What is the recommended adjuvant management for a 61‑year‑old woman who underwent robotic total hysterectomy with bilateral salpingo‑oophorectomy, sentinel‑node mapping and omental biopsy for a mixed endometrial carcinoma (30 % endometrioid grade 2, 70 % serous with p53 mutation), tumor size 4.5 cm, 86 % myometrial invasion, lymph‑vascular space invasion present, no cervical, serosal, nodal, omental or peritoneal involvement, negative peritoneal washings, pathologic stage pT1bN0 corresponding to FIGO 2023 stage IICm?

Adjuvant Management for Stage IICm Mixed Endometrial Carcinoma

This patient requires combined modality therapy with chemotherapy followed by radiotherapy due to the high-risk serous component (70%) with p53 mutation, deep myometrial invasion (86%), and LVSI, despite negative nodes. 1, 2

Risk Stratification Rationale

This case represents high-risk, non-endometrioid disease based on several critical features:

• Serous histology predominance (70%) with p53 abnormality—this is the dominant driver of prognosis and treatment decisions 1, 2
• Deep myometrial invasion (86%) extending to outer half 1
• Lymphovascular space invasion present (3 foci) 2
• Large tumor size (4.5 cm) 1

The 30% endometrioid component is overshadowed by the aggressive serous biology. Mixed carcinomas are treated according to their highest-risk component. 1, 2

Recommended Treatment Algorithm

Primary Adjuvant Therapy: Sequential Chemotherapy + Radiotherapy

Step 1: Systemic Chemotherapy (First-Line)

• Carboplatin/paclitaxel for 6 cycles is the standard regimen 2
• Initiate within 12 weeks of surgery, ideally once vaginal cuff has healed 1
• This addresses the high risk of distant micrometastatic disease inherent to serous histology 1, 2

Step 2: Radiotherapy (Following Chemotherapy)

• Pelvic external beam radiotherapy (EBRT) 45-48.6 Gy with vaginal brachytherapy boost 2, 3
• Sequential administration after chemotherapy completion provides superior outcomes compared to radiotherapy alone 1, 2
• The combination reduces risk of relapse or death by 36% (HR 0.64, P=0.04) and improves cancer-specific survival (HR 0.55, P=0.01) 1, 2

Evidence Supporting Combined Modality

Two pivotal randomized trials (NSGO-EC-9501/EORTC-55991 and MaNGO ILIADE-III) demonstrated that sequential chemotherapy plus radiotherapy significantly outperforms radiotherapy alone in high-risk endometrial cancer, including non-endometrioid histologies. 1, 2 The PORTEC-3 trial further validated this approach specifically for serous and clear-cell carcinomas. 1

Chemotherapy alone is insufficient because serous carcinomas have high locoregional recurrence risk despite negative nodes, necessitating pelvic radiation for local control. 1, 2

Radiotherapy alone is inadequate because serous histology carries substantial risk of distant metastases that radiation cannot address. 1, 2

Why This Patient Cannot Be Managed with Less Aggressive Therapy

Observation is Contraindicated

• Serous histology has recurrence rates significantly higher than endometrioid types even at early stage 2
• p53 mutation confers aggressive biology requiring systemic therapy 1

Vaginal Brachytherapy Alone is Insufficient

• This approach is reserved for intermediate-risk endometrioid disease with favorable features 2
• Serous component demands pelvic EBRT for adequate locoregional control 1, 2

Radiotherapy Without Chemotherapy is Suboptimal

• Level I evidence demonstrates inferior progression-free and overall survival compared to combined modality 1, 2
• The GOG-122 trial showed chemotherapy superiority over whole abdominal radiation in advanced disease 1

Critical Pitfalls to Avoid

Do not undertreate based on negative nodes. Node-negative status does not eliminate the need for adjuvant therapy in serous carcinoma—the histology itself drives treatment decisions. 1, 2

Do not use the endometrioid component to justify less aggressive therapy. Mixed carcinomas are managed according to the highest-risk element, which is the serous component here. 1, 2

Do not administer radiotherapy before chemotherapy. The sequential approach (chemotherapy first) is supported by randomized trial data and allows systemic therapy to address micrometastases early. 1, 2

Do not consider hormonal therapy. Progestins have no role in adjuvant treatment of endometrial cancer (Level I evidence) and are particularly ineffective in serous histology. 1, 3

Do not delay treatment beyond 12 weeks post-surgery. Adjuvant therapy should begin once the vaginal cuff has healed to optimize outcomes. 1

Surveillance Considerations

Most recurrences occur within the first 3 years, justifying intensive follow-up during this period with clinical examination, imaging as indicated, and attention to symptoms suggesting distant metastases (the predominant failure pattern in serous carcinoma). 2