What are the adjuvant treatment options for endometrial cancer according to risk categories and guidelines?

Adjuvant Treatment for Endometrial Cancer by Risk Categories

Adjuvant treatment for endometrial cancer should be stratified according to risk categories, with specific recommendations ranging from observation for low-risk disease to combined chemotherapy and radiotherapy for high-risk and advanced disease. 1, 2

Risk Stratification and Surgical Management

• Total hysterectomy with bilateral salpingo-oophorectomy is the standard surgical approach for all risk categories of endometrial cancer 2
• Lymphadenectomy recommendations vary by risk category:
  • Low risk (G1/2 and myometrial invasion <50%): Can be considered for staging with sentinel lymph node dissection (SLND) as an option 1, 3
  • Intermediate/High risk (G3 and myometrial invasion <50% or myometrial invasion >50%): Recommended to guide staging and adjuvant therapy 1, 3
  • Advanced disease (Stage III-IV): Recommended as part of comprehensive staging with para-aortic nodes up to the renal vessels 1, 3

Adjuvant Treatment by Risk Category

Low Risk Disease (Stage I, G1-2, <50% myometrial invasion, LVSI negative)

• Observation only is recommended after surgery 1, 4
• Recurrence risk is approximately 10.4% for Stage IA disease 5

Intermediate Risk Disease (Stage I endometrioid, G1-2, ≥50% myometrial invasion, LVSI negative)

• Adjuvant vaginal brachytherapy is recommended 1, 2
• No adjuvant treatment is an alternative option, especially for patients <60 years old 1, 2
• Recurrence risk is approximately 22.4% for Stage IB disease 5

High-Intermediate Risk Disease (Stage I with surgical nodal staging, node negative)

• For G1-2 with negative LVSI: Vaginal brachytherapy 1
• For G3 or LVSI unequivocally positive: Limited field external beam radiotherapy (EBRT) 1
• Consider adjuvant chemotherapy (combined and/or sequential) for G3 or LVSI positive cases 1, 2

High Risk Disease (Stage I, G3, ≥50% myometrial invasion)

• With surgical nodal staging, node negative:
  • Adjuvant EBRT with limited fields 1
  • Adjuvant brachytherapy is an alternative option 1
• Without surgical nodal staging:
  • Adjuvant EBRT 1
  • Consider adjuvant chemotherapy (combined and/or sequential) - greater evidence supports combined chemotherapy plus EBRT than either treatment alone 1, 6

High Risk, Non-Endometrioid Cancer (serous, clear-cell, undifferentiated, carcinosarcoma)

• More aggressive adjuvant therapy is warranted regardless of stage 1, 3
• Combined chemotherapy and radiotherapy should be considered 1, 6
• Recurrence rates are significantly higher than endometrioid types (5-year survival: endometrioid 83% vs. clear cell 62% vs. serous 53%) 5

Stage III Disease

• For Stage IIIC2 (positive para-aortic nodes): Chemotherapy plus extended field EBRT 1
• Recurrence risk is approximately 43% for Stage IIIC1 and 51% for Stage IIIC2 5

Advanced/Metastatic Disease

• Surgery is recommended only if optimal cytoreduction (no residual disease) can be achieved 1
• Radiotherapy:
  • Standard curative RT for isolated vaginal relapse after surgery 1
  • Radical RT (intrauterine brachytherapy ± EBRT) for unresectable disease or where surgery is contraindicated 1
• Chemotherapy:
  • Standard first-line chemotherapy is six cycles of paclitaxel/carboplatin 1
  • Combined chemoradiation can be considered for vaginal or pelvic nodal relapse with high-risk features 1
• Hormone therapy:
  • Progestins (MPA or MA) are preferred for patients with G1/2 endometrioid, hormone receptor-positive advanced/recurrent disease without visceral involvement 1
  • Other hormonal agents (tamoxifen, fulvestrant, aromatase inhibitors) can be considered after progestins 1

Molecular Classification Impact on Treatment

• Molecular classification has identified four endometrial cancer subtypes (POLE ultra-mutated, microsatellite instable hypermutated, copy-number-low, and copy-number-high) that have stronger prognostic impact than traditional histopathological characteristics 6
• These molecular subtypes are found across all stages, histological types, and grades, and may guide future personalized adjuvant treatment approaches 6, 7

Common Pitfalls and Caveats

• Overtreatment with EBRT when vaginal brachytherapy would suffice for intermediate risk disease 2
• Underestimating the importance of surgical staging for guiding adjuvant therapy decisions 2
• Failing to consider age and comorbidities when deciding on adjuvant therapy options 2
• Not recognizing that patients with G3 histology or positive LVSI may benefit from more aggressive adjuvant treatment approaches 2
• Most recurrences occur within the first 3 years after treatment, justifying intensive surveillance during this period 5