Endometrial Cancer
Endometrial Cancer
Endometrial Cancer Epidemiology in the USA: Incidence and Overview
Endometrial cancer (EC) is the most common gynecological malignancy in the United States, with approximately 66,200 new cases estimated in 2023, representing about 3.5% of all new cancer diagnoses among women. The incidence rate is around 19 to 28 per 100,000 women per year and has been steadily rising due to factors such as an aging population and increasing obesity rates .
The median age at diagnosis is 60 years, primarily affecting postmenopausal women, though younger women are increasingly affected. African American women are more likely to develop aggressive subtypes of EC compared to white women, contributing to significant racial disparities in outcomes .
This rising trend, linked to obesity and hormonal imbalances, underscores the need for preventive measures and early detection strategies to manage the growing burden of endometrial cancer in the U.S.
1. Pathology of Endometrial Cancer
Types of Endometrial Cancer:
Type I (Endometrioid carcinoma):
- Estrogen-dependent.
- More common (80-90%).
- Associated with hyperplasia.
- Common in perimenopausal women.
- Typically associated with a good prognosis.
- Histologically resembles normal endometrium.
Type II (Non-endometrioid carcinoma):
- Not estrogen-dependent.
- Occurs in older women.
- Less common (10-20%) but more aggressive.
- Frequently associated with p53 mutations and poor prognosis.
- Includes serous carcinoma, clear cell carcinoma, and carcinosarcoma.
2. Molecular Classification
The molecular classification of endometrial cancer is derived from The Cancer Genome Atlas (TCGA) and has four subgroups:
POLE ultramutated:
- Excellent prognosis.
- High mutation rates in the POLE gene.
- Low recurrence risk
Microsatellite instability (MSI-high):
- Intermediate prognosis.
- High mutation rates with defective mismatch repair (MMR) system.
Copy-number low (Endometrioid):
- Intermediate prognosis.
- Lower copy-number alterations.
Copy-number high (Serous-like):
- Poor prognosis.
- p53 mutations and significant chromosomal instability
3. Risk Factors for Endometrial Cancer
Endometrial cancer is the most common gynecological cancer, with certain factors significantly increasing the risk. Below are key risk factors, along with estimates of relative risk (RR) where available and further elaboration on two specific risk factors—Tamoxifen therapy and Lynch syndrome (hereditary nonpolyposis colorectal cancer – HNPCC).
1. Obesity
• Relative Risk (RR): 2.0 – 4.5
• Mechanism: Obesity is one of the most significant risk factors for endometrial cancer. Excess adipose tissue increases peripheral conversion of androgens to estrogens, leading to unopposed estrogen stimulation on the endometrium, promoting cellular proliferation.
2. Unopposed Estrogen Exposure
• RR: 2.0 – 10.0 (depending on duration of use and dose)
• Mechanism: Women who undergo hormone replacement therapy (HRT) using estrogen without progesterone have a significantly higher risk due to the continuous stimulation of the endometrium by estrogen without the counteracting effect of progesterone, leading to hyperplasia and potential malignancy.
3. Tamoxifen Therapy
• RR: 2.0 – 7.5
• Mechanism: Tamoxifen, used in the treatment of breast cancer, acts as an estrogen antagonist in breast tissue but behaves as an estrogen agonist in the endometrium. This paradoxical effect increases the risk of endometrial hyperplasia and cancer, especially with long-term use. The increased risk is dose-dependent and becomes more significant after five years of use.
4. Early Menarche or Late Menopause
• RR: 1.3 – 2.0
• Mechanism: Prolonged exposure to endogenous estrogen due to early onset of menstruation or delayed menopause increases lifetime exposure to estrogen, elevating the risk of endometrial cancer.
5. Nulliparity (Never Having Given Birth)
• RR: 2.0 – 3.0
• Mechanism: Pregnancy interrupts the cyclical estrogen exposure by increasing progesterone levels, providing protection to the endometrial lining. Nulliparous women do not benefit from this protective effect.
6. Polycystic Ovary Syndrome (PCOS)
• RR: 2.0 – 3.0
• Mechanism: PCOS is characterized by chronic anovulation, leading to sustained estrogen stimulation without progesterone opposition. This imbalance increases the risk of endometrial hyperplasia and cancer.
7. Family History of Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer – HNPCC)
• RR: 20 – 60% lifetime risk
• Mechanism: Lynch syndrome is a genetic condition caused by mutations in DNA mismatch repair genes. Women with Lynch syndrome have a significantly elevated lifetime risk of endometrial cancer (up to 60%) due to the accumulation of genetic mutations in the endometrial cells. This syndrome is also associated with a higher risk of colorectal and other cancers.
8. Diabetes and Hypertension
• RR: 1.5 – 2.0
• Mechanism: Both diabetes and hypertension are associated with metabolic and inflammatory changes that may promote endometrial carcinogenesis. Hyperinsulinemia, common in diabetics, increases bioavailable estrogen by reducing sex hormone-binding globulin (SHBG) levels, thus heightening the risk.
⦁ Kaaks, R., Lukanova, A., & Kurzer, M. S. (2002). Obesity, endogenous hormones, and endometrial cancer risk: a synthetic review. Cancer Epidemiology Biomarkers & Prevention, 11(12), 1531-1543.
⦁ Berstein, L. M. (2002). Tamoxifen use for the treatment of breast cancer: impact on the endometrium and the role of estrogen in the endometrial cancer development. International Journal of Gynecological Cancer, 12(3), 203-207.
⦁ Aarnio, M., Sankila, R., Pukkala, E., Salovaara, R., & Aaltonen, L. A. (1999). Cancer risk in mutation carriers of DNA-mismatch-repair genes. International Journal of Cancer, 81(2), 214-218.
⦁ Felix, A. S., Yang, H. P., Bell, D. W., & Sherman, M. E. (2017). Epidemiology of endometrial carcinoma: etiologic importance of hormonal and metabolic influences. Advances in Experimental Medicine and Biology, 943, 3-46
4. Diagnosis of Endometrial Cancer
⦁ Transvaginal ultrasound (TVUS):
⦁ Endometrial thickness >4 mm in postmenopausal women raises suspicion
⦁ Endometrial biopsy):
⦁ Gold standard for diagnosing endometrial carcinoma.
⦁ Dilation and curettage (D&C):
⦁ Used when biopsy results are inconclusive.
⦁ Hysteroscopy:
⦁ Allows visualization and biopsy of abnormal areas within the uterine cavity.
⦁ Imaging for staging:
⦁ MRI for local invasion and lymph node involvement.
⦁ CT scan for distant metastasis.
5. FIGO Staging for Endometrial Cancer (2018)
⦁ Stage I: Tumor confined to the uterus.
⦁ IA: Tumor limited to the endometrium or invades less than 50% of the myometrium.
⦁ IB: Tumor invades 50% or more of the myometrium.
⦁ Endometrial biopsy):
⦁ MRI for local invasion and lymph node involvement.
⦁ CT scan for distant metastasis.
⦁ Stage III: Local or regional spread
⦁ IIIA: Tumor invades serosa and/or adnexa.
⦁ IIIB: Vaginal or parametrial involvement.
⦁ IIIC: Metastasis to pelvic and/or para-aortic lymph nodes.
⦁ Stage IV: Distant spread.
⦁ IVA: Tumor invasion into bladder and/or bowel mucosa.
⦁ IVB: Distant metastasis, including intra-abdominal or inguinal lymph nodes.
6. Prognosis by Stage for Endometrial Cancer
The prognosis for endometrial cancer varies significantly depending on the stage at diagnosis. The 5-year survival rates for each stage are as follows:
⦁ Stage I: 5-year survival rate: 75-90%.
⦁ Stage II: 5-year survival rate: 60-75%.
⦁ Stage III: 5-year survival rate: 30-60%.
⦁ Stage IV: 5-year survival rate: 10-20%.
⦁ Creasman, W. T., Odicino, F., Maisonneuve, P., et al. (2006). Carcinoma of the corpus uteri. International Journal of Gynecology & Obstetrics, 95(Suppl 1), S105-S143.
⦁ SEER Cancer Statistics Review, 1975-2017, National Cancer Institute. Endometrial Cancer. Available at: https://seer.cancer.gov
⦁ Amant, F., Moerman, P., Neven, P., Timmerman, D., Van Limbergen, E., & Vergote, I. (2005). Endometrial cancer. The Lancet, 366(9484), 491-505.
Stage I Risk Stratification (GOG 99 and PORTEC Trials)
Risk stratification in Stage I endometrial cancer is essential to guide treatment decisions and determine the likelihood of cancer recurrence or progression. Stage I endometrial cancer is confined to the uterus, but the prognosis can vary widely depending on several factors. The goal of risk stratification is to identify patients who may benefit from additional treatments beyond surgery, such as radiation therapy or chemotherapy, to reduce the risk of recurrence.
GOG 99 Risk Stratification
The Gynecologic Oncology Group (GOG 99) trial stratified patients into risk groups based on stage I endometrial cancer. Key factors for risk include age, histologic grade, depth of invasion, and lymphovascular space invasion (LVSI).
PORTEC Risk Stratification
The PORTEC trial stratified patients with endometrial cancer into risk groups to guide adjuvant radiation therapy use. They identified the following groups:
Risk Group
Criteria
Low Risk
Grade 1 or 2, superficial invasion, no LVSI
Intermediate Risk
Grade 1 or 2, deep invasion or LVSI present; or Grade 3, superficial invasion without LVSI
High Risk
Grade 3 with deep invasion, or Grade 3 with superficial invasion and LVSI present
The trials suggest adjuvant radiation therapy for patients in the intermediate and high-risk groups to reduce locoregional recurrence
⦁ Recurrence
⦁ GOG LAP2:
⦁ Laparoscopy: 97/1,696 (5.9%).
⦁ Laparotomy: 53/920 (5.1%).
⦁ HR 1.14 (95% CI: 0.92–1.46, p = 0.25).
⦁ LACE:
⦁ Laparoscopy: 29/407 (7.1%).
⦁ Laparotomy: 24/353 (6.8%).
⦁ HR 1.14 (95% CI: 0.77–1.69, p = 0.52).
⦁ Disease-Free Survival (DFS):
⦁ GOG LAP2:
⦁ 3-year DFS: Laparoscopy 81.6% vs. Laparotomy 81.3%.
⦁ HR 1.06 (95% CI: 0.91–1.23, p = 0.44).
⦁ LACE:
⦁ 4.5-year DFS: Laparoscopy 81.6% vs. Laparotomy 81.3%.
⦁ HR 1.01 (95% CI: 0.79–1.29, p = 0.93).
⦁ Overall Survival (OS):
⦁ GOG LAP2:
⦁ 5-year OS: Laparoscopy 89.8% vs. Laparotomy 89.9%.
⦁ HR 1.04 (95% CI: 0.86–1.27, p = 0.67).
⦁ LACE:
⦁ 5-year OS: Laparoscopy 93.4% vs. Laparotomy 92.0%.
⦁ HR 1.02 (95% CI: 0.71–1.45, p = 0.91).
⦁ Walker, J. L., Piedmonte, M. R., Spirtos, N. M., et al. (2009). Recurrence and survival after random assignment to laparoscopy versus laparotomy for comprehensive surgical staging of uterine cancer: Gynecologic Oncology Group LAP2 Study. Journal of Clinical Oncology, 27(32), 5331-5336.
⦁ Janda, M., Gebski, V., Davies, L. C., et al. (2010). Effect of total laparoscopic hysterectomy versus total abdominal hysterectomy on disease-free and overall survival among women with stage I endometrial cancer: a randomized clinical trial. Journal of the American Medical Association (JAMA), 303(6), 559-567.
Sentinel Lymph node evaluation FIRES and SENTI-ENDO trials
FIRES Trial (2017):
⦁ Objective: To assess the accuracy of sentinel lymph node (SLN) biopsy in detecting lymph node metastases in early-stage endometrial cancer.
⦁ Inclusion Criteria:
⦁ Patients with clinical stage I endometrial cancer.
⦁ Histologically confirmed endometrioid, serous, clear cell, or mixed histologies.
⦁ Patients deemed suitable for hysterectomy and lymph node staging.
⦁ Key Findings:
⦁ Sensitivity: 97.2% for detecting node-positive disease.
⦁ Negative Predictive Value: 99.6%, confirming the reliability of SLN biopsy.
SENTI-ENDO Trial:
This study evaluated sentinel lymph node (SLN) biopsy in patients with FIGO stage I-II endometrial cancer using cervical dual injection with technetium and patent blue, followed by systematic pelvic-node dissection. The primary endpoint was the negative predictive value (NPV) of SLN biopsy per hemipelvis.
Findings:
⦁ Patients enrolled: 133 from nine centers in France (July 5, 2007 – Aug 4, 2009).
⦁ Safety: No complications were observed after the technetium or patent blue injections, and no surgical complications occurred during SLN biopsy, including cases requiring conversion to open surgery.
⦁ SLN detection: At least one SLN was detected in 111 out of 125 eligible patients (89%).
⦁ Metastasis: 19 of 111 patients (17%) had pelvic lymph node metastases, with 5% also having para-aortic SLNs.
⦁ NPV and Sensitivity:
⦁ Hemipelvis analysis: NPV was 100% (95% CI 95-100), and sensitivity was 100% (63-100).
⦁ Patient-level analysis: Three false-negative results were observed, giving an NPV of 97% (95% CI 91-99) and sensitivity of 84% (62-95). All false-negative patients had type 2 endometrial cancer.
⦁ Immunohistochemistry: Detected metastases missed by conventional histology in 8% of patients, representing 47% of those with metastases.
⦁ Upstaging: SLN biopsy upstaged 10% of patients with low-risk and 15% with intermediate-risk endometrial cancer.
NCCN Recommendations:
⦁ SLN biopsy is recommended for early-stage endometrial cancer as a less invasive alternative to complete pelvic and para-aortic lymphadenectomy, particularly for patients with intermediate- or high-risk histologies.
⦁ Indocyanine green (ICG) is the preferred tracer for SLN mapping, and ultrastaging should be used to detect micrometastases.
⦁ If SLN mapping fails, selective lymphadenectomy should be performed to ensure adequate staging.
The FIRES and SENTI-ENDO trials validate the NCCN’s guidelines by demonstrating the high sensitivity, accuracy, and feasibility of SLN biopsy, making it a safe and effective approach to staging in early-stage endometrial cancer.
NCCN Recommendations:
⦁ National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Uterine Neoplasms. Version 1.2024. Available at: https://www.nccn.org
⦁ Ballester, M., Dubernard, G., Lecuru, F., et al. (2011). Detection rate and diagnostic accuracy of sentinel-node biopsy in early stage endometrial cancer: SENTI-ENDO, aprospective multicentre study. The Lancet Oncology, 12(5), 469-476.
⦁ Rossi, E. C., Kowalski, L. D., Scalici, J., et al. (2017). A comparison of sentinel lymph node biopsy to lymphadenectomy for endometrial cancer staging (FIRES trial): a multicentre, prospective, cohort study. The Lancet Oncology, 18(3), 384-392.
Non-Surgical Treatment for Stage I and II Endometrial Cancer (with Recurrence Rates and Monitoring)
Non-surgical treatments, progesterone therapy and radiation therapy, are used in specific cases of stage I and II endometrial cancer, such as for patients who are not candidates for surgery or those wishing to preserve fertility. Below are the key non-surgical options, along with recurrence rates, monitoring recommendations, and when to consider surgery.
1. Hormonal Therapy (Progesterone Therapy)
⦁ Indications:
⦁ Early-stage (stage I) low-grade (grade 1 or 2) endometrioid adenocarcinoma.
⦁ Patients desiring fertility preservation or those with medical contraindications to surgery. 30-40% of women who achieve a complete response and attempt pregnancy may be able to successfully conceive and carry a pregnancy to term.
⦁ Agents:
⦁ Oral Progestins:
⦁ Medroxyprogesterone acetate (MPA) or megestrol acetate.
⦁ Levonorgestrel-Releasing Intrauterine Device (IUD):
⦁ Provides localized progestin delivery with fewer systemic side effects.
⦁ Effectiveness
⦁ Complete response rates range from 50% to 75% for low-grade stage I disease.
⦁ Recurrence Rates:
⦁ Recurrence after hormonal therapy is relatively common, with reported recurrence rates of up to 30-40% in certain cases, especially in higher-grade tumors or in patients with deep myometrial invasion
⦁ Monitoring on Progesterone Therapy:
⦁ Regular Endometrial Biopsies: Every 3 to 6 months is recommended to assess the response to therapy and check for disease persistence or recurrence.
⦁ Imaging Studies:
⦁ Use transvaginal ultrasound or MRI as needed to monitor endometrial thickness and uterine structure.
2. Radiation Therapy
⦁ Indications:
⦁ Used as primary treatment in patients who are not candidates for surgery due to comorbidities or advanced age.
⦁ Types:
⦁ Vaginal Brachytherapy (VBT): Focuses on preventing local recurrence in patients with early-stage disease.
⦁ External Beam Radiation Therapy (EBRT): Targets the pelvic lymph nodes and surrounding tissue, often reserved for more advanced disease or higher-risk patients.
Recurrence Rates by Treatment Modality:
⦁ Hormonal Therapy (Progesterone): 30-40% recurrence, especially in higher-risk cases.
⦁ Vaginal Brachytherapy (VBT): 5-10% recurrence in stage I, low-grade disease.
When to Consider Surgery:
⦁ Failure to respond to hormonal therapy after 6 months.
⦁ Progression of disease during non-surgical treatment.
⦁ Recurrence after hormonal or radiation therapy.
⦁ Higher-grade or more aggressive histologies (e.g., grade 3 or non-endometrioid tumors).
⦁ National Comprehensive Cancer Network (NCCN). Uterine Neoplasms (Version 1.2024). NCCN Clinical Practice Guidelines in Oncology. ⦁ https://www.nccn.org
⦁ Colombo, N., et al. (2016). ESMO-ESGO-ESTRO consensus conference on endometrial cancer: Diagnosis, treatment, and follow-up. Annals of Oncology, 27(1), 16-41.
⦁ Randall, M. E., et al. (2017). Phase III trial of pelvic radiation therapy versus vaginal brachytherapy followed by chemotherapy in high-risk early-stage endometrial cancer. Journal of Clinical Oncology, 35(34), 4030-4035.
Adjuvant Treatment:
Low-Risk Group (Stage IA, Grade 1-2)
⦁ Surgical management typically consists of hysterectomy ± BSO without the need for adjuvant therapy.
⦁ No myometrial invasion or minimal invasion (<50%).
Intermediate-Risk Group (Stage IA, Grade 3 or Stage IB, Grade 1-2)
⦁ Adjuvant treatment: Vaginal brachytherapy (VBT) is often used in patients with intermediate risk to prevent local recurrence, particularly in stage IB.
⦁ Lymphovascular space invasion (LVSI) influences the decision for adjuvant therapy.
High-Risk Group (Stage IB, Grade 3, Stage II)
⦁ Surgical management: Hysterectomy, BSO, and pelvic lymphadenectomy.
⦁ Adjuvant therapy: External beam radiation therapy (EBRT) ± chemotherapy is often considered.
⦁ Stage II patients may require radical hysterectomy or post-operative radiotherapy and chemotherapy.
PORTEC-1 Trial (Post-Operative Radiation Therapy in Endometrial Carcinoma)
⦁ Published: 2000
⦁ Objective: Evaluated the role of post-operative radiation therapy in patients with stage I endometrial cancer.
⦁ Inclusion Criteria: Stage IB Grade 1 or 2, Stage IA Grade 3, or Stage IB Grade 3 (endometrioid type).
⦁ Treatment Arms:
⦁ Arm 1: Observation.
⦁ Arm 2: Pelvic radiotherapy (46 Gy in 23 fractions).
⦁ Results:
⦁ Recurrence rate: Lower in the radiotherapy arm (5%) vs. observation (14%) (p < 0.001).
⦁ 5-year progression-free survival (PFS): 85% in the radiotherapy group vs. 75% in the observation group.
⦁ Overall survival (OS): No significant difference (82% vs. 85%).
PORTEC-2 Trial
⦁ Published: 2010
⦁ Objective: Compared pelvic radiotherapy (EBRT) with vaginal brachytherapy (VBT) in high-intermediate risk endometrial cancer patients.
⦁ Inclusion Criteria: Stage IA Grade 3 with LVSI, Stage IB Grade 1 or 2, Stage IB Grade 3, or Stage II.
⦁ Treatment Arms:
⦁ Arm 1: EBRT (46 Gy in 23 fractions).
⦁ Arm 2: VBT (21 Gy in 3 fractions or 30 Gy in 5 fractions).
⦁ Results:
⦁ 5-year recurrence rate: Similar between groups (VBT: 1.8%, EBRT: 1.6%).
⦁ PFS: 82% in both groups.
⦁ OS: No significant difference (80% vs. 85%).
⦁ Conclusion: VBT is an effective alternative to EBRT with fewer side effects.
GOG-99 Trial (Gynecologic Oncology Group)
⦁ Published: 2004
⦁ Objective: Studied the benefit of pelvic radiation therapy in early-stage endometrial cancer.
⦁ Inclusion Criteria: Stage IB Grade 1 or 2 with deep myometrial invasion or Stage IB Grade 3.
⦁ Treatment Arms:
⦁ Arm 1: Pelvic radiotherapy (50.4 Gy).
⦁ Arm 2: Observation.
⦁ Results:
⦁ 5-year recurrence rate: 3% in the radiation group vs. 12% in the observation group.
⦁ 5-year OS: 92% in the radiation group vs. 86% in the observation group (p = 0.007).
⦁ Conclusion: Radiation significantly reduced locoregional recurrence but did not impact overall survival.
PORTEC-3 (Stage I and II Results)
⦁ Published: 2018
⦁ Objective: Evaluated the benefit of chemoradiotherapy (CRT) vs. radiotherapy (RT) alone in high-risk endometrial cancer.
⦁ Treatment Arms:
⦁ Arm 1: Radiotherapy alone (48.6 Gy in 27 fractions).
⦁ Arm 2: Chemoradiotherapy (CRT) – 48.6 Gy radiotherapy with concurrent cisplatin (50 mg/m²), followed by 4 cycles of carboplatin AUC 5 and paclitaxel 175 mg/m².
⦁ Stage I/II Outcomes:
⦁ 5-year PFS:
⦁ CRT: 78%
⦁ RT alone: 68%
⦁ Hazard Ratio (HR): 0.65 (95% CI: 0.41–1.04), p = 0.07.
⦁ 5-year OS:
⦁ CRT: 86%
⦁ RT alone: 80%
⦁ HR: 0.65 (95% CI: 0.37–1.16), p = 0.15.
The results suggest that while there was a trend toward improved progression-free survival (PFS) in stage I/II patients receiving CRT, statistical significance was not reached(ESMO)(SpringerLink).
GOG-249
⦁ Published: 2019
⦁ Objective: Compared vaginal brachytherapy (VBT) with chemotherapy (carboplatin and paclitaxel) vs. pelvic radiation therapy (RT) in high-intermediate and high-risk early-stage endometrial cancer.
⦁ Stage I/II Outcomes:
⦁ 5-year PFS:
⦁ VBT + chemotherapy: 76%
⦁ Pelvic RT: 83%
⦁ HR: 1.20 (95% CI: 0.82–1.75), p = 0.36.
⦁ 5-year OS
⦁ VBT + chemotherapy: 88%
⦁ Pelvic RT: 91%
⦁ HR: 1.32 (95% CI: 0.71–2.46), p = 0.38.
In stage I and II patients, the study showed no significant benefit of adding chemotherapy to VBT over pelvic RT alone in terms of PFS or OS(ESMO)(SpringerLink).
⦁ Creutzberg CL et al. “PORTEC-1: Radiotherapy in Stage I Endometrial Cancer” J Clin Oncol, 2000.
⦁ Nout RA et al. “PORTEC-2: Vaginal Brachytherapy vs. Pelvic Radiotherapy” Lancet, 2010.
⦁ Keys HM et al. “GOG-99: Pelvic Radiation in Stage I Endometrial Cancer” Gynecol Oncol, 2004.
⦁ de Boer SM et al. “PORTEC-3: Chemoradiation vs. Radiotherapy Alone” Lancet Oncol, 2018.
⦁ Randall ME et al. “GOG-249: Vaginal Brachytherapy vs. Pelvic Radiation” J Clin Oncol, 2019.
Stage III/IV Endometrial Cancer
Surgical Treatment for Stage III and IV (IVA/IVB) Endometrial Cancer
In stage III and IV endometrial cancer, the primary goal is maximal cytoreduction to remove as much tumor as possible. Complete resection may not always be achievable, particularly in stage IV disease, but reducing tumor burden can improve outcomes.
Stage III Endometrial Cancer
⦁ Total Hysterectomy and Bilateral Salpingo-Oophorectomy (TH/BSO):
⦁ Standard procedure for removing the uterus, ovaries, and fallopian tubes.
⦁ Lymph Node Dissection:
⦁ Pelvic and Para-aortic Lymphadenectomy is performed to evaluate lymph node involvement and to remove any affected nodes.
⦁ Cytoreductive Surgery:
⦁ The goal is to remove all visible tumors or reduce the tumor burden to improve patient outcomes. This may involve the removal of nearby affected tissues or organs, such as the bowel or bladder, if invaded by the cancer.
⦁ Omentectomy:
⦁ In some cases, removal of the omentum (a fatty layer in the abdomen) may be performed if there is suspected metastasis.
Stage IV (IVA/IVB) Endometrial Cancer
⦁ Maximal Cytoreduction:
⦁ For stage IVA and IVB, surgery aims to debulk or remove as much of the tumor as possible. This may involve:
⦁ Bladder or Bowel Resection: Partial resection of the bladder or bowel may be necessary if the tumor has invaded these structures.
⦁ Removal of Metastatic Lesions: In patients with stage IVB disease, surgery may include removing large or symptomatic metastases, though complete resection may not be feasible in most cases.
⦁ Palliative Surgery:
In advanced cases, surgery may be performed to alleviate symptoms (such as bowel obstruction or excessive bleeding) rather than to cure the disease.
⦁ Total Hysterectomy with Bilateral Salpingo-Oophorectomy
As in stage III, a hysterectomy with removal of the ovaries and fallopian tubes is often performed, even in cases with distant metastasis, as part of cytoreductive efforts.
In conclusion, surgery for advanced-stage endometrial cancer focuses on cytoreduction to improve outcomes, particularly in patients with stage III and IVA/IVB disease, even when complete removal of the tumor is not always possible.
⦁ National Comprehensive Cancer Network (NCCN). Uterine Neoplasms (Version 1.2024). NCCN Clinical Practice Guidelines in Oncology. Available at: ⦁ https://www.nccn.org.
⦁ Colombo, N., Creutzberg, C., Amant, F., et al. (2016). ESMO-ESGO-ESTRO consensus conference on endometrial cancer: Diagnosis, treatment, and follow-up. Annals of Oncology, 27(1), 16-41.
⦁ Bristow, R. E., et al. (2000). Cytoreductive surgery for advanced stage endometrial carcinoma: The role of maximal surgical effort. Gynecologic Oncology, 78(1), 85-91.
Adjuvant systemic chemotherapy and radiation therapy for Stage III/IVa Disease
Adjuvant Therapy in Stage III and IVA Endometrial Cancer
For Stage III and IVA endometrial cancer. Adjuvant therapies typically include chemotherapy, radiation therapy, or a combination of both (chemoradiation), depending on the extent of disease and patient risk factors. More recently immunotherapy has been combined with chemotherapy as we will review later.
1. Adjuvant Chemotherapy
⦁ Carboplatin and Paclitaxel:
⦁ The recommended chemotherapy regimen for Stage III and IVA endometrial cancer is carboplatin and paclitaxel. This platinum-based regimen targets both local and distant microscopic disease and has been shown to improve progression-free survival (PFS) and overall survival (OS) in patients with advanced disease.
⦁ Trials such as NRG GY018 and RUBY (GOG-3031) suggest the addition of pembrolizumab or dostarlimab to standard chemotherapy for patients with both pMMR and dMMR tumors, significantly improving PFS and OS.
2. Adjuvant Radiation Therapy
⦁ External Beam Radiation Therapy (EBRT):
⦁ Pelvic radiation (EBRT) is recommended for local control in patients with pelvic lymph node involvement or parametrial extension.
⦁ Radiation therapy can help reduce the risk of local recurrence in both Stage III and IVA disease, especially when combined with chemotherapy.
⦁ Vaginal Brachytherapy (VBT):
⦁ VBT may be added to reduce the risk of vaginal recurrence, especially for patients with high-risk features or after extensive local resection.
3. Adjuvant Chemoradiation
⦁ External Beam Radiation Therapy (EBRT):
⦁ Either sequential chemoradiation or concurrent chemoradiation (where chemotherapy and radiation are administered together). This approach is recommended for patients with high-risk Stage III and IVA disease to provide both local control and systemic disease management.
Chemoradiation Therapy in Stage III Endometrial Cancer:
Both the EORTC 55991 and MANGO ILIADE-III trials are pivotal studies investigating the role of chemoradiation therapy in patients with Stage III and high-risk endometrial cancer. Below is a detailed summary of each trial, including inclusion criteria, number of patients, treatment arms, and outcomes (Progression-Free Survival, Overall Survival, HR, CI, and p-values).
1. EORTC 55991 Trial
⦁ To evaluate whether chemotherapy combined with radiation therapy (sequential chemoradiation) improves outcomes compared to radiation therapy alone in patients with high-risk endometrial cancer, including Stage III disease.
⦁ High-risk Stage I–III endometrial cancer. Patients with Stage III disease were included if they had pelvic lymph node involvement, deep myometrial invasion, or other high-risk features. Patients were required to have undergone surgery (total hysterectomy and bilateral salpingo-oophorectomy).
⦁ 382 patients with high-risk Stage I–III endometrial cancer. A significant portion had Stage III disease.
Treatment Arms:
⦁ Radiation Alone: External beam radiation therapy (EBRT) to the pelvis.
⦁ Sequential Chemoradiation: External beam radiation therapy followed by chemotherapy (cisplatin + doxorubicin).
Outcomes:
The NSGO-EC-9501/EORTC-55991 study compared radiation therapy (RT) alone with combined radiation and chemotherapy (RT-CT) in patients with endometrial cancer. The following are the key findings:
Progression-Free Survival (PFS):
⦁ Events: 50 in the RT group, 26 in the RT-CT group.
⦁ Hazard Ratio (HR): 0.64 (95% CI 0.41-0.99), P = 0.04, indicating a significant benefit for RT-CT.
⦁ 5-year PFS probability: 72% for RT vs. 79% for RT-CT.
Overall Survival (OS):
⦁ Events: 40 in the RT group, 21 in the RT-CT group.
⦁ HR: 0.66 (95% CI 0.40-1.08), P = 0.10, showing a non-significant trend toward improved OS with RT-CT.
⦁ 5-year OS probability: 76% for RT vs. 83% for RT-CT.
Overall Survival (OS):
⦁ Events: 34 in the RT group, 18 in the RT-CT group.
⦁ HR: 0.51 (95% CI 0.28-0.90), P = 0.02, indicating a significant improvement in CSS with RT-CT.
⦁ 5-year CSS probability: 79% for RT vs. 88% for RT-CT.
⦁ Sequential chemoradiation improved progression-free survival and local control in high-risk and Stage III endometrial cancer patients compared to radiation alone. The combination therapy also showed a trend toward improved overall survival.
2. MANGO ILIADE-III Trial
⦁ To assess whether concurrent chemoradiation (chemotherapy given during radiation) improves outcomes over radiation therapy alone in patients with high-risk endometrial cancer, with a particular focus on Stage III disease.
⦁ Patients with Stage III endometrial cancer or other high-risk features (e.g., deep myometrial invasion, lymph node involvement). All patients had undergone surgery (total hysterectomy and bilateral salpingo-oophorectomy).
⦁ 156 patients were enrolled, with a significant portion having Stage III disease.
Treatment Arms:
⦁ Radiation Alone:
⦁ External beam radiation therapy (EBRT) to the pelvis.
⦁ Concurrent Chemoradiation:
⦁ External beam radiation therapy (EBRT) + concurrent chemotherapy (cisplatin).
Outcomes:
MaNGO ILIADE III study compared radiation therapy (RT) alone with combined radiation and chemotherapy (RT-CT) in patients with endometrial cancer. Here are the key findings:
Progression-Free Survival (PFS):
⦁ Events: 26 in the RT group, 34 in the RT-CT group.
⦁ Hazard Ratio (HR): 0.61 (95% CI 0.33-1.12), P = 0.10, showing a non-significant trend toward improved PFS with RT-CT.
⦁ 5-year PFS probability: 61% for RT vs. 74% for RT-CT.
Overall Survival (OS):
⦁ Events: 17 in the RT group, 22 in the RT-CT group.
⦁ HR: 0.74 (95% CI 0.36-1.52), P = 0.41, indicating no significant difference in OS between the groups.
⦁ 5-year OS probability: 73% for RT vs. 78% for RT-CT.
Cancer-Specific Survival (CSS):
⦁ Events: 15 in the RT group, 20 in the RT-CT group.
⦁ HR: 0.65 (95% CI 0.30-1.44), P = 0.29, showing no significant difference in CSS between the groups.
⦁ 5-year CSS probability: 76% for RT vs. 82% for RT-CT.
Summary:
In the MaNGO ILIADE III study, there was a trend toward improved PFS and CSS with RT-CT compared to RT alone, but the differences were not statistically significant. The OS was also not significantly different between the two groups.
Systemic Therapy with or without radiation therapy
Chemotherapy is vital in treating stage III and IV endometrial cancer, either alone or combined with radiation therapy, as evidenced by key clinical trials. The GOG-122 trial established that chemotherapy with doxorubicin and cisplatin significantly improves progression-free and overall survival compared to whole abdominal radiotherapy (5-year OS: 55% vs. 42%; hazard ratio [HR] 0.68; p < 0.01). The PORTEC-3 trial showed that adding chemotherapy to pelvic radiotherapy enhances 5-year failure-free survival (75.5% vs. 68.6%; HR 0.71; p = 0.022) but doesn’t significantly improve overall survival, suggesting better disease control without extending survival for all high-risk patients. The GOG-249 trial found no significant difference in 5-year recurrence-free survival or overall survival between vaginal brachytherapy plus chemotherapy and pelvic radiotherapy alone, indicating that radiotherapy alone remains effective for certain patients. Similarly, the GOG-258 trial revealed no significant difference in recurrence-free survival or overall survival between chemoradiotherapy and chemotherapy alone in stage III/IVA disease, though chemoradiotherapy reduced locoregional recurrences but had higher distant metastases, suggesting chemotherapy alone is effective for systemic control. In summary, chemotherapy remains fundamental for systemic disease management in advanced endometrial cancer; while combining it with radiation therapy may reduce local recurrences in specific patients, it doesn’t universally enhance overall survival, so treatment should be individualized based on patient needs and evidence from these trials.Chemotherapy Trials for Stage III/IV with or without radiation therapy
1. GOG-122 (Published 2004)
⦁ Inclusion Criteria: Stage III/IV post-surgery.
⦁ Treatment Arms:
⦁ Arm 1: Whole abdominal radiotherapy (WAR).
⦁ Arm 2: Chemotherapy (doxorubicin 60 mg/m² + cisplatin 50 mg/m² for 8 cycles).
⦁ PFS: 50% in the chemotherapy group vs. 38% in the WAR group.
⦁ OS: 5-year OS was 55% in the chemotherapy group vs. 42% in the WAR group.
⦁ HR: HR for OS = 0.68 (95% CI: 0.52–0.89), p < 0.01.
⦁ Reference: Marcus E. Randall, et al., 2004.
2. PORTEC-3 (Published 2018)
⦁ Inclusion Criteria: Stage IB Grade 3, Stage II/III, or serous/clear cell histology.
⦁ Treatment Arms:
⦁ Arm 1: Pelvic radiotherapy (48.6 Gy).
⦁ Arm 2: Chemoradiotherapy (cisplatin 50 mg/m² during RT, followed by carboplatin AUC 5 + paclitaxel 175 mg/m² for 4 cycles).
⦁ FFS: 5-year FFS was 75.5% in the chemoradiotherapy group vs. 68.6% in the RT group. HR: HR 0.71, 95% CI 0.53–0.95; p=0.022).
⦁ OS: 5-year OS was 81.8% in the chemoradiotherapy group vs. 76.7% in the RT group, HR 0.76, 95% CI (0.54–1·06; p=0.11);
⦁ Reference: de Boer et al., 2018.
3. GOG-249 (Published 2019)
⦁ Inclusion Criteria: Stage III/IV or high-risk early-stage (IB Grade 3, Stage II).
⦁ Treatment Arms:
⦁ Arm 1: Vaginal brachytherapy (VBT) + chemotherapy (carboplatin AUC 6 + paclitaxel 175 mg/m²).
⦁ Arm 2: Pelvic radiation therapy (RT).
⦁ RFS: 5-year RFS was 76%% in the VBT + chemotherapy group vs. 76% in the RT group, HR 0.92 95% CI(0.65 – 1.30), p=0.31
⦁ OS: 5-year OS was 85% in the VBT + chemotherapy group vs. 87% in the RT group, HR for OS = 1.04 (95% CI: 0.66 – 1.63), p = 0.52.
⦁ Reference: Creutzberg et al., 2019.
4. GOG-258 (Published 2019)
⦁ Inclusion Criteria: Stage III/IVA endometrial cancer, Stage I/II serous/clear cell histologies.
⦁ Treatment Arms:
⦁ Arm 1: Chemotherapy (carboplatin AUC 5 + paclitaxel 175 mg/m² for 6 cycles).
⦁ Arm 2: Chemoradiotherapy (pelvic RT + cisplatin during RT, followed by carboplatin + paclitaxel).
⦁ RFS: 59% chemoradiotherapy vs. 58% chemotherapy group, HR for PFS = 0.90 (95% CI: 0.74–1.10), p = 0.55.
⦁ OS: Overall survival not significant, median follow-up of 112 months documented 134 deaths in the chemoradiotherapy group and 125 in the chemotherapy-alone group (HR = 1.05; 95% CI = 0.82–1.34).
⦁ Reference: Matei D, Filiaci V, Randall ME, et al: Adjuvant chemotherapy plus radiation for locally advanced endometrial cancer. ⦁ N Engl J Med 380:2317-2326, 2019.
⦁ Homesley, H. D., Filiaci, V., Gibbons, S. K., et al. (2004). Randomized phase III trial in advanced endometrial carcinoma of whole-abdominal irradiation versus doxorubicin and cisplatin chemotherapy: a Gynecologic Oncology Group Study. Journal of Clinical Oncology, 22(1), 123-126. DOI: 10.1200/JCO.2004.03.049
⦁ de Boer, S. M., Powell, M. E., Mileshkin, L., et al. (2018). Adjuvant chemoradiotherapy versus radiotherapy alone for women with high-risk endometrial cancer (PORTEC-3): final results of an international, open-label, multicentre, randomised, phase 3 trial. The Lancet Oncology, 19(3), 295-309. DOI: 10.1016/S1470-2045(18)30079-2
⦁ Creutzberg, C. L., van Putten, W. L., Kitchener, H. C., et al. (2019). Adjuvant chemotherapy versus radiotherapy alone for women with high-risk endometrial cancer (GOG-249): an open-label, multicentre, randomised, phase 3 trial. The Lancet, 394(10206), 1929-1935. DOI: 10.1016/S0140-6736(19)32510-2
⦁ Matei, D., Filiaci, V., Randall, M. E., et al. (2019). Adjuvant chemotherapy plus radiation for locally advanced endometrial cancer. The New England Journal of Medicine, 380(24), 2317-2326. DOI: 10.1056/NEJMoa1813181
Chemoimmunotherapy for Stage III/IV or recurrent endometrial cancer:
Recent trials have shown the growing impact of immunotherapy in advanced and recurrent endometrial cancer, especially in patients with dMMR tumors. The AtTEnd trial found atezolizumab combined with chemotherapy modestly improved PFS, with greater benefits seen in dMMR patients. The DUO-E trial showed that adding durvalumab plus olaparib significantly enhanced PFS and OS compared to chemotherapy alone. The NRG-GY018 trial demonstrated that pembrolizumab with chemotherapy improved PFS, particularly in dMMR patients, while pMMR patients saw a smaller benefit. The RUBY trial confirmed that dostarlimab combined with chemotherapy improved PFS for dMMR patients and overall. These trials collectively highlight the effectiveness of combining immunotherapy with chemotherapy in improving outcomes, particularly for dMMR endometrial cancer.
1. NRG GY018 (Published 2023)
⦁ Inclusion Criteria: Stage III/IV or recurrent endometrial cancer.
⦁ Treatment Arms:
⦁ Arm 1: Chemotherapy (carboplatin + paclitaxel) + pembrolizumab.
⦁ Arm 2: Chemotherapy alone.
⦁ mPFS:
⦁ dMMR cohort: Not reached vs. 7.6 months in chemotherapy alone. 12 months PFS 78% vs 38%, HR 0.30 (95% CI, 0.19–0.48) p < 0.001.
⦁ pMMR cohort: 13.1 vs. 8.7 months in the chemotherapy alone group HR 0.54 (95% CI, 0.41–0.71), p < 0.001.
⦁ OS: Ongoing follow-up.
⦁ Reference: Eskander et al., 2023.
2. RUBY (GOG-3031, Published 2023)
⦁ Inclusion Criteria: Stage III/IV or recurrent endometrial cancer (dMMR and pMMR).
⦁ Treatment Arms:
⦁ Arm 1: Chemotherapy + dostarlimab.
⦁ Arm 2: Chemotherapy alone.
dMMR–MSI-H population:
⦁ PFS at 24 months: 61.4% with dostarlimab vs. 15.7% with placebo (HR 0.28; 95% CI 0.16-0.50; P < 0.001).
In the overall population:
⦁ PFS at 24 months: 36.1% with dostarlimab vs. 18.1% with placebo (HR 0.64; 95% CI 0.51-0.80; P < 0.001).
⦁ OS at 24 months: 71.3% with dostarlimab vs. 56.0% with placebo (HR 0.64; 95% CI 0.46-0.87).
3. DUO-E Trial (Published 2023)
⦁ Inclusion Criteria: Newly diagnosed advanced or recurrent endometrial cancer.
⦁ Treatment Arms:
⦁ Arm 1: Chemotherapy + durvalumab + olaparib.
⦁ Arm 2: Chemotherapy + durvalumab.
⦁ Arm 3: Chemotherapy alone.
In this study, 718 patients were randomly assigned to three treatment arms: durvalumab, durvalumab + olaparib, or control. Here are the key findings:
⦁ Progression-Free Survival (PFS):
⦁ Durvalumab vs. control: HR 0.71 (95% CI, 0.57-0.89); P = 0.003, with median PFS of 10.2 months (durvalumab) vs. 9.6 months (control).
⦁ Durvalumab + olaparib vs. control: HR 0.55 (95% CI, 0.43-0.69); P < 0.0001, with median PFS of 15.1 months (durvalumab + olaparib) vs. 9.6 months (control).
The PFS Kaplan-Meier curves showed separation starting at approximately 6 months, favoring both durvalumab and durvalumab + olaparib over control, suggesting a delayed treatment effect for durvalumab. Sensitivity analyses were consistent with the investigator-assessed results.
⦁ Subgroup analyses:
⦁ dMMR:
⦁ Durvalumab vs. control: HR 0.42 (95% CI, 0.22-0.80), median PFS not reached (durvalumab) vs. 7.0 months (control).
⦁ Durvalumab + olaparib vs. control: HR 0.41 (95% CI, 0.21-0.75), median PFS of 31.8 months (durvalumab + olaparib) vs. 7.0 months (control).
⦁ PD-L1 status:
⦁ PD-L1–positive:
⦁ Durvalumab vs. control: HR 0.63 (95% CI, 0.48-0.83), median PFS 11.3 vs. 9.5 months.
⦁ Durvalumab + olaparib vs. control: HR 0.42 (95% CI, 0.31-0.57), median PFS 20.8 vs. 9.5 months.
⦁ PD-L1–negative:
⦁ Durvalumab vs. control: HR 0.89 (95% CI, 0.59-1.34), median PFS 9.7 vs. 9.9 months.
⦁ Durvalumab + olaparib vs. control: HR 0.80 (95% CI, 0.55-1.16), median PFS 10.1 vs. 9.9 months.
⦁ Reference: Shannon N. Westin, et al., 2023.
4. ATTEND Trial (9/2024)
⦁ Inclusion Criteria: Advanced or recurrent endometrial cancer.
⦁ Treatment Arms: Chemoimmunotherapy arms.
551 patients were randomized to atezolizumab (n=362) or placebo (n=189), with a median follow-up of 28.3 months.
⦁ dMMR population
⦁ PFS: Atezolizumab: not estimable (95% CI 12.4 months–NE) vs. placebo: 6.9 months (95% CI 6.3–10.1), HR 0.36 (95% CI 0.23–0.57), P = 0.0005.
⦁ pMMR population
⦁ Atezolizumab treatment did not improve progression-free survival or overall survival
⦁ Overall population
⦁ PFS: Atezolizumab: 10.1 months (95% CI 9.5–12.3) vs. placebo: 8.9 months (95% CI 8.1–9.6), HR 0.74 (95% CI 0.61–0.91), P = 0.022.
⦁ OS: Atezolizumab: 38.7 months (95% CI 30.6–NE) vs. placebo: 30.2 months (95% CI 25.0–37.2), HR 0.82 (95% CI 0.63–1.07), P = 0.048.
Adverse events:
⦁ Neutropenia (grade 3-4): Atezolizumab: 27% vs. placebo: 28%.
⦁ Anemia (grade 3-4): Atezolizumab: 14% vs. placebo: 13%.
⦁ Serious AEs: Atezolizumab: 13% vs. placebo: 3%.
⦁ Treatment-related deaths: Two total (one per group).
Reference: Atezolizumab and chemotherapy for advanced or recurrent endometrial cancer (AtTEnd): a randomised, double-blind, placebo-controlled, phase 3 trial Colombo, NicolettaZola, Paolo et al. The Lancet Oncology, Volume 25, Issue 9, 1135 – 1146
Abbreviations:
⦁ Chemo: Chemotherapy (carboplatin + paclitaxel)
⦁ PFS: Progression-Free Survival
⦁ OS: Overall Survival
⦁ HR: Hazard Ratio
⦁ CI: Confidence Interval
⦁ dMMR: Deficient Mismatch Repair
⦁ pMMR: Proficient Mismatch Repair
⦁ MSI-H: Microsatellite Instability-High
⦁ NE: Not Estimable
Single agent immunotherapy for Advanced or recurrent endometrial cancer:
PHAEDRA (Phase II, 2018)
Patients with advanced endometrial cancer, categorized as either MMR-deficient (dMMR) or MMR-proficient (pMMR), who had progressed after 0-3 lines of chemotherapy. Patients received durvalumab 1500 mg IV every 4 weeks. ORR was 47% (17/36) in dMMR patients and 3% (1/35) in pMMR patients. The median PFS was 8.3 months for dMMR patients and 1.8 months for pMMR patients.
KEYNOTE-158 (Phase II, 2020)
Patients with advanced MSI-H/dMMR endometrial cancer who were previously treated. Patients received pembrolizumab 200 mg once every 3 weeks for up to 35 cycles. The objective response rate (ORR) was 48% (95% CI, 37% to 60%). The median progression-free survival (PFS) was 13.1 months (95% CI, 4.3 to 34.4 months).
GARNET (Phase I, 2021)
Patients with advanced or recurrent dMMR solid tumors, including endometrial cancer. Patients received dostarlimab 500 mg IV every 3 weeks for 4 doses, followed by 1000 mg every 6 weeks. The ORR for dMMR solid tumors was 44% (95% CI, 38.6% to 49.6%). The median PFS was 6.9 months (95% CI, 4.2 to 13.6 months).
Phase II Avelumab (2019)
Patients with recurrent or persistent endometrial cancer that was either mismatch repair deficient (MMRD) or mismatch repair proficient (MMRP). Patients received avelumab 10 mg/kg IV every 2 weeks. The ORR for MMRD patients was 26.7% (95% CI, 7.8% to 55.1%). The PFS6 rate was 40.0% (95% CI, 16.3% to 66.7%). a median follow-up of 18.6 (range, 4.4 to 22.2) months, the median PFS was 4.4 months (95% CI, 1.7 months to not reached) for the MMRD cohort, and 1.9 (95% CI, 1.6 to 2.8) months for the MMRP/non-POLE cohort (Fig 2). Median overall survival for the MMRP/non-POLE cohort was 6.6 (95% CI, 2.0 to 10.2) months; the median survival for the MMRD cohort has not been reached yet
Hormonal treatment for with advanced or recurrent endometrial carcinoma:
High-dose Megestrol Acetate 800 mg
This study assessed the efficacy of tamoxifen in patients with advanced or recurrent endometrial carcinoma who had not received prior systemic therapy. A total of 68 eligible patients were treated with oral tamoxifen at 20 mg twice daily until disease progression or unacceptable toxicity occurred.
⦁ Patients: 63 enrolled; 58 assessable for toxicity, 54 for response.
⦁ Response Rates:
⦁ 24% overall response rate (11% complete response, 13% partial response).
⦁ Four responses lasted more than 18 months.
⦁ Patients with grade 1 or 2 tumors had a significantly higher response rate (37%) compared to those with poorly differentiated tumors (8%).
⦁ Stable Disease: 22% of patients had stable disease.
⦁ Survival
⦁ Median progression-free survival (PFS): 2.5 months.
⦁ Median overall survival: 7.6 months.
⦁ Toxicity:
⦁ Grade 3 weight gain (>20%) in three patients.
⦁ Grade 3/4 hyperglycemia in three patients.
⦁ Three deaths from cardiovascular events, possibly related to therapy, with diabetes as a contributing factor.
Conclusion:
High-dose MA showed activity in endometrial carcinoma, with a 24% response rate. However, it did not demonstrate any clear advantage over lower-dose progestins, and the treatment was associated with significant toxicities, including cardiovascular events and hyperglycemia.
GOG 81-F – Tamoxifen in the Treatment of Advanced or Recurrent Endometrial Carcinoma: A Gynecologic Oncology Group Study
This study assessed the efficacy of tamoxifen in patients with advanced or recurrent endometrial carcinoma who had not received prior systemic therapy. A total of 68 eligible patients were treated with oral tamoxifen at 20 mg twice daily until disease progression or unacceptable toxicity occurred.
⦁ Response Rate: 10% overall (4% complete responses and 6% partial responses).
⦁ Progression-Free Survival (PFS): Median PFS was 1.9 months (90% CI, 1.7 to 3.2 months).
⦁ Overall Survival (OS): Median survival was 8.8 months (90% CI, 7.0 to 10.1 months).
⦁ Tumor Response: Patients with more anaplastic tumors responded less frequently.
Conclusion:
Tamoxifen demonstrated limited activity in this population, with a modest overall response rate. Based on these results, tamoxifen does not warrant further investigation as a single-agent therapy for advanced or recurrent endometrial carcinoma. Future trials will focus on the sequential use of tamoxifen and progestins.
Phase II Trial of Megestrol Acetate and Tamoxifen (GOG 119) – 2004
This Gynecologic Oncology Group (GOG-119) phase II study evaluated the efficacy and toxicity of combining daily tamoxifen (40 mg) with intermittent weekly medroxyprogesterone acetate (MPA) (200 mg) in patients with advanced or recurrent endometrial carcinoma. Out of 61 patients enrolled, 58 were eligible for analysis.
⦁ Response Rate: 33% (95% CI: 21-46%), including 6 complete and 13 partial responses.
⦁ Progression-Free Survival (PFS): Median PFS was 3 months.
⦁ Overall Survival (OS): Median OS was 13 months.
Conclusion:
The combination of daily tamoxifen and intermittent weekly MPA showed activity against advanced or recurrent endometrial carcinoma, with a 33% response rate. Further research into this combination is warranted based on these results.
Phase II Trial of Megestrol Acetate and Tamoxifen (GOG 119) – 2004
This Gynecologic Oncology Group (GOG-119) phase II study evaluated the efficacy and toxicity of combining daily tamoxifen (40 mg) with intermittent weekly medroxyprogesterone acetate (MPA) (200 mg) in patients with advanced or recurrent endometrial carcinoma. Out of 61 patients enrolled, 58 were eligible for analysis.
⦁ Response Rate:
⦁ Overall response rate: 27% (90% CI: 17-38%).
⦁ 12 complete responses (CR) and 3 partial responses (PR).
⦁ 53% of responders had a response duration exceeding 20 months.
⦁ Response rates based on tumor grade:
⦁ 38% for grade 1 tumors.
⦁ 24% for grade 2 tumors.
⦁ 22% for grade 3 tumors.
⦁ Response rates based on age:
⦁ 44% in patients ≤60 years.
⦁ 20% in patients >60 years.
⦁ Response rates based on disease location:
⦁ 31% in patients with extra-pelvic disease.
⦁ 14% in patients with pelvic/vaginal disease only.
⦁ Progression-Free Survival (PFS): Median PFS was 2.7 months.
⦁ Overall Survival (OS): Median OS was 14.0 months.
⦁ Toxicity:
⦁ Two patients experienced grade 4 thromboembolic events.
⦁ Additional toxicities: one case each of grade 3 gastrointestinal, neurologic, and genitourinary toxicities.
Conclusion:
The alternating regimen of megestrol acetate and tamoxifen demonstrated activity in treating advanced or recurrent endometrial carcinoma, with a 27% response rate and prolonged complete responses in some patients. The regimen was associated with some significant toxicities, including thromboembolic events.
GOG 3007 (Everolimus/Letrozole or Medroxyprogesterone/Tamoxifen) – 2016
This randomized phase II trial (GOG 3007) evaluated the efficacy and tolerability of everolimus (E) combined with letrozole (L) versus medroxyprogesterone acetate (M) and tamoxifen (T) in patients with advanced, persistent, or recurrent endometrial carcinoma. A total of 74 women were enrolled, with 37 patients in each arm.
⦁ Response Rate:
⦁ Everolimus/letrozole (EL) arm: 22% (95% CI, 11% to 37%), including one complete response (CR).
⦁ Medroxyprogesterone/tamoxifen (MT) arm: 25% (95% CI, 14% to 41%), with three CRs.
⦁ Progression-Free Survival (PFS):
⦁ Median PFS: 6 months for EL, 4 months for MT.
⦁ Chemo-naïve patients on EL had a median PFS of 28 months, compared to 4 months in patients with prior chemotherapy.
⦁ Chemo-naïve patients on MT had a median PFS of 5 months, compared to 3 months in patients with prior chemotherapy.
⦁ Adverse Events:
⦁ Grade 3 anemia: 24% in the EL arm vs 6% in the MT arm.
⦁ Grade 3 mucositis: 5% in EL, none in MT.
⦁ Grade 3/4 thromboembolic events: 11% in MT, none in EL.
Conclusion:
Both everolimus/letrozole (EL) and medroxyprogesterone/tamoxifen (MT) showed clinically meaningful efficacy in recurrent endometrial carcinoma, particularly in chemo-naïve patients. EL demonstrated a longer progression-free survival in chemo-naïve patients, and future studies are warranted to confirm these findings. The safety profiles differed between the two treatments, with more thromboembolic events observed in the MT arm.
HER-2 directed treatment advanced (Stage III-IV) or recurrent HER2/Neu-positive uterine carcinoma.
HER2-positive endometrial cancer, particularly uterine serous carcinoma, is an aggressive subtype that overexpresses the HER2/neu receptor.
The updated survival analysis of the NCT01367002 trial demonstrated that adding trastuzumab to carboplatin-paclitaxel significantly improved progression-free survival (PFS: 12.9 vs 8.0 months, HR: 0.46, P = 0.005) and overall survival (OS: 29.6 vs 24.4 months, HR: 0.58, P = 0.046) in patients with HER2/Neu-positive uterine serous carcinoma, particularly in those with stage III-IV disease. Toxicity was similar between the treatment arms, with no unexpected safety signals. This suggests that trastuzumab enhances survival without adding significant toxicity.
Surgical Treatment:
Recurrent/Metastatic: Options include chemoimmunotherapy or hormone therapy (for hormone-receptor-positive tumors). Single-agent pembrolizumab or dostarlimab is preferred for MSI-H/dMMR tumors. HER2-Positive, trastuzumab in combination with chemotherapy.
⦁ Surgery: Maximal Cytoreduction:
⦁ For stage IVA and IVB, surgery aims to debulk or remove as much of the tumor as possible. This may involve:
⦁ Total Hysterectomy with Bilateral Salpingo-Oophorectomy as part of cytoreductive efforts.
⦁ Bladder or Bowel Resection: Partial resection of the bladder or bowel may be necessary if the tumor has invaded these structures.
⦁ Removal of Metastatic Lesions: In patients with stage IVB disease, surgery may include removing large or symptomatic metastases, though complete resection may not be feasible in most cases.
⦁ Palliative Surgery:
⦁ In advanced cases, surgery may be performed to alleviate symptoms (such as bowel obstruction or excessive bleeding) rather than to cure the disease.
In conclusion, surgery for advanced-stage endometrial cancer focuses on cytoreduction to improve outcomes, particularly in patients with stage III and IVA/IVB disease, even when complete removal of the tumor is not always possible..
Systemic Therapy:
⦁ Chemotherapy: Carboplatin and paclitaxel are the mainstays of first-line treatment in both Stage III and IV disease. Chemoradiotherapy is considered for high-risk histologies or advanced-stage disease.
⦁ Chemoimmunotherapy: Trials such as NRG GY018 and RUBY (GOG-3031) suggest the addition of pembrolizumab or dostarlimab to standard chemotherapy for patients with both pMMR and dMMR tumors, significantly improving PFS and OS.
⦁ Hormonal therapy (megestrol, tamoxifen, aromatase inhibitors, or combinations with everolimus) is recommended for patients with hormone receptor-positive tumors. Everolimus + letrozole has shown promising results in combination therapy for hormone-sensitive tumors.
⦁ Immunotherapy dMMR/MSI-high patients benefit from immune checkpoint inhibitors such as pembrolizumab and dostarlimab. Single-agent immune therapy (e.g., pembrolizumab, avelumab) shows efficacy in dMMR and pMMR patients based on data from trials such as KEYNOTE-158 and GARNET.
⦁ HER2-Positive: Trastuzumab in combination with chemotherapy is recommended for HER2-positive endometrial cancer patients based on promising results from small studies.
The treatment of Stage III/IV recurrent/metastatic endometrial cancer has evolved to include a combination of surgery, chemotherapy, hormonal therapy, and immunotherapy.
Surgical and Adjuvant Treatment of Stage IA, IB, and II Endometrial Cancer
Surgical Treatment
Surgery is the mainstay of treatment for early-stage endometrial cancer and includes:
⦁ Total hysterectomy with or without bilateral salpingo-oophorectomy (BSO). Lymph node assessment, such as sentinel lymph node mapping or lymphadenectomy, is considered based on the risk group. Sentinel lymph node SLN biopsy is recommended per guidelines for early-stage endometrial cancer as a less invasive alternative to complete pelvic and para-aortic lymphadenectomy, particularly for patients with intermediate- or high-risk histologies. Indocyanine green (ICG) is the preferred tracer for SLN mapping, and ultrastaging should be used to detect micrometastases. If SLN mapping fails, selective lymphadenectomy should be performed to ensure adequate staging.
Non-Surgical Treatment for Stage I and II Endometrial Cancer (with Recurrence Rates and Monitoring)
⦁ Non-surgical treatments, progesterone therapy and radiation therapy, are used in specific cases of stage I and II endometrial cancer, such as for patients who are not candidates for surgery or those wishing to preserve fertility. Hormonal therapy, particularly progesterone therapy, is indicated for patients with early-stage, low-grade endometrioid adenocarcinoma, especially those desiring fertility preservation or with medical contraindications to surgery. Common agents include oral progestins such as medroxyprogesterone acetate (MPA) or megestrol acetate, and levonorgestrel-releasing intrauterine devices (IUDs) for localized delivery. Complete response rates for low-grade stage I disease range from 50% to 75%, but recurrence rates can be as high as 30-40%, particularly in higher-grade tumors or cases with deep myometrial invasion. Regular endometrial biopsies every 3 to 6 months and imaging studies, such as transvaginal ultrasound or MRI, are essential for monitoring treatment response. Surgery should be considered if there is no response after 6 months, disease progression, or recurrence.
Adjuvant Treatment:
Low-Risk Group (Stage IA, Grade 1-2)
⦁ Surgical management typically consists of hysterectomy ± BSO without the need for adjuvant therapy. No myometrial invasion or minimal invasion (<50%).
Intermediate-Risk Group (Stage IA, Grade 3 or Stage IB, Grade 1-2)
⦁ Adjuvant treatment, vaginal brachytherapy (VBT) is often used in patients with intermediate risk to prevent local recurrence, particularly in stage IB. Lymphovascular space invasion (LVSI) influences the decision for adjuvant therapy.
High-Risk Group (Stage IB, Grade 3, Stage II)
⦁ Surgical management: Hysterectomy, BSO, and pelvic lymphadenectomy. Adjuvant therapy, external beam radiation therapy (EBRT) ± chemotherapy is often considered.
Stage III/IV disease
⦁ The standard approach for stage III/IV involves a total hysterectomy and bilateral salpingo-oophorectomy (TH/BSO) along with pelvic and para-aortic lymph node dissection to assess and remove affected lymph nodes. Cytoreductive surgery is performed to remove visible tumors, which may require the removal of nearby organs. In some cases, an omentectomy may be performed to address suspected metastasis. distant metastasis, TH/BSO is often part of the treatment strategy to optimize cytoreduction. Overall, surgical intervention in advanced-stage endometrial cancer focuses on reducing tumor size ideally < 2 cm.⦁ Adjuvant therapy for stage III and IVA endometrial cancer typically involves a combination of chemotherapy, radiation therapy, or chemoradiation, with the goal of improving local and systemic control.
⦁ Radiation therapy, including external beam radiation therapy (EBRT) and vaginal brachytherapy (VBT), is often used in patients with pelvic lymph node involvement or high-risk features to reduce local recurrence rates.
⦁ Chemoradiation, either sequential or concurrent, is a viable option for high-risk patients, providing both systemic and local disease control.
⦁ The standard chemotherapy regimen includes carboplatin and paclitaxel, which has been shown to improve progression-free survival (PFS) and overall survival (OS).
⦁ Moreover, emerging evidence from trials involving chemoimmunotherapy, such as the AtTEnd, DUO-E, and RUBY trials, underscores the growing impact of immunotherapy in enhancing PFS and OS, particularly in patients with dMMR tumors, marking a shift toward more personalized and effective treatment options.
⦁ dMMR/MSI-high patients benefit from single agent immune checkpoint inhibitors such as pembrolizumab and dostarlimab. Single-agent immune therapy (e.g., pembrolizumab, avelumab) shows efficacy in dMMR and pMMR patients based on data from trials such as KEYNOTE-158 and GARNET.
⦁ HER2-positive endometrial cancer, particularly uterine serous carcinoma, is an aggressive subtype characterized by overexpression of the HER2/neu receptor. The NCT01367002 trial demonstrated that adding trastuzumab to the carboplatin-paclitaxel regimen significantly improved progression-free survival and overall survival in patients with HER2-positive uterine serous carcinoma, especially in advanced stage III-IV disease. Additionally, the DESTINY-PanTumor02 trial found that trastuzumab deruxtecan (T-DXd) offered a 57.5% response rate, 11.1 months PFS, and 26.0 months OS, making it a promising option for patients with HER2-expressing endometrial cancer.
⦁ Several studies have evaluated hormonal therapies for advanced or recurrent endometrial cancer, showing varying levels of efficacy. High dose megestrol acetate demonstrated moderate efficacy with a 24% response rate but limited survival benefits. Combining megestrol acetate with tamoxifen improved outcomes, with a 27% response rate and a median overall survival of 14 months. Everolimus and letrozole improved progression-free survival (6 vs. 4 months) and overall survival (28 vs. 5 months).
⦁ The KEYNOTE-775 (Study 309) trial demonstrated that Lenvatinib plus Pembrolizumab significantly improved progression-free survival (PFS) and overall survival (OS) compared to chemotherapy in patients with advanced endometrial cancer who had previously been treated with at least one platinum-based chemotherapy regimen. PFS was 7.2 vs. 3.8 months, and OS was 18.3 vs. 11.4 months. Despite a higher rate of adverse events, the combination offers a substantial survival benefit, making it a strong option for patients who have failed prior platinum-based therapies.