Does a patient with stage 1 grade 3 endometrial cancer, lymphovascular space invasion (LVSI), and deep myometrial invasion benefit from adjuvant chemoradiotherapy, considering the PORTEC-3 trial primarily showed benefits in stage 3 and serous histology?

Stage 1 Grade 3 Endometrial Cancer with LVSI and Deep Myometrial Invasion: Adjuvant Treatment Recommendations

For stage I grade 3 endometrial cancer with deep (≥50%) myometrial invasion and LVSI, combined chemoradiotherapy should be strongly considered, particularly if lymph node staging was not performed, as this represents high-risk disease with substantial risk of both pelvic and distant recurrence. 1

Understanding the Risk Classification

Your patient falls into the high-risk category, not high-intermediate risk, based on the combination of:

• Grade 3 histology
• Deep myometrial invasion (≥50%)
• LVSI present 1

This is distinct from high-intermediate risk disease, which includes either grade 3 with <50% invasion OR grade 1-2 with deep invasion and LVSI. 1

Treatment Algorithm Based on Nodal Staging Status

If Surgical Nodal Staging Was Performed and Nodes Are Negative:

• Adjuvant EBRT with limited fields is recommended to decrease locoregional recurrence 1
• Adjuvant brachytherapy may be considered as an alternative to decrease vaginal recurrence 1
• Adjuvant systemic chemotherapy should be considered, particularly given the combination of grade 3, deep invasion, and LVSI 1

If No Surgical Nodal Staging Was Performed:

• Adjuvant EBRT is generally recommended for pelvic control and relapse-free survival 1
• Combined chemoradiotherapy provides greater evidence of benefit than either treatment modality alone 1
• Sequential adjuvant chemotherapy may be considered to improve progression-free survival and cancer-specific survival 1

Why PORTEC-3 Is Relevant to Your Patient

You are correct that PORTEC-3 primarily enrolled stage III and serous histology patients, but it also included stage I grade 3 with deep myometrial invasion and/or LVSI, which matches your patient's profile. 2, 3

The 10-year PORTEC-3 results demonstrate:

• Overall survival benefit: 74.4% vs 67.3% (HR 0.73, p=0.032) with chemoradiotherapy 3
• Recurrence-free survival: 72.8% vs 67.4% (HR 0.74, p=0.034) with chemoradiotherapy 3
• Stage I patients with high-risk features were included and contributed to these outcomes 2, 3

Why Stage II Is Included in Chemoradiotherapy Recommendations

Stage II endometrial cancer (cervical stromal invasion) is grouped with high-risk stage I disease because:

• Both have increased frequency of deep myometrial invasion and grade 3 histology 1
• Both demonstrate increased risk of pelvic recurrence and distant metastases 1
• The PORTEC-3 trial included stage II patients and showed benefit from combined therapy 2, 3
• Current guidelines recommend similar treatment approaches for stage II as for high-risk stage I 1

Molecular Classification Considerations

If molecular profiling is available, treatment decisions should be refined: 4, 3

• p53-abnormal tumors: Show the greatest benefit from chemoradiotherapy (10-year RFS 52.6% vs 37.0%, HR 0.42, p=0.0027) 3
• POLE-ultramutated tumors: Excellent prognosis without chemotherapy (100% vs 97% RFS), may not require intensive treatment 4, 3
• MMR-deficient tumors: Less clear benefit from chemotherapy 3
• NSMP tumors: Benefit modulated by estrogen receptor status 3

Standard Chemoradiotherapy Regimen

The recommended regimen is: 4, 2, 5

• EBRT 48.6 Gy in 1.8 Gy fractions
• Concurrent cisplatin 50 mg/m² for two cycles (weeks 1 and 4)
• Followed by four cycles of carboplatin AUC5 and paclitaxel 175 mg/m² at 3-week intervals

Critical Toxicity Considerations

Grade 3 or worse adverse events occur in 60% during treatment (vs 12% with radiotherapy alone), predominantly hematological (45%). 2, 5

Persistent sensory neuropathy (grade 2 or worse) occurs in 8-10% at 2-3 years, compared to <1% with radiotherapy alone. 2, 5

Quality of life returns to baseline by 12-24 months in most patients, though neuropathy symptoms persist in 25% at 24 months. 5

Common Pitfalls to Avoid

Do not use radiotherapy alone without considering chemotherapy in high-risk stage I disease without nodal staging, as this results in higher distant recurrence rates. 1, 4

Do not use chemotherapy alone without radiotherapy, as GOG-258 showed significantly more vaginal and pelvic/para-aortic recurrences with this approach. 4

Do not dismiss LVSI as insignificant—it is a strong predictor of distant spread, with recurrence rates of 19.2% in patients with 0-1 other risk factors and 25.5% in those with 2-3 risk factors despite adjuvant radiotherapy. 6

The modest absolute survival benefit (5-7% at 10 years) must be weighed against significant toxicity, particularly in patients without p53 abnormalities or those with POLE mutations. 4, 3