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What is Endometrial Cancer?

Endometrial cancers are malignant tumors that originate in the endometrium, the tissue that lines the uterus. Endometrial cancer is the second most common gynecologic cancer affecting women worldwide and the most common gynecologic malignancy in the United States. It affects about 3% of women in the United States. Endometrial cancers are most commonly diagnosed in women between the ages of 60-70 years old and are strongly associated with obesity. When caught early, many types of endometrial cancers are highly treatable.

The Basics

Diagnosis and Prognosis

The Basics

Endometrial cancers are malignant tumors that originate in the endometrium, the tissue that lines the uterus. The uterus is a small, pear-shaped organ in a female's pelvis, and is where a fetus develops and grows. These tumors account for the majority (>90%) of uterine cancers, with the remainder arising from uterine muscle tissue (see uterine sarcoma section).[see References: 1] They encompass a wide variety of different types of tumors - including endometrioid adenocarcinomas, carcinosarcomas, clear cell carcinomas, and mucinous carcinomas - and are classified by their appearance under a microscope, characterized by how abnormal the cells look (their histology) and how aggressive they are (as described by “grade”).

Endometrial cancer is the second most common gynecologic cancer affecting women worldwide and the most common gynecologic malignancy in the United States. It affects about 3% of women in the United States.[2, 3] The American Cancer Society estimates that in 2024, approximately 68,000 new cases will have been diagnosed, with the number of cases rising by approximately 2-3% annually over the last decade. Most patients are diagnosed with a favorable histology, meaning that the cancer is less aggressive (lower grade), and at an early stage (has not spread). Therefore, most patients have an excellent prognosis with a 5-year survival rate of up to 95%. However, the prognosis for long-term survival decreases with more aggressive tumor types, the presence of distant metastases, or recurrence.

Endometrial cancers are most commonly diagnosed in women between the ages of 60-70 years old and are strongly associated with obesity. Some cases can also be caused by inherited genetic conditions, such as Lynch syndrome, which also increases the risk of developing colon cancer. Recent advancements in understanding the genetic and molecular changes behind endometrial cancer have helped doctors better tailor treatments and predict outcomes, leading to more personalized care for patients.

When caught early, many types of endometrial cancers are highly treatable. Most cases will be treated with some form of surgery, and for those with evidence of spread throughout the abdomen, cytoreductive surgery (CRS) may be a viable treatment option. While there is limited data on the addition of hyperthermic intraperitoneal chemotherapy (HIPEC) to CRS, there may be a survival benefit of CRS/HIPEC for the most advanced-stage cases, especially in the first 1-2 years.

Risk Factors

Obesity: the strongest risk factor and linked to hormone changes
Age: Endometrial cancer affects mostly post-menopausal women, with an average age of diagnosis of 60 years
Race: Endometrial cancer is more common in black women
Type II diabetes
Menopausal hormone therapy / Hormone-replacement drugs after menopause
Tamoxifen use
Family history of endometrial or colorectal cancer
History of endometrial hyperplasia
History of breast or ovarian cancer
History of radiation therapy to the pelvis for another cancer
Genetic factors like Lynch syndrome

Signs & Symptoms

Post-menopausal bleeding
Abnormal uterine bleeding/spotting (i.e.. heavy, irregular, bleeding between periods)
Pelvic pain
Pelvic mass
Unintentional weight loss

Evaluation

Physical exam
Imaging studies: pelvic ultrasound, CT scan, MRI scan
Blood work to include tumor markers
Endometrial tissue sampling: endometrial biopsy (EMB); hysteroscopy/dilation and curettage (D&C)
Surgical biopsy of metastatic tumor: fine needle biopsy, diagnostic laparoscopy
Testing of abdominal fluid (ascites)

Key Facts

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Endometrial cancers are the most common gynecologic malignancy in the United States and are largely hormonally driven.

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Endometrial cancers are categorized into low-risk and high-risk groups based on histology, stage, and grade. This categorization is based on the surgical pathology and molecular analysis of the tumor and will guide treatment decisions and prognosis.

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The main treatment for endometrial cancer is surgery, which will include a hysterectomy (a removal of the uterus) and usually a bilateral salpingo-oophorectomy (removal of both the fallopian tubes and ovaries), and lymph node sampling. Other complementary therapies include radiation, systemic chemotherapy, immunotherapy, and hormone therapy.

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With recent evidence demonstrating a significant survival benefit, there has been a shift away from palliative systemic chemotherapy and towards cytoreductive surgery (CRS) as the primary treatment option for patients with metastatic endometrial cancer. The survival benefit is greatest with a complete cytoreduction.

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While there is limited data on the addition of HIPEC to CRS, a meta-analysis analyzing all available data concluded that there is likely a survival benefit of CRS/HIPEC, especially in the first 1-2 years, compared to CRS alone. Recommendations for CRS/HIPEC in this population are currently based on ovarian cancer guidelines.

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There are many emerging treatment options for endometrial cancers, which are discussed below. Ask your care team, which may include a gynecologic oncologist, surgical oncologist (specializing in peritoneal surface malignancies), radiation oncologist, and/or a medical oncologist, about which options are best for you.

Treatment

The treatment sequence for newly diagnosed endometrial cancer generally follows these steps: 1) make a diagnosis through a biopsy or dilation and curettage (D&C), 2) assess whether the cancer has spread (metastatic) or has a high potential for metastases, and 3) perform a hysterectomy (removal of the uterus) with lymph node assessment in patients at increased risk of metastasis. Depending on how far the cancer has spread and its histologic subtype, additional medical therapies may be recommended by your oncologist.

Surgery:

Almost all endometrial cancers are treated with surgery, and the extent of the procedure depends on how advanced the cancer is at the time of diagnosis. If the tumor is confined to the uterus, a hysterectomy with regional lymph node removal will be performed. In general, this typically includes the removal of both ovaries and fallopian tubes (bilateral salpingo-oophorectomy). In some high-risk subtypes like clear cell or serous carcinoma, additional procedures such as an omentectomy (a surgical procedure designed to remove the omentum, which is the fatty tissue that encases most abdominal organs) and/or pelvic washings (a surgical procedure used to assess the presence of intraperitoneal metastases for malignancies within the pelvis) may be performed to check for spread. The type of surgery – open, laparoscopic, robotic, or vaginal – depends on several patient and tumor factors. If the endometrial cancer involves the cervix, a more extensive hysterectomy, called a radical hysterectomy, is recommended. Regardless of the approach, morcellation (cutting the uterus into pieces for removal through smaller incisions) should be avoided to reduce the risk of spreading cancer cells in the abdomen.[4] The goal of the initial surgery is to gain a complete histologic assessment and thorough staging of the disease. This will help inform if any additional medical therapy is warranted.

The pathology report from the hysterectomy helps the oncologist determine whether the tumor is “low-risk” or “high-risk” for recurrence based on factors like histologic subtype, grade, stage, and depth of invasion into the uterine muscle (myometrium). Increasingly, detailed molecular testing is also used to assess markers like mismatch repair (MMR), microsatellite instability (MSI), TP53, and POLE.9 This information will guide follow-up care and any additional treatment.

Chemotherapy:

Systemic chemotherapy is mainly used for high-risk or advanced endometrial cancers. The standard chemotherapy regimen includes 6 cycles of carboplatin and paclitaxel (common chemotherapy drugs for many gynecologic malignancies), though other common chemotherapy agents like cisplatin, doxorubicin, and docetaxel may also be used. Chemotherapy is not recommended for patients with low-risk endometrial cancer due to the lack of survival benefit and increased risk for side effects. However, it is recommended after surgery (adjuvant) for patients with high-risk endometrial cancer, including those with early or localized disease, given the increased likelihood of poor prognosis and recurrence.[13, 14]

For some patients, chemotherapy may be combined with radiation therapy, either as a sandwich therapy (a few cycles of chemotherapy, followed by radiation, followed by remaining chemotherapy cycles) or together, called chemoradiation. For select intermediate-risk cancers, systemic chemotherapy with or without VBT can be used as an alternative to EBRT.15

With metastatic disease, systemic chemotherapy can be given after CRS, with or without hyperthermic intraperitoneal chemotherapy (HIPEC), or as interval therapy (3 cycles of chemotherapy, then CRS with or without HIPEC, followed by 3 cycles of chemotherapy) to shrink tumors and make them easier to remove, following ovarian cancer treatment guidelines. For patients with unresectable metastatic disease or those who are not surgical candidates, palliative chemotherapy is the preferred option.[16]

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC):

Although only a small percentage of patients (~2%) have peritoneal metastases at the time of diagnosis, positive peritoneal cytology, which suggests microscopic peritoneal metastasis, is present in approximately 20% of early stage cases.[17, 18] Additionally, around 28% of endometrial cancer relapses occur in the peritoneal cavity.[19] This highlights the potential role of CRS/HIPEC as a treatment option for select patients, particularly since patients with peritoneal metastases have a poor prognosis (median survival: 12 months) and CRS/HIPEC has been demonstrated to be successful in treating other similar malignancies.[20, 21]

Cytoreductive surgery (CRS) is the aggressive surgical removal or destruction of cancer. It is performed through an incision down the midline of the abdomen and may include removal of parts of or the entirety of organs such as: the spleen, gallbladder, liver, peritoneum (lining of the abdominal cavity), uterus, fallopian tubes/ovaries, and bowel. Following CRS, heated chemotherapy (HIPEC) is circulated directly into the abdominal cavity to kill any remaining microscopic cancer cells.

Recent trends favor cytoreductive surgery over palliative systemic chemotherapy to treat peritoneal metastases of endometrial cancer. While multiple studies have demonstrated the efficacy of CRS, especially with complete cytoreduction, there is limited data on the role of HIPEC. Most available reports are small case series or observational studies, but interest is growing, partly due to positive results in treating ovarian cancer.[22, 23] Though no studies have directly compared CRS to CRS/HIPEC in endometrial cancer, one meta-analysis found that adding HIPEC to CRS improves clinical outcomes, especially in the first 2 years.[24] One of the largest reports of 33 patients reported a median overall survival of 33.1 months after CRS/HIPEC, emphasizing the importance of complete cytoreduction and low tumor burden for optimal results.[25] As data evolves, careful patient selection is key and an experienced HIPEC surgeon will help guide treatment decisions.

Radiation

Radiation therapy is commonly used after surgery to reduce the risk of local recurrence in endometrial cancer. It can be delivered as pelvic external beam radiation therapy (EBRT), which targets the entire pelvis, and/or vaginal brachytherapy (VBT), which is a more localized treatment targeting the vaginal vault, a common site of recurrence.[10] With a more targeted field, VBT has less toxicity than EBRT and helps reduce local recurrences, but it does not improve overall survival.[11] The choice of radiation treatment depends on the stage and grade of the cancer Your radiation oncologist will work with your oncology team to develop the optimal treatment plan.

In some rare cases, radiation can be given before surgery to help shrink a tumor, making it easier to remove. It can also be used as the primary treatment for patients who cannot undergo surgery.[12]

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC):

Recent studies have shown a significant increase in survival with the use of extensive cytoreduction (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC).[7, 8] Cytoreductive surgery is the aggressive surgical removal or destruction of cancer. It is performed through an incision down the midline of the abdomen and may include removal of parts of or the entirety of organs such as: the spleen, gallbladder, liver, peritoneum (lining of the abdominal cavity), uterus, fallopian tubes/ovaries, and bowel. Following CRS, heated chemotherapy is circulated directly into the abdominal cavity to kill any remaining microscopic cancer cells. CRS/HIPEC is the recommended treatment when the appendix has ruptured and there is evidence of disease in the abdominal cavity (peritoneal spread). Patients who undergo complete CRS, with no residual disease (CC-0/1), immediately followed by HIPEC have the best chance at long-term survival.[8, 9] CRS/HIPEC is now considered the standard of care treatment for all subtypes of advanced appendix cancers.

Cytoreductive surgery (CRS)

For cases that include evidence of metastatic disease (cancer that has spread beyond the uterus), surgery may be recommended for several reasons: 1) to establish a definitive diagnosis, 2) to relieve symptoms, and/or 3) to improve survival. When surgery is indicated, an open procedure with a larger abdominal incision is preferred for better visibility of the whole abdominal cavity. For patients who are diagnosed with metastatic endometrial cancer, the treatment of choice is cytoreductive surgery (CRS). This is based on increasing data showing the survival benefit of surgery over palliative systemic chemotherapy.[5] Cytoreductive surgery refers to the aggressive surgical removal or destruction of cancer with the goal to remove all visible disease.

For example, a large study of over 3,000 patients with metastatic endometrial cancer demonstrated that those who underwent complete CRS had significantly longer overall survival compared to those treated with chemotherapy alone (median: 20 vs 11 months).[6] It is important to remove as much of the tumor as possible because patients with remaining cancer after surgery tend to live for a shorter time.[7] Since data on cytoreductive surgery in endometrial cancer is limited, the approach follows guidelines used for advanced ovarian cancer.[8] This emphasizes the importance of an experienced surgical team for handling advanced gynecologic cancers with abdominal spread.

Immunotherapy

Immunotherapy helps the immune system recognize and attack cancer cells. PD-1 inhibitors, like dostarlimab and pembrolizumab, have recently been shown to help shrink or slow the growth of endometrial cancers.[26, 27] These drugs may be used with chemotherapy and then continued alone as maintenance therapy if the tumor has specific molecular changes. In general, they are given as IV infusions every 3-6 weeks for approximately 2-3 years, depending on tolerance. Pembrolizumab can also be used to treat advanced endometrial cancers that have not responded to other treatments. The choice of drug depends on factors like institutional preferences, availability, and insurance coverage. Molecular testing performed on your biopsy or surgery is necessary to identify if these changes are present and if you qualify for this therapy. Your medical oncologist will guide you on whether immunotherapy is recommended.

Hormone Therapies

Hormone therapy uses hormones or hormone-blocking drugs to treat cancer. Since endometrial cancers are often driven by excess estrogen, these therapies aim to stop estrogen production. Hormone therapy can be used to treat advanced or recurrent disease and is often combined with chemotherapy.[28] Progestins (i.e. Provera & Megace) can help control endometrial cancer for patients who wish to preserve fertility. Other types of hormone therapies include lutenizing hormone-releasing hormone (LHRH) agonists (i.e. Goserelin, Lupron) and aromatase inhibitors (ie. letrozole, anastrozole, and exemestane), which are also commonly used to treat breast cancers.

Diagnosis and Prognosis

The prognosis of endometrial cancer largely depends on whether the cancer is classified as low-risk or high-risk.[9] Patients with low-risk endometrial cancer have an excellent prognosis, with a survival rate of over 90% and a low risk for recurrence.[29, 31] Women with low-intermediate-risk endometrial cancer also have an excellent prognosis, with recurrence rates of 5-6% without any additional therapy.[32] In contrast, patients with high-intermediate-risk endometrial cancers have a 30% risk of recurrence if no adjuvant therapy is used. However, this risk decreases to only 5% when adjuvant radiation is given. Regardless, overall survival remains >80% with or without radiation.[33] In high-risk endometrial cancer, the risk of disease progression and death is higher, and prognosis is highly dependent on histologic subtype, stage, and grade, which is further discussed below.[34]

Endometrioid Carcinoma

Endometrioid carcinoma is the most common type of endometrial cancer, accounting for 75-80% of cases.[35] Since it is by far the most common type, the majority of endometrial cancer research and guidelines are based on this subtype. Most of these cancers are low-grade (tumor grade 1 or 2), diagnosed early, and have a good prognosis, with survival rates as high as 80-90%.[36] Therefore, surgery is often the only treatment recommended for this subtype. However, a small number are grade 3 or have a p53 molecular alteration, which is linked with a poorer prognosis. In fact, grade 3 endometrioid carcinomas have been found to have similar survival and recurrence rates to serous and clear cell carcinomas, with 5-year overall survival rates of around 50%.[37, 38] Because of this, additional chemotherapy and/or radiation is recommended with surgery to help delay recurrence.

Serous & Clear Cell Carcinomas

Serous endometrial cancer is the second most common type of endometrial cancer, accounting for about 10% of cases, while clear cell carcinoma makes up <5%.[39, 40] Both of these subtypes are more aggressive than endometrioid carcinoma and are often diagnosed at a later stage, with 50-70% of serous carcinoma cases presenting with extrauterine spread. Overall survival for serous and clear cell carcinomas are similar, with estimated 5-year survival rates of 55% and 68%, respectively, and are strongly correlated with stage.[41] For serous carcinoma, survival ranges from 92% in stage I disease to only 17.3% at stage IV. Regardless of stage, achieving a complete cytoreduction is the most important prognostic factor. In advanced stages (stage III/IV), patients with optimal cytoreduction had a median overall survival of 51 months compared to only 12 months for those with residual disease.[42] Adjuvant chemotherapy with radiation may also improve survival after complete cytoreduction, though data is limited.[43] Due to the rarity, recommendations are often generalized from ovarian cancer studies given the similar tumor type.

Other Rare Endometrial Cancer Subtypes

Other rare endometrial cancer subtypes include mixed carcinomas, undifferentiated/dedifferentiated carcinoma, and carcinosarcomas. These subtypes are generally not well understood, with undifferentiated/dedifferentiated carcinomas being the least studied.44, 45 As the name suggests, mixed carcinomas have at least two distinct histologic components, typically endometrioid and another non-endometrioid type like serous or clear cell. Carcinosarcomas also have mixed histology, but include both a carcinoma and sarcoma component. These subtypes tend to be more aggressive than endometrioid carcinomas with worse survival seen in more advanced stages. For example, in carcinosarcoma, 5-year survival rates were 59% for stage I/II disease, but only 9% for stage IV.[46] Due to the limited data and poor prognosis, clinical trial enrollment is often recommended for these patients

Disease Recurrence

Most recurrences will occur within 3 years of treatment.[29] The majority of relapses occur in the vaginal cuff and pelvis.[19] Isolated vaginal recurrences are best detected through a physical exam with a pelvic examination. They can be treated by radiation therapy or surgery in patients who previously have had radiation to the same area.[30] Patients who develop metastatic endometrial cancer after being treated for localized disease are typically recommended systemic therapy (chemotherapy + immunotherapy). However, emerging evidence suggests that selected patients with recurrence may be candidates for cytoreduction (CRS) with or without HIPEC.[5, 6, 22] Some of the criteria that are used to define good candidates include patient performance status, how long the patient has been without recurrence and off treatment, and, importantly, whether a complete cytoreduction is feasible.

Research

Clinical Trials

Below is a sample of a few of the clinical trials listed on www.ClinicalTrials.gov for endometrial cancers. Your medical and surgical oncologists can also help you review clinical trial options and recommendations.

There are over 300 actively recruiting clinical trials for endometrial cancer registered online. Below is a sample of a few of the clinical trials listed on www.ClinicalTrials.gov for endometrial cancers (as of February 2025). Your oncologists (medical, surgical, and gynecologic) can also help you review clinical trial options and recommendations.

Phase I Clinical Trial of Lenvatinib, Pembrolizumab and Hypofractionated Pelvic Radiation Therapy for pMMR Recurrent/Unresectable Endometrial Carcinoma (NCT05603910)

Status: Recruiting
This study explores the feasibility of a combination treatment of pembrolizumab, lenvatinib, and abbreviated pelvic external bean radiation therapy to prevent cancer cells in multiplying and spreading to other body sites
Inclusion criteria: Age ≥18, diagnosis recurrent or unresectable endometrial cancer, pMMR subtype, willing and physically able to tolerate treatment

Sacituzumab Tirumotecan (MK-2870) in Post Platinum and Post Immunotherapy Endometrial Cancer (MK-2870-005) (TroFuse-005) (NCT06132958)

Status: Recruiting
This is a randomized study comparing overall survival in patients who receive MK-2870 sacituzumab tirumotecan (an immunotherapy) to standard systemic chemotherapy after failing other treatments
Inclusion criteria: diagnosis of endometrial cancer, previously treated with platinum-based chemotherapy and PD-L1 therapy (either separately or in combination)

Frontline Immunotherapy Combined with Radiation and Chemotherapy in High Risk Endometrial Cancer (FIERCE) (NCT03932409)

Status: Recruiting
This is a single arm study to evaluate the feasibility of pembrolizumab with vaginal cuff brachytherapy, followed by pembrolizumab and chemotherapy
Inclusion criteria: Age ≥18, underwent a hysterectomy for newly diagnosed endometrial cancer, have a tumor that is categorized as high-risk (ie. serous/clear cell histology, advanced stage endometrioid carcinomas, or grade 2/3), ability to tolerate treatment

Other Resources

More Information on Endometrial Cancer

Patient Support

The Laughlin Foundation

thelaughlinfamilyfoundation.org

Endometrial Cancer Action Network for African-Americans

ecanawomen.org

Ovarian Cancer Research Alliance Woman to Woman Program

ocrahope.org

Facing cancer is hard.
But you are not alone - we’re right here with you.

Patient and Caregiver Network

Stories of hope

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References

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What is Endometrial Cancer?

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Endometrioid Carcinoma

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Facing cancer is hard.
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Oír todo lo relacionado con PFCCAP durante todo el año.