Systemic Therapy and Management of Endometrial Cancer

Exam Tip: If a question asks for the most active single-agent therapy in the second-line setting for endometrial cancer, the answer is paclitaxel.

Biomarker-Directed Therapies

The most significant advancement in endometrial cancer care is the use of molecular biomarkers to direct immunotherapy and targeted agents.

MSI-H/dMMR and TMB-H

Tumors characterized by Microsatellite Instability-High (MSI-H) or mismatch repair deficiency (dMMR) are highly sensitive to PD-1/PD-L1 blockade. Recommended immunotherapy options include pembrolizumab, dostarlimab, nivolumab, avelumab, and tislelizumab.

Similarly, patients with High Tumor Mutational Burden (TMB-H), defined as $\ge 10$ mutations/megabase (mut/Mb), may benefit from checkpoint inhibitor combinations such as nivolumab + ipilimumab upon progression.

pMMR (Microsatellite Stable) Tumors

For patients with pMMR tumors who progress on platinum-based therapy, the combination of lenvatinib + pembrolizumab is a Category 1 recommendation. Another option for this group is axitinib + avelumab.

Gene Fusions and HER2 Status

Precision medicine extends to specific genetic alterations:

• NTRK gene fusion-positive: Treated with larotrectinib or entrectinib.
• RET gene fusion-positive: Treated with selpercatinib.
• HER2-positive (Uterine Serous Carcinoma): For stage III/IV or first-line recurrent disease, a triplet regimen of carboplatin/paclitaxel/trastuzumab is preferred.

Radiotherapy and Local Management

Radiotherapy (RT) is utilized for both locoregional control and adjuvant treatment.

• External Beam Radiation Therapy (EBRT): Used for broader field coverage.
• Vaginal Brachytherapy: Often preferred for adjuvant treatment because it can offer better quality of life outcomes compared to more extensive radiation.

In cases of isolated metastases, clinicians may consider resection or ablative RT/SBRT if the primary cancer is controlled.

Surveillance and Fertility-Sparing Options

Post-Treatment Surveillance Protocol

Surveillance is focused on clinical monitoring rather than intensive, routine imaging. The standard protocol involves:

1. Years 1–3: Physical examinations every 3–6 months.
2. Years 3–5: Physical examinations every 6–12 months.

It is important to note that vaginal cytology is no longer recommended for asymptomatic patients during surveillance.

Fertility-Sparing Treatment

For patients desiring uterine preservation, fertility-sparing options are considered primarily for well-differentiated (Grade 1) endometrioid adenocarcinoma.

• Preferred Therapy: Levonorgestrel IUD.
• Criteria: Patients must be premenopausal, have stage IA G1 disease, normal-appearing ovaries, and no family history of Lynch syndrome or ovarian cancer.
• Monitoring: Requires endometrial evaluation (hysteroscopy, D&C, or biopsy) every 3–6 months.

Clinical Pearl: When considering ovarian preservation, the absence of $p53$ abnormality, MMR deficiency, and lymphovascular space invasion (LVSI) are preferred clinical indicators.