What is the recommended treatment plan for a woman diagnosed with endometrioid cancer?

Treatment of Endometrioid Endometrial Cancer

The treatment of endometrioid endometrial cancer begins with total hysterectomy and bilateral salpingo-oophorectomy, with adjuvant therapy decisions based on surgical stage and risk stratification. 1

Initial Surgical Management

All patients require surgical staging as the foundation of treatment:

• Perform total abdominal hysterectomy with bilateral salpingo-oophorectomy 1
• Obtain peritoneal washings or fluid at the start of surgery 1
• Conduct thorough exploration of the abdominal cavity and retroperitoneal nodal areas 1
• The role of systematic pelvic lymphadenectomy remains controversial—two large randomized trials (Italian study and ASTEC) showed no survival benefit in stage I disease, though lymphadenectomy provides prognostic information for tailoring adjuvant therapy 1
• For intermediate-high risk disease (stage IA G3 and IB), consider complete surgical staging including lymphadenectomy 1
• Minimally invasive approaches (laparoscopy or robotic surgery) provide equivalent oncologic outcomes with shorter hospital stays, less pain, and fewer complications compared to laparotomy 1

Risk Stratification for Stage I Disease

Stage I patients are divided into three risk categories that determine adjuvant treatment: 1

Low-Risk (Stage IA/IB, Grade 1-2, Endometrioid Histology)

• No adjuvant therapy is recommended 1, 2
• Surveillance consists of physical examination every 3-6 months for 2 years, then every 6 months through year 5, then annually 2
• Vaginal cytology every 6 months for 2 years, then annually 2
• Do not order routine imaging (CT, chest X-ray, PET) or CA-125 in asymptomatic low-risk patients—these have poor detection rates (0-20%) and do not improve survival 2
• 5-year disease-free survival is approximately 94% with only 2-10% recurrence rate 2

Intermediate-Risk

• Adjuvant pelvic radiotherapy significantly reduces pelvic/vaginal relapses but does not improve overall survival 1
• The PORTEC-2 trial demonstrated that vaginal brachytherapy alone is equally effective as external beam radiation with better quality of life in intermediate-risk patients 1
• Vaginal brachytherapy is preferred over external beam radiation for intermediate-risk disease 1

High-Risk (Stage IB-IC Grade 3, Deep Myometrial Invasion)

• Combined sequential chemotherapy and radiotherapy is strongly recommended 1, 3
• This combined approach reduces risk of relapse or death by 36% (HR 0.64,95% CI 0.41-0.99; P=0.04) and improves cancer-specific survival (HR 0.55,95% CI 0.35-0.88; P=0.01) compared to radiation alone 1
• Preferred chemotherapy regimen: carboplatin (AUC 6) plus paclitaxel (175 mg/m²) every 21 days for 6 cycles, due to lower toxicity than cisplatin-based regimens 3
• Add pelvic external beam radiation therapy for locoregional control 3
• Add vaginal brachytherapy for optimal vaginal cuff control 3

Stage II Disease

• Perform total hysterectomy with bilateral salpingo-oophorectomy 1
• Consider adjuvant therapy similar to high-risk stage I disease 1

Stage III-IV Advanced Disease

For optimally debulked stage III-IV disease, chemotherapy is superior to radiation alone: 1

• The GOG-122 trial demonstrated that doxorubicin-cisplatin chemotherapy significantly improves both progression-free survival (50% vs 38%; P=0.07) and overall survival (55% vs 42%; P=0.004) compared to whole abdominal radiation 1
• Preferred first-line regimen: carboplatin plus paclitaxel 1
• Alternative: doxorubicin (60 mg/m²) plus cisplatin (50 mg/m²) every 3 weeks for 7 cycles, though this has higher toxicity 1
• For stage IIIA with ovarian involvement, maximal surgical cytoreduction followed by platinum-based chemotherapy is standard 4

Primary Advanced or Recurrent Disease

For primary advanced or recurrent endometrioid cancer, pembrolizumab combined with chemotherapy is now FDA-approved: 5

• Pembrolizumab 200 mg every 3 weeks plus carboplatin and paclitaxel for 6 cycles, followed by pembrolizumab 400 mg every 6 weeks as maintenance for up to 14 cycles 5
• This combination is approved for all patients with primary advanced or recurrent endometrial carcinoma regardless of biomarker status 5

Metastatic and Recurrent Disease

Locoregional Recurrence

• For vaginal recurrence: radiation therapy (external beam plus vaginal brachytherapy) is standard, achieving 50% 5-year survival 1
• For central pelvic recurrence: surgery or radiation therapy 1
• For regional pelvic recurrences: radiation therapy combined with chemotherapy when possible 1

Systemic Therapy for Metastatic Disease

• Hormonal therapy is recommended for endometrioid histologies only 1
• Medroxyprogesterone acetate 200 mg daily achieves 25% overall response rate in well-differentiated, steroid-receptor positive tumors 1
• Tamoxifen and aromatase inhibitors are alternative hormonal options 1
• For chemotherapy-naïve patients: paclitaxel-based combination regimens (carboplatin/paclitaxel or cisplatin/paclitaxel) are preferred, with response rates >60% 1
• For chemotherapy-resistant recurrent disease, only paclitaxel consistently shows response rates >20% 1

Advanced pMMR or Non-MSI-H Disease After Prior Chemotherapy

Pembrolizumab 200 mg every 3 weeks plus lenvatinib 20 mg orally daily is FDA-approved for patients with disease progression after prior platinum-based chemotherapy 5

Advanced MSI-H or dMMR Disease

Pembrolizumab 200 mg every 3 weeks as monotherapy is FDA-approved for MSI-H or dMMR endometrial cancer after prior systemic therapy 5

Special Considerations

Aggressive Histologic Subtypes (Serous, Clear Cell)

• These Type II cancers require complete staging including omentectomy, appendectomy, and peritoneal biopsies 1
• Platinum-based adjuvant chemotherapy improves progression-free and overall survival even in early-stage (I-II) disease 1
• Use the same chemotherapy regimens as for epithelial ovarian cancer 1

Elderly Patients

• Elderly patients (>63 years) have significantly worse outcomes independent of other factors 3
• Carboplatin/paclitaxel should be strongly considered as it is better tolerated than older regimens unless performance status is prohibitively poor 3

Critical Pitfalls to Avoid

• Do not use progestins as adjuvant treatment—current evidence shows no survival benefit 1
• Do not rely on vaginal cytology alone for surveillance—it has extremely poor sensitivity (0-7%) for detecting recurrence 2
• Most recurrences (80%) in high-risk stage I disease are extra-pelvic, occurring despite locoregional therapy, with median time to recurrence of 22.5 months 6
• 90% of recurrences occur in stage IB/IC patients, and 75% of patients with recurrence die of disease within a median of 8 months, emphasizing the need for systemic therapy in high-risk disease 6
• Patients should be counseled to immediately report symptoms (vaginal bleeding, abdominal/pelvic pain, unexplained weight loss, persistent cough) as 41-83% of recurrences are detected symptomatically rather than by surveillance testing 2