusted based on molecular subtype: 7, 1

• POLE-ultramutated tumors: Excellent prognosis without chemotherapy; may not require intensive treatment and could potentially be managed with EBRT alone or observation. 7, 1
• p53-abnormal tumors: Should receive combined chemoradiotherapy regardless of stage due to aggressive biology. 7, 1
• Mismatch repair deficient (MMRd) and No specific molecular profile (NSMP): Intermediate risk; treatment based on clinicopathologic features as outlined above. 7

Standard Chemoradiotherapy Regimen

When combined chemoradiotherapy is indicated, the established protocol consists of: 1, 2, 3

• Concurrent phase: EBRT 48.6 Gy in 1.8 Gy fractions with cisplatin 50 mg/m² on days 1 and 28
• Sequential phase: Four cycles of carboplatin AUC5 plus paclitaxel 175 mg/m² every 3 weeks

Critical Toxicity Considerations

Grade 3 or worse adverse events during treatment occur in 60% of chemoradiotherapy patients versus 12% with radiotherapy alone (p<0.0001), with most grade 3 events being hematological (45%). 3, 8

• Sensory neuropathy (grade 2 or worse) persists in 6-8% of patients at 5 years with chemoradiotherapy versus 0-1% with radiotherapy alone. 3, 8
• For stage I-II endometrioid disease, the modest outcome benefit (2% overall survival improvement, 4% failure-free survival improvement) must be weighed against increased adverse events. 1

Common Pitfalls to Avoid

• Do not treat all PORTEC-3 eligible patients uniformly—the trial included heterogeneous populations with varying benefit from chemotherapy. 1, 3
• Do not equate "any LVSI" with "substantial LVSI"—only substantial LVSI warrants treatment intensification. 5
• Do not omit radiotherapy when giving chemotherapy alone—the GOG-258 trial showed significantly more vaginal and pelvic/para-aortic recurrences with chemotherapy alone compared to chemoradiotherapy. 1
• Do not ignore molecular classification when available—it provides the strongest prognostic information and should guide treatment intensity. 7, 1