Treatment Protocol for Stage I Grade 3 Endometrioid Endometrial Cancer with Significant LVSI
For stage I grade 3 endometrioid endometrial cancer with substantial LVSI, combined chemoradiotherapy (concurrent EBRT with cisplatin followed by adjuvant chemotherapy) should be administered regardless of nodal staging status, as substantial LVSI is the strongest independent predictor of distant metastases and pelvic recurrence. 1, 2
Risk Stratification Based on LVSI Status
Substantial LVSI Present (Your Primary Scenario)
Substantial LVSI is the most powerful independent prognostic factor for distant metastases (HR 4.5), pelvic regional recurrence (HR 6.2), and overall survival (HR 2.0), surpassing even grade and depth of invasion in predictive value. 1
Recommended treatment: Combined chemoradiotherapy consisting of EBRT 48.6 Gy with concurrent cisplatin 50 mg/m² (days 1 and 28), followed by 4 cycles of carboplatin AUC5 and paclitaxel 175 mg/m². 3, 2
This recommendation applies regardless of whether nodal dissection was performed, because substantial LVSI independently predicts both locoregional and distant failure. 1, 4
The rationale: EBRT alone reduces pelvic recurrence (HR 0.3) but does not address the 11.5-17% distant recurrence rate seen with substantial LVSI. 1, 5 Chemotherapy is essential to address systemic disease risk. 4
No LVSI or Focal LVSI Only
If nodal staging performed and node-negative:
- Adjuvant EBRT with limited fields is recommended to decrease locoregional recurrence. 6
- Adjuvant brachytherapy alone may be considered as an alternative. 6
- Adjuvant systemic therapy remains under investigation in this subset. 6
If no nodal staging performed:
- Adjuvant EBRT is generally recommended for pelvic control. 6
- Sequential or concurrent chemotherapy plus EBRT should be considered, with greater evidence supporting combined therapy over either modality alone. 6, 3
Critical Evidence Supporting This Protocol
LVSI as the Dominant Risk Factor
The pooled PORTEC-1 and PORTEC-2 analysis definitively established that substantial LVSI (not just "any" LVSI) using a 3-tiered scoring system is the critical distinction. 1 Only 4.8% of patients had substantial LVSI, but this subset experienced dramatically worse outcomes across all endpoints. 1
- Patients with substantial LVSI had distant metastasis rates of 11.5-17% despite adjuvant radiotherapy. 5, 1
- Grade 1 disease with LVSI had minimal recurrence risk, but grade 3 with LVSI showed particularly poor outcomes. 5, 7
Chemotherapy Benefit in High-Risk Disease
The combined analysis of NSGO 9501/EORTC 55991 and MaNGO-ILIADE III trials demonstrated that adding chemotherapy to EBRT improved 5-year PFS (78% vs 69%, P=0.009) with a trend toward improved OS (82% vs 75%, P=0.07). 6
Most importantly for your protocol: In grade 3 endometrioid tumors with LVSI, chemotherapy plus radiation improved PFS compared to radiation alone (HR 0.25) or observation (HR 0.10). 4
The PORTEC-3 trial showed that combined chemoradiotherapy improved 5-year OS (81.4% vs 76.1%, HR 0.70, P=0.034) in high-risk disease, with the greatest benefit in stage III and serous histologies, but also demonstrable benefit in high-risk stage I disease. 3
Recent Evidence on LVSI-Positive Disease
A 2024 study specifically addressing stage IIC disease (which includes stage I grade 3 with LVSI under 2023 FIGO staging) found that adjuvant treatment improved OS in patients with LVSI (P=0.020), particularly those with grade 3 endometrioid histology (P=0.007). 7
Your Proposed Protocol Assessment
Your protocol is largely correct but requires one critical modification:
✓ Correct Elements:
- All stage III, serous, and p53-abnormal tumors receive chemoradiotherapy followed by chemotherapy. 6, 3
- Stage I grade 3 with substantial LVSI receives chemoradiotherapy followed by chemotherapy. 2, 1, 4
✗ Modification Needed:
Your protocol suggests EBRT alone for node-negative patients after nodal dissection. This is insufficient for substantial LVSI cases. Even with negative nodes, substantial LVSI independently predicts distant metastases (HR 4.5). 1 These patients require chemotherapy in addition to radiation. 4, 7
The correct approach for substantial LVSI with negative nodes: Combined chemoradiotherapy (not EBRT alone), as the nodal status does not eliminate the high distant recurrence risk conferred by substantial LVSI. 1, 4
Molecular Classification Considerations
If molecular profiling is available, treatment should be refined: 6, 2, 3
- p53-abnormal tumors: Strongest indication for chemotherapy (23% absolute RFS improvement). 3
- POLE-ultramutated tumors: Excellent prognosis without chemotherapy; may not require intensive treatment even with LVSI. 6, 3
- MMR-deficient/NSMP tumors: Follow standard risk-based algorithms as outlined above. 6
Common Pitfalls to Avoid
Do not equate "any LVSI" with "substantial LVSI." The 3-tiered scoring system (absent, focal, substantial) is critical—only substantial LVSI warrants escalation to combined modality therapy. 1
Do not rely on nodal status alone to de-escalate therapy in substantial LVSI cases. The negative predictive value of absent LVSI is 95.6%, but once substantial LVSI is present, nodal status becomes less determinative of systemic risk. 8, 1
Do not use EBRT alone for grade 3 disease with substantial LVSI, even if nodes are negative. This addresses locoregional control but leaves distant recurrence risk (11.5-17%) unaddressed. 5, 1, 4