NCCN Guidelines for Endometrial Carcinoma and Uterine Neoplasms

Surgical Staging and Primary Treatment

For patients with disease limited to the uterus who are suitable for surgery, the standard of care is total hysterectomy and bilateral salpingo-oophorectomy (TH/BSO) combined with surgical staging. The extent of surgical staging depends on preoperative and intraoperative findings.

Treatment by Disease Extent

The NCCN guidelines divide treatment strategies based on the anatomical spread of the cancer:

• Disease Limited to the Uterus: If the patient is a surgical candidate, TH/BSO with staging is preferred. If surgery is not feasible due to comorbidities, external beam radiation therapy (EBRT) and/or brachytherapy are recommended.
• Cervical Involvement: If gross cervical involvement is suspected, clinicians should perform a cervical biopsy or pelvic MRI; treatment may require a radical hysterectomy (RH) and BSO.
• Extrauterine/Locoregional Disease: Management may involve debulking surgery, preoperative systemic therapy, or a combination of definitive EBRT and brachytherapy.
• Distant Metastases: The focus shifts to systemic therapy, which may be combined with EBRT or stereotactic body RT (SBRT) for local control.

Exam Tip: In cases of suspected extrauterine disease, the decision to use preoperative systemic therapy or debulking surgery is heavily influenced by whether the disease is considered "pelvic-confined".

Adjuvant Therapy and Risk Stratification

Adjuvant treatment is tailored to the FIGO stage and the histologic grade of the tumor. The goal is to reduce the risk of recurrence in patients who have undergone surgery.

Stage-Specific Recommendations

• Stage IA: For G1/G2 tumors, observation is often preferred. However, vaginal brachytherapy may be considered if LVSI is present or if the patient is $\ge 60$ years old. G3 tumors typically require radiation.
• Stage IB: For G1/G2, vaginal brachytherapy is preferred. For G2 patients, EBRT is recommended if they are $\ge 60$ years old or have LVSI. G3 tumors require radiation and potentially systemic therapy.
• Stage II: Treatment generally involves EBRT and/or vaginal brachytherapy, with systemic therapy considered for advanced cases.

Advanced Management and Systemic Therapy

For recurrent or metastatic disease, the treatment landscape is increasingly driven by biomarkers.

Systemic Therapy Pathways

• Platinum-Based Regimens: Carboplatin/Paclitaxel remains a cornerstone of therapy.
• Biomarker-Directed Therapy:
  • dMMR/MSI-H tumors: Immunotherapy (e.g., pembrolizumab) is a key consideration.
  • p53 aberrant/HER2-positive tumors: HER2 testing is recommended, and targeted agents like fam-trastuzumab deruxtecan-nxki may be used for carcinosarcoma.
  • TMB-H tumors: Ipilimumab + Nivolumab may be utilized.

Fertility-Sparing Options

For select premenopausal patients with early-stage (Stage IA) G1 endometrioid cancer, ovarian preservation may be safe. This is preferred when there is an absence of p53 abnormality, MMR deficiency, and LVSI, and no family history of Lynch syndrome. The preferred treatment in these cases is often a Levonorgestrel IUD.

Summary of Key Clinical Considerations

In conclusion, the NCCN Guidelines emphasize a multidisciplinary approach, integrating surgical precision, advanced imaging, and molecular profiling to manage the diverse spectrum of uterine neoplasms.