National Cancer Institute


Expert-reviewed information summary about the treatment of endometrial cancer.

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of endometrial cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Endometrial Cancer Treatment

General Information About Endometrial Cancer

Cancer of the endometrium is the most common gynecologic malignancy in the United States and accounts for 6% of all cancers in women. The majority of cases are diagnosed at an early stage and are amenable to treatment with surgery alone. However, patients with pathologic features predictive of a high rate of relapse and patients with extrauterine spread at diagnosis have a high rate of relapse despite adjuvant therapy.

Incidence and Mortality

Estimated new cases and deaths from cancer of the uterine corpus, which includes the endometrium, in the United States in 2017:

  • New cases: 61,380.
  • Deaths: 10,920.

Endometrial cancer is usually diagnosed and treated at an early stage. Cardiovascular disease is the most common cause of death in patients with endometrial cancer because of the related metabolic risk factors.

Anatomy

The endometrium is the inner lining of the uterus and has both functional and basal layers. The functional layer is hormonally sensitive and is shed in a cyclical pattern during menstruation in reproductive-age women. Both estrogen and progesterone are necessary to maintain a normal endometrial lining. However, factors that lead to an excess of estrogen, including obesity and anovulation, lead to an increase in the deposition of the endometrial lining. These changes may lead to endometrial hyperplasia, and, in some cases, endometrial cancer. Whatever the cause, a thickened lining will lead to sloughing of the endometrial tissue through the endometrial canal and into the vagina. As a result, heavy menstrual bleeding or bleeding after menopause are often the initial signs of endometrial cancer. This symptom tends to happen early in the disease course, allowing for identification of the disease at an early stage for most women.

Anatomy of the female reproductive system; drawing shows the uterus, myometrium (muscular outer layer of the uterus), endometrium (inner lining of the uterus), ovaries, fallopian tubes, cervix, and vagina.Anatomy of the female reproductive system.

Risk Factors

Risk factors for endometrial cancer include the following:

  • Endometrial hyperplasia.
  • Hormone therapy.
  • Tamoxifen therapy.
  • Obesity.
  • Reproductive factors (nulliparity, early menarche/late menopause, or polycystic ovarian syndrome).
  • Family history/genetic predisposition.
  • Hyperinsulinemia.

Refer to the PDQ summary on Endometrial Cancer Prevention for more information.

Prolonged, unopposed estrogen exposure has been associated with an increased risk of endometrial cancer. However, combined estrogen and progesterone therapy prevents the increase in risk of endometrial cancer associated with unopposed estrogen use.

Tamoxifen, which is used for both the treatment and prevention of breast cancer (NSABP-B-14), is associated with an increased risk of endometrial cancer related to the estrogenic effect of tamoxifen on the endometrium. It is important that patients who are receiving tamoxifen and experiencing abnormal uterine bleeding have follow-up examinations and biopsy of the endometrial lining. The U.S. Food and Drug Administration released a black box warning that includes data about the increase in uterine malignancies associated with tamoxifen use. (Refer to the Lynch Syndrome (LS) section in the PDQ summary on Genetics of Breast and Gynecologic Cancers for more information about risk factors for LS-associated endometrial cancer.)

Clinical Features

Irregular vaginal bleeding is the most common presenting sign of endometrial cancer. It generally occurs early in the disease process, and is the reason why most patients are diagnosed with highly curable stage I endometrial cancer.

Diagnostic Evaluation

The following procedures may be used to detect endometrial cancer:

  • Transvaginal ultrasound.
  • Endometrial biopsy.
  • Pelvic exam.
  • Dilatation and curettage (D&C).
  • Hysteroscopy.

To definitively diagnose endometrial cancer, a procedure that directly samples the endometrial tissue is necessary.

The Pap smear is not a reliable screening procedure for the detection of endometrial cancer, even though a retrospective study found a strong correlation between positive cervical cytology and high-risk endometrial disease (i.e., high-grade tumor and deep myometrial invasion). A prospective study found a statistically significant association between malignant cytology and increased risk of nodal disease.

Prognostic Factors

Prognostic factors for endometrial cancer include the following:

  • Tumor stage and grade (including extrauterine nodal spread).
  • Hormone receptor status.

Tumor stage and grade (including extrauterine nodal spread)

The following table highlights the risk of nodal metastasis based on findings at the time of staging surgery:

A Gynecologic Oncology Group study related surgical-pathologic parameters and postoperative treatment to recurrence-free interval and recurrence site. Grade 3 histology and deep myometrial invasion in patients without extrauterine spread were the greatest determinants of recurrence. In this study, the frequency of recurrence was greatly increased with the following:

  • Positive pelvic nodes.
  • Adnexal metastasis.
  • Positive peritoneal cytology.
  • Capillary space involvement.
  • Involvement of the isthmus or cervix.
  • Positive periaortic nodes (includes all grades and depth of invasion). Of the cases with aortic node metastases, 98% were in patients with positive pelvic nodes, intra-abdominal metastases, or tumor invasion of the outer 33% of the myometrium.

When the only evidence of extrauterine spread is positive peritoneal cytology, the influence on outcome is unclear. The value of therapy directed at this cytologic finding is not well founded, and some data are contradictory. Although the collection of cytology specimens is still suggested, a positive result does not upstage the cancer. Other extrauterine disease must be present before additional postoperative therapy is considered.

Involvement of the capillary-lymphatic space on histopathologic examination correlates with extrauterine and nodal spread of tumor.

Hormone receptor status

Progesterone and estrogen receptors, assessed either by biochemical or immunohistochemical methods, are included, when possible, in the evaluation of patients with stage I and stage II cancer.

One report found progesterone receptor levels to be the single most important prognostic indicator of 3-year survival in clinical stages I and II disease. Patients with progesterone receptor levels above 100 had a 3-year disease-free survival (DFS) of 93%, compared with a 36% DFS for a level below 100. After adjusting for progesterone receptor levels, only cervical involvement and peritoneal cytology were significant prognostic variables.

Other reports confirm the importance of hormone receptor status as an independent prognostic factor. Additionally, immunohistochemical staining of paraffin-embedded tissue for both estrogen and progesterone receptors has been shown to correlate with Féderation Internationale de Gynécologie et d’Obstétrique (FIGO) grade and survival.

Other prognostic factors

Other factors predictive of poor prognosis include the following:

  • A high S-phase fraction.
  • Aneuploidy.
  • Absence of .
  • mutation status.
  • mutation status.
  • Her-2/neu overexpression.
  • Oncogene expression (e.g., overexpression of the oncogene has been associated with a poor overall prognosis).

A general review of prognostic factors has been published.

Related Summaries

Other PDQ summaries containing information related to endometrial (uterine corpus) cancer include the following:

  • Endometrial Cancer Prevention
  • Endometrial Cancer Screening
  • Uterine Sarcoma Treatment

Cellular Classification of Endometrial Cancer

Endometrial cancers are classified as one of the following two types:

  • Type 1 may arise from complex atypical hyperplasia and is pathogenetically linked to unopposed estrogenic stimulation.
  • Type 2 develops from atrophic endometrium and is not linked to hormonally driven pathogenesis.

The most common type of endometrial cancer is endometrioid adenocarcinoma.

Frequency of endometrial cancer cell types is as follows:

Molecular Subgroups

mutations are more common in type 1 endometrial cancers; and overexpression are more common in type 2 endometrial cancers, although some overlap exists.

The Cancer Genome Atlas's full genetic display of hundreds of endometrial cancers identified four subtypes to further characterize endometrial cancers:

  • . This subtype has clinical significance, and adjuvant therapies are avoided.
  • Microsatellite instability hypermutated.
  • Copy number low.
  • Copy number high.

These categories can be used to stratify patients into low- and high-risk prognostic categories. A modification of The Cancer Genome Atlas methods into more accessible tests was also successful in discriminating cancers into relevant prognostic categories. However, a combination of previously known risk factors with the genetic data was the most effective at determining prognostic categories.

Stage Information for Endometrial Cancer

The pattern of endometrial cancer spread is partially dependent on the degree of cellular differentiation. Well-differentiated tumors tend to limit their spread to the surface of the endometrium; myometrial invasion is less common. Myometrial invasion occurs much more frequently in patients with poorly differentiated tumors and is frequently a harbinger of lymph node involvement and distant metastases.

Metastatic spread occurs in a characteristic pattern. Regional spread to the pelvic and periaortic nodes is common. Distant metastasis most commonly involves the following sites:

  • Lungs.
  • Inguinal and supraclavicular nodes.
  • Liver.
  • Bones.
  • Brain.
  • Vagina.

FIGO Staging

The Féderation Internationale de Gynécologie et d’Obstétrique (FIGO) and the American Joint Committee on Cancer (AJCC) have both designated staging systems for endometrial cancer. The FIGO system is the most commonly used staging system for endometrial cancer.

FIGO stages I to IV are further subdivided by the histologic grade (G) of the tumor, for example, stage IB G2. Carcinosarcomas, which had previously been designated as sarcomas, are now considered poorly differentiated adenocarcinomas; as such, they are included in this system.

Treatment Option Overview for Endometrial Cancer

The degree of tumor differentiation has an important effect on the natural history of this disease and on treatment selection.

Patients with endometrial cancer who have localized disease are usually cured. Best results are obtained with one of two standard treatments:

  • Hysterectomy with bilateral salpingo-oophorectomy.
  • Hysterectomy with bilateral salpingo-oophorectomy and adjuvant radiation therapy (when deep invasion of the myometrial muscle [more than 50% of the myometrium] or grade 3 tumor with myometrial invasion is present).

Patients with regional and distant metastases are rarely cured, although they are occasionally responsive to standard hormone therapy.

Progestational agents have been evaluated as adjuvant therapy in several randomized trials; a meta-analysis by the Cochrane group confirms no clinical benefit to adjuvant progestogens in clinical stage I disease.[]

The treatment options for each stage of endometrial cancer are presented in Table 6.

Stage I and Stage II Endometrial Cancer Treatment

Standard Treatment Options for Stage I and Stage II Endometrial Cancer

Treatment of stage I and stage II endometrial cancer depends on the grade and histologic type.

In the current Féderation Internationale de Gynécologie et d’Obstétrique (FIGO) staging system, stage II describes tumor that invades the cervical stroma; this is equivalent to the prior stage IIB. Almost all randomized trials for early-stage cancer excluded stage IIB patients. As a result, there is a paucity of quality data on which to base clinical decisions for stage II patients.

Low-risk histology:

Grades 1 and 2 tumors are considered low-risk unless they are serous or clear cell subtype.

Standard treatment for patients with low-risk histologic subtypes of stage I endometrial cancer include the following:

Most patients do well with surgery alone. A subset of patients with stage I disease is at a high risk of recurrence and is eligible for adjuvant therapy.

High-risk histology:

Grade 3 tumors of any histology and any serous tumors, clear cell tumors, or carcinosarcomas are considered high-risk.

Treatment options for patients with stage I or stage II endometrial cancer with high-risk histology include the following:

Patients with serous or clear cell histologies have higher rates of recurrence than do patients with other stage I or stage II endometrioid carcinomas. The outcomes in institutional case series that utilize a regimen of adjuvant carboplatin plus paclitaxel, occasionally including radiation therapy for this histologic subtype, have been published and form the basis of management guidelines.

Carcinosarcomas have been evaluated in clinical trials both separately and with other sarcomas because of their prior designation in this group. In a nonrandomized Gynecologic Oncology Group (GOG) study of patients with stage I or II carcinosarcomas, patients who underwent pelvic radiation therapy had a significant reduction in recurrences within the radiation treatment field but no improvement in survival. One nonrandomized study that predominantly included patients with carcinosarcomas appeared to show benefit for adjuvant therapy with cisplatin and doxorubicin.

Surgery

If the uterine cervix is involved, options include one or more of the following:

  • Standard hysterectomy with bilateral salpingo-oophorectomy followed by adjuvant radiation therapy.
  • Radical hysterectomy.
  • Pelvic and periaortic lymph node dissection.

Single-institution reviews suggest that radical hysterectomy is more beneficial than standard hysterectomy in cases of cervical involvement of the tumor.

Surgery with or without lymph node sampling

The following table highlights the risk of nodal metastasis based on findings at the time of staging surgery:

For patients in Group A, lymph node dissection has limited utility. Conversely, full pelvic and paraaortic lymph node dissection is important forpatients in Group C, given the likelihood of positive findings. The difficulty lies in determining how to manage patients in Group B.

There are several accepted surgical approaches for patients with presumed stage I endometrial cancer, with intermediate risk for lymphatic spread.

Both retrospective and prospective data supports stratifying patients with presumed stage I endometrial cancer into two groups based on the following characteristics:

  • Low risk: well-differentiated or moderately differentiated tumor and/or depth of myometrial invasion is less than 50% and/or tumor is smaller than 2 cm.
  • High risk: poorly differentiated tumor and/or depth of myometrial invasion is 50% or more and/or tumor is 2 cm or larger.

Evidence (lymph node dissection):

Evidence (treatment or surgical staging using laparoscopy vs. laparotomy):

Future analyses may determine whether there are subgroups of patients for whom there is a clinically significant decrement when laparoscopic staging is utilized.[]

Postoperative vaginal brachytherapy

While adjuvant radiation therapy will reduce the incidence of local and regional recurrence, improved survival has not been proven, and toxic effects are worse with radiation therapy. Vaginal cuff brachytherapy is associated with less radiation-related morbidity than is external-beam radiation therapy (EBRT) and has been shown to be equivalent to EBRT in the short term for patients with stage I disease. However, long-term follow up of a randomized trial comparing EBRT plus vaginal brachytherapy (VBT) to VBT alone found decreased OS and increased toxicity in the EBRT plus VBT arm.

Evidence (VBT):

Postoperative radiation therapy

If the cervix is clinically uninvolved, but extension to the cervix is noted on postoperative pathology, radiation therapy is considered.[]

Radiation therapy alone

Patients who have medical contraindications to surgery may be treated with radiation therapy alone, but cure rates may be lower than those attained with surgery.

Treatment Options Under Clinical Evaluation for Stage I and Stage II Endometrial Cancer

Current Clinical Trials

Check the list of NCI-supported cancer clinical trials that are now accepting patients with stage I endometrial carcinoma and stage II endometrial carcinoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI website.

Stage III, Stage IV, and Recurrent Endometrial Cancer Treatment

Standard Treatment Options for Stage III, Stage IV, and Recurrent Endometrial Cancer

Standard treatment options for stage III, stage IV, and recurrent endometrial cancer include the following:

Treatment of patients with stage IV endometrial cancer is dictated by the site of metastatic disease and symptoms related to disease sites.

Surgery followed by chemotherapy or radiation therapy

In general, patients with stage III or stage IV endometrial cancer are treated with surgery, followed by chemotherapy or radiation therapy, or both. Observational studies support maximal cytoreductive surgery for patients with stage IV disease, although these conclusions need to be interpreted with care because of the small number of cases and likely selection bias.

For many years, radiation therapy was the standard adjuvant treatment for patients with endometrial cancer. However, several randomized trials have confirmed improved survival when adjuvant chemotherapy is used instead of radiation therapy.

Doxorubicin was historically the most active anticancer agent employed, with useful but temporary responses obtained in as many as 33% of patients with recurrent disease. Paclitaxel, in combination with platinum chemotherapy or as a single agent, also has significant anticancer activity.

Evidence (surgery followed by chemotherapy or radiation therapy):

Chemotherapy and radiation therapy

Patients with inoperable disease caused by tumor that extends to the pelvic wall may be treated with a combination of chemotherapy and radiation therapy. The usual approach for radiation therapy is to use a combination of intracavitary and external-beam radiation therapy.

For patients with localized recurrences (pelvic and paraaortic lymph nodes) or distant metastases in selected sites, radiation therapy may be an effective palliative therapy. Pelvic radiation therapy may be curative in pure vaginal recurrence when no previous radiation therapy has been used.

Hormone therapy

Progesterone and estrogen hormone receptors are commonly found in endometrial carcinoma tissues. Response to hormone therapy is correlated with the presence and level of hormone receptors and the degree of tumor differentiation. Patients with tumors that are positive for estrogen and progesterone receptors respond best to progestin therapy.

When distant metastases, especially pulmonary metastases, are present, hormonal therapy is indicated. Patients who are not candidates for either surgery or radiation therapy may be treated with progestational agents, the most common hormonal treatment. Progestational agents produce good antitumor responses in 15% to 30% of patients. These responses are associated with significant improvement in survival.

Standard progestational agents include the following:

  • Hydroxyprogesterone.
  • Medroxyprogesterone.
  • Megestrol.

Evidence (progestin therapy):

A receptor-poor status may predict a poor response to progestins and a better response to cytotoxic chemotherapy.

Other hormonal agents have shown benefit in treating endometrial cancer. Tamoxifen (20 mg bid) yields a response rate of 20% in patients who do not respond to standard progesterone therapy.

Aromatase inhibitors have also been evaluated for the treatment of advanced and recurrent endometrial cancer, although they yield lower response rates than progestational agents.

Biologic therapy

Several biologic agents have been evaluated for the treatment of endometrial cancer.

Treatment Options Under Clinical Evaluation for Stage III, Stage IV, and Recurrent Endometrial Cancer

All patients with advanced disease should be considered for clinical trials that evaluate single-agent or combination therapy for this disease.

Studies of treatment failure patterns have found a high rate of distant metastases in the upper abdomen and in extra-abdominal sites. For this reason, patients with stage III disease may be candidates for innovative clinical trials.

Treatment options under clinical evaluation for stage IV endometrial cancer include the following agents:

Current Clinical Trials

Check the list of NCI-supported cancer clinical trials that are now accepting patients with stage III endometrial carcinoma, stage IV endometrial carcinoma and recurrent endometrial carcinoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI website.

Changes to This Summary (02/02/2017)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

General Information About Endometrial Cancer

Updated statistics with estimated new cases and deaths for 2017 (cited American Cancer Society as reference 1).

This summary was comprehensively reviewed, extensively revised, and reformatted.

This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of endometrial cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Endometrial Cancer Treatment are:

  • Leslie R. Boyd, MD (New York University Medical Center)
  • Franco M. Muggia, MD (New York University Medical Center)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”

The preferred citation for this PDQ summary is:

PDQ® Adult Treatment Editorial Board. PDQ Endometrial Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated . Available at: https://www.cancer.gov/types/uterine/hp/endometrial-treatment-pdq. Accessed . [PMID: 26389270]

Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

Disclaimer

Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

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