What is the recommended management for a patient with stage 2 endometrial cancer, considering the use of concurrent External Beam Radiation Therapy (EBRT) with chemotherapy?

Management of Stage II Endometrial Cancer

For stage II endometrial cancer (cervical stromal invasion), combined chemoradiotherapy with concurrent cisplatin-based EBRT followed by adjuvant carboplatin/paclitaxel is recommended, as stage II disease was specifically included in the PORTEC-3 trial and demonstrated improved recurrence-free survival with this approach. 1

Evidence Supporting Combined Chemoradiotherapy for Stage II Disease

Inclusion in Major Trials

• Stage II endometrial cancer was explicitly part of the inclusion criteria for PORTEC-3, which demonstrated improved 5-year recurrence-free survival with combined chemoradiotherapy (75.5%) versus radiotherapy alone (68.6%), HR 0.63 (95% CI 0.44-0.89). 1

• The GOG 249 trial also included stage II disease in its treatment arms, comparing VBT plus chemotherapy versus pelvic EBRT plus VBT for stage II patients, particularly those with serous or clear cell histology. 1

• Stage II disease shares similar high-risk features with stage III disease, including increased frequency of deep myometrial invasion and grade 3 histology, which drives the higher risk of both locoregional and distant recurrence. 1

Guideline Recommendations

• The ESMO-ESGO-ESTRO consensus conference groups stage II with high-risk endometrial cancer and recommends similar treatment approaches, noting that cervical stromal invasion increases recurrence risk and warrants aggressive adjuvant therapy. 1

• Radiotherapy (independent of surgery type) was associated with survival benefit in stage II disease based on SEER analysis of 1,577 patients. 1

• The evidence supports giving chemotherapy and EBRT in combination rather than either treatment modality alone for stage II disease (Level II evidence, Strength B). 1

Recommended Treatment Protocol

Standard Chemoradiotherapy Regimen

• Concurrent phase: Pelvic EBRT 48.6 Gy in 1.8 Gy fractions with concurrent cisplatin 50 mg/m² on days 1 and 29. 1, 2

• Adjuvant phase: Four cycles of carboplatin (AUC 5-6) plus paclitaxel (175 mg/m²) every 3 weeks following completion of radiotherapy. 1

• Vaginal brachytherapy boost may be added if there is concern for vaginal involvement or positive margins, though routine use remains controversial. 1

Alternative Approaches (Less Preferred)

• Chemotherapy alone (6 cycles carboplatin/paclitaxel) plus VBT is an option based on GOG 249, but showed significantly more pelvic and para-aortic recurrences compared to combined chemoradiotherapy in GOG 258. 2

• EBRT alone is inferior to combined modality treatment for stage II disease and should not be used as monotherapy. 1

Molecular Classification Considerations

• If molecular profiling is available, treatment should be refined based on molecular subtype. 2, 3

• p53-abnormal tumors show the greatest benefit from chemoradiotherapy, with a 23% absolute recurrence-free survival improvement, and should definitely receive combined treatment. 2, 3

• POLE-ultramutated tumors have excellent prognosis and may not require intensive chemoradiotherapy even with stage II disease. 2, 3

• MMR-deficient/NSMP tumors should follow standard risk-based algorithms as outlined above. 2

Key Clinical Considerations

Why Stage II Requires Combined Modality Treatment

• Stage II disease (FIGO 2009 definition includes only cervical stromal invasion) carries higher risk than stage I due to proximity to parametrial tissues and increased lymphovascular space invasion. 1, 3

• The pattern of failure in stage II includes both pelvic recurrence (addressed by EBRT) and distant metastases (addressed by chemotherapy), necessitating combined treatment. 1

• Sequential chemotherapy alone has shown inadequate pelvic control compared to combined chemoradiotherapy in randomized trials. 2

Common Pitfalls to Avoid

• Do not treat stage II with VBT alone, as this provides inadequate pelvic nodal coverage and is associated with higher recurrence rates. 1, 4

• Do not omit chemotherapy in stage II disease, as distant recurrence risk is substantial and requires systemic therapy. 1, 5

• Ensure adequate surgical staging was performed; if lymph nodes were not assessed, the risk profile may be underestimated and more aggressive treatment is warranted. 1

Toxicity Profile

• Grade 3 or worse adverse events occur in approximately 60% of patients receiving chemoradiotherapy versus 12% with radiotherapy alone, with most being hematological (45%). 2

• Persistent sensory neuropathy occurs in 6% of patients at 5 years. 2

• Acute grade 1-2 gastrointestinal and genitourinary toxicities are more common with EBRT but are generally manageable. 6