Endometrial Cancer Treatment (PDQ®)–Health Professional Version

  • Resize font
  • Print
  • Email
  • Facebook
  • Twitter
  • Google+
  • Pinterest

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:[1]

  • 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.[2]

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.

Enlarge 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.[3,4]
  • Tamoxifen therapy.[5,6]
  • Obesity.
  • Reproductive factors (nulliparity, early menarche/late menopause, or polycystic ovarian syndrome).
  • Family history/genetic predisposition.[7,8]
  • Hyperinsulinemia.[9]

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.[3,4] However, combined estrogen and progesterone therapy prevents the increase in risk of endometrial cancer associated with unopposed estrogen use.[10,11]

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.[5,6] 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).[12] A prospective study found a statistically significant association between malignant cytology and increased risk of nodal disease.[13]

Prognostic Factors

Prognostic factors for endometrial cancer include the following:

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:[14]

Table 1. Risk of Nodal Metastasis in Clinical Stage I Endometrial Cancer
Prognostic Group Patient Characteristics Risk of Nodal Involvement
A Grade 1 tumors involving only endometrium <5%
No evidence of intraperitoneal spread
B Grade 2–3 tumors 5%–9% pelvic nodes
Invasion of <50% of myometrium
No intraperitoneal spread 4% periaortic nodes
C Deep muscle invasion 20%–60% pelvic nodes
High-grade tumors 10%–30% periaortic nodes
Intraperitoneal spread

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:[15,16]

  • 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,[17-22] and some data are contradictory.[23] 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.[24]

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.[25-27]

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.[28]

Other reports confirm the importance of hormone receptor status as an independent prognostic factor.[29] 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.[25-27]

Other prognostic factors

Other factors predictive of poor prognosis include the following:[27,30,31]

  • A high S-phase fraction.
  • Aneuploidy.
  • Absence of PTEN.
  • PIK3CA mutation status.
  • p53 mutation status.
  • Her-2/neu overexpression.
  • Oncogene expression (e.g., overexpression of the Her-2/neu oncogene has been associated with a poor overall prognosis).

A general review of prognostic factors has been published.[32]

Related Summaries

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

References
  1. American Cancer Society: Cancer Facts and Figures 2017. Atlanta, Ga: American Cancer Society, 2017. Available online. Last accessed January 13, 2017.
  2. Ward KK, Shah NR, Saenz CC, et al.: Cardiovascular disease is the leading cause of death among endometrial cancer patients. Gynecol Oncol 126 (2): 176-9, 2012. [PUBMED Abstract]
  3. Ziel HK, Finkle WD: Increased risk of endometrial carcinoma among users of conjugated estrogens. N Engl J Med 293 (23): 1167-70, 1975. [PUBMED Abstract]
  4. Jick SS, Walker AM, Jick H: Estrogens, progesterone, and endometrial cancer. Epidemiology 4 (1): 20-4, 1993. [PUBMED Abstract]
  5. van Leeuwen FE, Benraadt J, Coebergh JW, et al.: Risk of endometrial cancer after tamoxifen treatment of breast cancer. Lancet 343 (8895): 448-52, 1994. [PUBMED Abstract]
  6. Fisher B, Costantino JP, Redmond CK, et al.: Endometrial cancer in tamoxifen-treated breast cancer patients: findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14. J Natl Cancer Inst 86 (7): 527-37, 1994. [PUBMED Abstract]
  7. Lynch HT, Lynch J, Conway T, et al.: Familial aggregation of carcinoma of the endometrium. Am J Obstet Gynecol 171 (1): 24-7, 1994. [PUBMED Abstract]
  8. Lu KH, Schorge JO, Rodabaugh KJ, et al.: Prospective determination of prevalence of lynch syndrome in young women with endometrial cancer. J Clin Oncol 25 (33): 5158-64, 2007. [PUBMED Abstract]
  9. Nead KT, Sharp SJ, Thompson DJ, et al.: Evidence of a Causal Association Between Insulinemia and Endometrial Cancer: A Mendelian Randomization Analysis. J Natl Cancer Inst 107 (9): , 2015. [PUBMED Abstract]
  10. Jick SS: Combined estrogen and progesterone use and endometrial cancer. Epidemiology 4 (4): 384, 1993. [PUBMED Abstract]
  11. Bilezikian JP: Major issues regarding estrogen replacement therapy in postmenopausal women. J Womens Health 3 (4): 273-82, 1994.
  12. DuBeshter B, Warshal DP, Angel C, et al.: Endometrial carcinoma: the relevance of cervical cytology. Obstet Gynecol 77 (3): 458-62, 1991. [PUBMED Abstract]
  13. Larson DM, Johnson KK, Reyes CN Jr, et al.: Prognostic significance of malignant cervical cytology in patients with endometrial cancer. Obstet Gynecol 84 (3): 399-403, 1994. [PUBMED Abstract]
  14. Takeshima N, Hirai Y, Tanaka N, et al.: Pelvic lymph node metastasis in endometrial cancer with no myometrial invasion. Obstet Gynecol 88 (2): 280-2, 1996. [PUBMED Abstract]
  15. Morrow CP, Bundy BN, Kurman RJ, et al.: Relationship between surgical-pathological risk factors and outcome in clinical stage I and II carcinoma of the endometrium: a Gynecologic Oncology Group study. Gynecol Oncol 40 (1): 55-65, 1991. [PUBMED Abstract]
  16. Lanciano RM, Corn BW, Schultz DJ, et al.: The justification for a surgical staging system in endometrial carcinoma. Radiother Oncol 28 (3): 189-96, 1993. [PUBMED Abstract]
  17. Ambros RA, Kurman RJ: Combined assessment of vascular and myometrial invasion as a model to predict prognosis in stage I endometrioid adenocarcinoma of the uterine corpus. Cancer 69 (6): 1424-31, 1992. [PUBMED Abstract]
  18. Turner DA, Gershenson DM, Atkinson N, et al.: The prognostic significance of peritoneal cytology for stage I endometrial cancer. Obstet Gynecol 74 (5): 775-80, 1989. [PUBMED Abstract]
  19. Piver MS, Recio FO, Baker TR, et al.: A prospective trial of progesterone therapy for malignant peritoneal cytology in patients with endometrial carcinoma. Gynecol Oncol 47 (3): 373-6, 1992. [PUBMED Abstract]
  20. Kadar N, Homesley HD, Malfetano JH: Positive peritoneal cytology is an adverse factor in endometrial carcinoma only if there is other evidence of extrauterine disease. Gynecol Oncol 46 (2): 145-9, 1992. [PUBMED Abstract]
  21. Lurain JR: The significance of positive peritoneal cytology in endometrial cancer. Gynecol Oncol 46 (2): 143-4, 1992. [PUBMED Abstract]
  22. Lurain JR, Rice BL, Rademaker AW, et al.: Prognostic factors associated with recurrence in clinical stage I adenocarcinoma of the endometrium. Obstet Gynecol 78 (1): 63-9, 1991. [PUBMED Abstract]
  23. Garg G, Gao F, Wright JD, et al.: Positive peritoneal cytology is an independent risk-factor in early stage endometrial cancer. Gynecol Oncol 128 (1): 77-82, 2013. [PUBMED Abstract]
  24. Hanson MB, van Nagell JR Jr, Powell DE, et al.: The prognostic significance of lymph-vascular space invasion in stage I endometrial cancer. Cancer 55 (8): 1753-7, 1985. [PUBMED Abstract]
  25. Carcangiu ML, Chambers JT, Voynick IM, et al.: Immunohistochemical evaluation of estrogen and progesterone receptor content in 183 patients with endometrial carcinoma. Part I: Clinical and histologic correlations. Am J Clin Pathol 94 (3): 247-54, 1990. [PUBMED Abstract]
  26. Chambers JT, Carcangiu ML, Voynick IM, et al.: Immunohistochemical evaluation of estrogen and progesterone receptor content in 183 patients with endometrial carcinoma. Part II: Correlation between biochemical and immunohistochemical methods and survival. Am J Clin Pathol 94 (3): 255-60, 1990. [PUBMED Abstract]
  27. Gurpide E: Endometrial cancer: biochemical and clinical correlates. J Natl Cancer Inst 83 (6): 405-16, 1991. [PUBMED Abstract]
  28. Ingram SS, Rosenman J, Heath R, et al.: The predictive value of progesterone receptor levels in endometrial cancer. Int J Radiat Oncol Biol Phys 17 (1): 21-7, 1989. [PUBMED Abstract]
  29. Creasman WT: Prognostic significance of hormone receptors in endometrial cancer. Cancer 71 (4 Suppl): 1467-70, 1993. [PUBMED Abstract]
  30. Friberg LG, Norén H, Delle U: Prognostic value of DNA ploidy and S-phase fraction in endometrial cancer stage I and II: a prospective 5-year survival study. Gynecol Oncol 53 (1): 64-9, 1994. [PUBMED Abstract]
  31. Hetzel DJ, Wilson TO, Keeney GL, et al.: HER-2/neu expression: a major prognostic factor in endometrial cancer. Gynecol Oncol 47 (2): 179-85, 1992. [PUBMED Abstract]
  32. Binder PS, Mutch DG: Update on prognostic markers for endometrial cancer. Womens Health (Lond Engl) 10 (3): 277-88, 2014. [PUBMED Abstract]

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:

  1. Endometrioid (75%) comprises malignant glandular epithelial elements; an admixture of squamous metaplasia is not uncommon.
    1. Ciliated adenocarcinoma.
    2. Secretory adenocarcinoma.
    3. Papillary and villoglandular adenocarcinomas are histologically similar to those noted in the ovary and the fallopian tube. The prognosis is worse for these tumors.[1]
    4. Adenocarcinoma with squamous differentiation.
      • Adenoacanthoma.
      • Adenosquamous cells contain malignant glandular and squamous epithelial elements.[2]
  2. Mixed, defined as two carcinomatous cell types, with the smaller component making up at least 10% of the total (10%).
  3. Uterine papillary serous (<10%).
  4. Clear cell (4%) is histologically similar to those noted in the ovary and the fallopian tube. The prognosis for clear cell tumors is worse.[1]
  5. Carcinosarcoma (3%), also known as malignant mixed mesodermal tumor, has both carcinomatous and sarcomatous elements. This tumor was historically categorized as a subtype of uterine sarcomas; however, recent evidence points to its origin as an adenocarcinoma that has undergone differentiation into the sarcomatous elements.
  6. Mucinous (1%).
  7. Squamous cell (<1%).
  8. Undifferentiated (<1%).

Molecular Subgroups

PTEN mutations are more common in type 1 endometrial cancers; p53 and Her-2/neu 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:[3]

  • POLE (polymerase epsilon) ultramutated tumors. 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.[4]

References
  1. Gusberg SB: Virulence factors in endometrial cancer. Cancer 71 (4 Suppl): 1464-6, 1993. [PUBMED Abstract]
  2. Zaino RJ, Kurman R, Herbold D, et al.: The significance of squamous differentiation in endometrial carcinoma. Data from a Gynecologic Oncology Group study. Cancer 68 (10): 2293-302, 1991. [PUBMED Abstract]
  3. Kandoth C, Schultz N, Cherniack AD, et al.: Integrated genomic characterization of endometrial carcinoma. Nature 497 (7447): 67-73, 2013. [PUBMED Abstract]
  4. Talhouk A, McConechy MK, Leung S, et al.: A clinically applicable molecular-based classification for endometrial cancers. Br J Cancer 113 (2): 299-310, 2015. [PUBMED Abstract]

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.[1,2]

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.[3,4]

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.[4]

Table 2. FIGO Definitions for Stage I Carcinoma of the Endometriuma
Stage Description Illustration
FIGO = Féderation Internationale de Gynécologie et d’Obstétrique.
aAdapted from FIGO Committee on Gynecologic Oncology.[3]
bG1, G2, or G3 (G = grade).
Ib Tumor confined to the corpus uteri.
Enlarge Stage IA and stage IB endometrial cancer shown in two cross-section drawings of the uterus and cervix. Drawing on the left shows stage IA, with cancer in the endometrium and myometrium of the uterus. Drawing on the right shows stage IB, with cancer more than halfway through the myometrium. Also shown are the fallopian tubes, ovaries, and vagina
IAb No or less than half myometrial invasion.
IBb Invasion equal to or more than half of the myometrium.
Table 3. FIGO Definitions for Stage II Carcinoma of the Endometriuma
Stage Description Illustration
FIGO = Féderation Internationale de Gynécologie et d’Obstétrique.
aAdapted from FIGO Committee on Gynecologic Oncology.[3]
bG1, G2, or G3 (G = grade).
cEndocervical glandular involvement is considered stage I; it is no longer considered stage II.
IIb Tumor invades cervical stroma but does not extend beyond the uterus.c
Enlarge Stage II endometrial cancer shown in a cross-section drawing of the uterus, cervix, fallopian tubes, ovaries, and vagina. Cancer is shown in the endometrium and myometrium of the uterus and in the cervix.
Table 4. FIGO Definitions for Stage III Carcinoma of the Endometriuma
Stage Description Illustration
FIGO = Féderation Internationale de Gynécologie et d’Obstétrique.
aAdapted from FIGO Committee on Gynecologic Oncology.[3]
bG1, G2, or G3 (G = grade).
cPositive cytology has to be reported separately without changing the stage.
IIIb Local and/or regional spread of the tumor.  
IIIAb Tumor invades the serosa of the corpus uteri and/or adnexae.c
Enlarge Stage IIIA endometrial cancer shown in a cross-section drawing of the uterus, ligaments of the uterus, cervix, fallopian tubes, ovaries, and vagina. Cancer is shown in the endometrium of the uterus, the outer layer of the uterus, a fallopian tube, an ovary, and a ligament of the uterus.
IIIBb Vaginal and/or parametrial involvement.c
Enlarge Stage IIIB endometrial cancer shown in a cross-section drawing of the uterus, cervix, fallopian tubes, ovaries, and vagina.  Cancer is shown in the endometrium of the uterus, the parametrium, the cervix, and the vagina.
IIICb Metastases to pelvic and/or periaortic lymph nodes.c
Enlarge Stage IIIC endometrial cancer shown in a cross-section drawing of the uterus, cervix, fallopian tubes, ovaries, and vagina. Also shown are the lymph nodes in the pelvis and the aorta with nearby lymph nodes. Cancer is shown in the endometrium and myometrium of the uterus and in lymph nodes in the pelvis and near the aorta.
IIIC1b Positive pelvic nodes.
IIIC2b Positive periaortic lymph nodes with or without positive pelvic lymph nodes.
Table 5. FIGO Definitions for Stage IV Carcinoma of the Endometriuma
Stage Description Illustration
FIGO = Féderation Internationale de Gynécologie et d’Obstétrique.
aAdapted from FIGO Committee on Gynecologic Oncology.[3]
bG1, G2, or G3 (G = grade).
IVb Tumor invades bladder and/or bowel mucosa, and/or distant metastases.  
IVAb Tumor invasion of bladder and/or bowel mucosa.
Enlarge Stage IVA endometrial cancer shown in a side-view cross-section drawing of the uterus, bladder, cervix, vagina, small intestine, and large intestine. Cancer is shown in the bladder, uterus, and bowel.
IVBb Distant metastases, including intra-abdominal metastases and/or inguinal lymph nodes.
Enlarge Stage IVB endometrial cancer; drawing shows cancer has spread to parts of the body outside the pelvis, including the abdomen and/or lymph nodes in the groin. An inset shows cancer cells spreading from the endometrium, through the blood and lymph system, to another part of the body where  metastatic cancer has formed.
References
  1. Hendrickson M, Ross J, Eifel PJ, et al.: Adenocarcinoma of the endometrium: analysis of 256 cases with carcinoma limited to the uterine corpus. Pathology review and analysis of prognostic variables. Gynecol Oncol 13 (3): 373-92, 1982. [PUBMED Abstract]
  2. Nori D, Hilaris BS, Tome M, et al.: Combined surgery and radiation in endometrial carcinoma: an analysis of prognostic factors. Int J Radiat Oncol Biol Phys 13 (4): 489-97, 1987. [PUBMED Abstract]
  3. Pecorelli S: Revised FIGO staging for carcinoma of the vulva, cervix, and endometrium. Int J Gynaecol Obstet 105 (2): 103-4, 2009. [PUBMED Abstract]
  4. Corpus uteri. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 403-18.

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.[1][Level of evidence: 1iiA]

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

Table 6. Treatment Options for Endometrial Cancer
Stage (FIGO Staging Definitions) Treatment Options
FIGO = Féderation Internationale de Gynécologie et d’Obstétrique.
Stage I and stage II endometrial cancer Grades 1 and 2 Surgery with or without lymph node sampling
Postoperative vaginal brachytherapy
Radiation therapy alone
Grade 3 (includes serous, clear cell, and carcinosarcoma) Surgery
Postoperative chemotherapy with or without radiation therapy
Stage III, stage IV, and recurrent endometrial cancer Operable disease Surgery followed by chemotherapy or radiation therapy
Inoperable disease Chemotherapy and radiation therapy
Inoperable disease in which the patient is not a candidate for radiation therapy Hormone therapy
Biologic therapy
References
  1. Martin-Hirsch PP, Bryant A, Keep SL, et al.: Adjuvant progestagens for endometrial cancer. Cochrane Database Syst Rev (6): CD001040, 2011. [PUBMED Abstract]

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:

  1. Surgery: hysterectomy with bilateral salpingo-oophorectomy and possible lymph node dissection.
  2. Postoperative vaginal brachytherapy.
  3. Radiation therapy alone.

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:

  1. Surgery: hysterectomy with bilateral salpingo-oophorectomy, with pelvic and paraaortic lymph node dissection.
  2. Postoperative chemotherapy with or without radiation therapy.

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.[1-9]

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.[10] One nonrandomized study that predominantly included patients with carcinosarcomas appeared to show benefit for adjuvant therapy with cisplatin and doxorubicin.[11]

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.[12-14]

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:[15]

Table 7. Risk of Nodal Metastasis in Clinical Stage I Endometrial Cancer
Prognostic Group Patient Characteristics Risk of Nodal Involvement
A Grade 1 tumors involving only endometrium <5%
No evidence of intraperitoneal spread
B Grade 2–3 tumors 5%–9% pelvic nodes
Invasion of <50% of myometrium
No intraperitoneal spread 4% periaortic nodes
C Deep muscle invasion 20%–60% pelvic nodes
High-grade tumors 10%–30% periaortic nodes
Intraperitoneal spread

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):

  1. In these studies, patients with low-risk cancer had a sufficiently low risk of lymph node metastasis such that lymph node sampling could be omitted. For patients meeting high-risk criteria, a full pelvic and paraaortic lymph node dissection was suggested, given patterns of lymphatic spread.[16,17]
  2. An alternative strategy is the use of sentinel lymph node dissection in patients with presumed stage I endometrial cancer.[18] Although this strategy has been widely adopted at various academic centers, a prospective multicenter trial to determine the false-negative rate for this protocol is lacking. For cases in which isolated tumor cells are identified using the sentinel lymph node approach, it is unclear whether treatment is necessary.
  3. In patients with high-risk histology (serous, clear cell, carcinosarcoma, or undifferentiated tumors), hysterectomy and bilateral salpingo-oophorectomy with pelvic and paraaortic lymph node dissection is the standard.
  4. Laparotomy has been the standard surgical approach; however, laparoscopy is now favored, given the improvement in patients' postoperative recovery without significant impact on oncologic outcomes.

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

  1. For patients with early-stage endometrial cancer, several randomized trials have compared total laparoscopic hysterectomy (TLH) with the standard open procedure, total abdominal hysterectomy (TAH). Feasibility of the laparoscopic approach has been confirmed, but this approach is associated with a longer operative time.[15,19,20] TLH has an improved [15,19] or similar [20] adverse event profile and a shorter hospital stay [15,19,20] than does TAH.
    • TLH is associated with less pain and quicker resumption of daily activities,[20,21] although one study found that most of the gains in quality of life favoring laparoscopy at the 6-week postsurgical period were no longer significant at 6 months.[20,21]
  2. A GOG trial (GOG-LAP2) included 2,616 patients with clinical stages I to IIA disease and randomly assigned them in a 2:1 ratio to comprehensive surgical staging via laparoscopy or laparotomy.[22][Level of evidence: 1iiA]

    Time to recurrence was the primary endpoint, with noninferiority defined as a difference in recurrence rate of less than 5.3% between the two groups at 3 years.

    1. The recurrence rate at 3 years was 10.24% for patients in the laparotomy arm and 11.39% for patients in the laparoscopy arm, with an estimated difference between groups of 1.14% (90% lower bound, -1.278; 95% upper bound, 3.996).
      • Although this difference was lower than the prespecified limit, the statistical requirements for noninferiority were not met because of fewer-than-expected recurrences in both groups.
    2. The overall survival (OS) at 5 years was 89.8% in both groups.
  3. A Cochrane review of the use of laparoscopic staging included four randomized controlled trials that reported OS and progression-free survival (PFS). Ninety percent of the patients were from the GOG-LAP2 trial.[23][Level of evidence: 1iiA]
    • Overall, laparoscopy and laparotomy were associated with similar OS and PFS rates.

Future analyses may determine whether there are subgroups of patients for whom there is a clinically significant decrement when laparoscopic staging is utilized.[22][Level of evidence: 1iiDiii]

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.[24-28] 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.[29] 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.[30]

Evidence (VBT):

  1. Results of two randomized trials that used adjuvant radiation therapy in patients with stage I disease did not show improved survival but did show reduced locoregional recurrence (3%–4% in the radiation therapy group vs. 12%–14% in the control group after median follow-up of 5–6 years; P < .001), with an increase in side effects.[27,31,32][Level of evidence: 1iiDii]
  2. Results of a study by the Danish Endometrial Cancer Group suggest that the absence of radiation therapy does not improve the survival of patients with stage I intermediate-risk disease (grades 1 and 2 with >50% myometrial invasion or grade 3 with <50% myometrial invasion).[33]
  3. The PORTEC-2 (NCT00411138) trial randomly assigned patients with stage I endometrial cancer who did not undergo lymph node dissection to undergo VBT or EBRT, with prevention of vaginal recurrence as the primary outcome.[29,34][Level of evidence: 1iA]
    • At 5 years, there was no difference in the rates of vaginal recurrence, locoregional recurrence, PFS, or OS (84.8% [95% confidence interval (CI), 79.3–90.3] for VBT vs. 79.6% [95% CI, 71.2–88.0] for EBRT; P = .57).
    • There were significantly fewer gastrointestinal toxic effects and improved quality of life in the VBT group, making VBT the preferred option for adjuvant treatment of patients with stage I disease.
  4. The Norwegian Radium Hospital trial randomly assigned treatment to 568 patients with clinical stage I endometrial cancer between the 1968 and 1974 (before FIGO surgical staging was initiated).[30][Level of evidence: 1iiA] After hysterectomy and bilateral salpingo-oophorectomy, patients were randomly assigned to receive either EBRT and VBT or VBT alone.
    • An updated report presenting over 20 years of follow-up data showed no difference in OS between the treatment groups. Median OS was 20.5 years in the EBRT/VBT group and 20.48 in the VBT-alone group (P = .186). In all women, there was an increased risk of secondary cancers after EBRT (hazard ratio [HR], 1.42; 95% CI, 1.01–2.0).
    • A post-hoc subset analysis of women younger than 60 years at the time of trial registration showed increased mortality in the EBRT arm (HR, 1.36; 95% CI, 1.06–1.76). Further, the risk of secondary cancers doubled in this group (HR, 2.02; 95% CI, 1.3–3.15).

Postoperative radiation therapy

If the cervix is clinically uninvolved, but extension to the cervix is noted on postoperative pathology, radiation therapy is considered.[22][Level of evidence: 1iiA]

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.[35-37]

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

  1. The GOG-0249 (NCT00807768) trial compared the combination of adjuvant carboplatin and paclitaxel and vaginal cuff brachytherapy versus adjuvant pelvic EBRT in high-risk endometrial cancer patients with stage I or II disease. The study is closed to accrual, and preliminary findings have been presented in abstract form, showing no significant difference between the two treatment arms.
  2. The GOG-0261 (NCT00954174) trial compared paclitaxel and carboplatin with paclitaxel and ifosfamide in patients with newly diagnosed stages I to IV persistent or recurrent uterine, ovarian, fallopian tube, or peritoneal cavity 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.

References
  1. Kiess AP, Damast S, Makker V, et al.: Five-year outcomes of adjuvant carboplatin/paclitaxel chemotherapy and intravaginal radiation for stage I-II papillary serous endometrial cancer. Gynecol Oncol 127 (2): 321-5, 2012. [PUBMED Abstract]
  2. Boruta DM 2nd, Gehrig PA, Fader AN, et al.: Management of women with uterine papillary serous cancer: a Society of Gynecologic Oncology (SGO) review. Gynecol Oncol 115 (1): 142-53, 2009. [PUBMED Abstract]
  3. Huh WK, Powell M, Leath CA 3rd, et al.: Uterine papillary serous carcinoma: comparisons of outcomes in surgical Stage I patients with and without adjuvant therapy. Gynecol Oncol 91 (3): 470-5, 2003. [PUBMED Abstract]
  4. Fader AN, Drake RD, O'Malley DM, et al.: Platinum/taxane-based chemotherapy with or without radiation therapy favorably impacts survival outcomes in stage I uterine papillary serous carcinoma. Cancer 115 (10): 2119-27, 2009. [PUBMED Abstract]
  5. Kelly MG, O'malley DM, Hui P, et al.: Improved survival in surgical stage I patients with uterine papillary serous carcinoma (UPSC) treated with adjuvant platinum-based chemotherapy. Gynecol Oncol 98 (3): 353-9, 2005. [PUBMED Abstract]
  6. Havrilesky LJ, Secord AA, Bae-Jump V, et al.: Outcomes in surgical stage I uterine papillary serous carcinoma. Gynecol Oncol 105 (3): 677-82, 2007. [PUBMED Abstract]
  7. Dietrich CS 3rd, Modesitt SC, DePriest PD, et al.: The efficacy of adjuvant platinum-based chemotherapy in Stage I uterine papillary serous carcinoma (UPSC). Gynecol Oncol 99 (3): 557-63, 2005. [PUBMED Abstract]
  8. Townamchai K, Berkowitz R, Bhagwat M, et al.: Vaginal brachytherapy for early stage uterine papillary serous and clear cell endometrial cancer. Gynecol Oncol 129 (1): 18-21, 2013. [PUBMED Abstract]
  9. Barney BM, Petersen IA, Mariani A, et al.: The role of vaginal brachytherapy in the treatment of surgical stage I papillary serous or clear cell endometrial cancer. Int J Radiat Oncol Biol Phys 85 (1): 109-15, 2013. [PUBMED Abstract]
  10. Hornback NB, Omura G, Major FJ: Observations on the use of adjuvant radiation therapy in patients with stage I and II uterine sarcoma. Int J Radiat Oncol Biol Phys 12 (12): 2127-30, 1986. [PUBMED Abstract]
  11. Peters WA 3rd, Rivkin SE, Smith MR, et al.: Cisplatin and adriamycin combination chemotherapy for uterine stromal sarcomas and mixed mesodermal tumors. Gynecol Oncol 34 (3): 323-7, 1989. [PUBMED Abstract]
  12. Ayhan A, Taskiran C, Celik C, et al.: The long-term survival of women with surgical stage II endometrioid type endometrial cancer. Gynecol Oncol 93 (1): 9-13, 2004. [PUBMED Abstract]
  13. Eltabbakh GH, Moore AD: Survival of women with surgical stage II endometrial cancer. Gynecol Oncol 74 (1): 80-5, 1999. [PUBMED Abstract]
  14. Orezzoli JP, Sioletic S, Olawaiye A, et al.: Stage II endometrioid adenocarcinoma of the endometrium: clinical implications of cervical stromal invasion. Gynecol Oncol 113 (3): 316-23, 2009. [PUBMED Abstract]
  15. Walker JL, Piedmonte MR, Spirtos NM, et al.: Laparoscopy compared with laparotomy for comprehensive surgical staging of uterine cancer: Gynecologic Oncology Group Study LAP2. J Clin Oncol 27 (32): 5331-6, 2009. [PUBMED Abstract]
  16. Mariani A, Dowdy SC, Cliby WA, et al.: Prospective assessment of lymphatic dissemination in endometrial cancer: a paradigm shift in surgical staging. Gynecol Oncol 109 (1): 11-8, 2008. [PUBMED Abstract]
  17. Mariani A, Webb MJ, Keeney GL, et al.: Low-risk corpus cancer: is lymphadenectomy or radiotherapy necessary? Am J Obstet Gynecol 182 (6): 1506-19, 2000. [PUBMED Abstract]
  18. Barlin JN, Khoury-Collado F, Kim CH, et al.: The importance of applying a sentinel lymph node mapping algorithm in endometrial cancer staging: beyond removal of blue nodes. Gynecol Oncol 125 (3): 531-5, 2012. [PUBMED Abstract]
  19. Janda M, Gebski V, Brand A, et al.: Quality of life after total laparoscopic hysterectomy versus total abdominal hysterectomy for stage I endometrial cancer (LACE): a randomised trial. Lancet Oncol 11 (8): 772-80, 2010. [PUBMED Abstract]
  20. Mourits MJ, Bijen CB, Arts HJ, et al.: Safety of laparoscopy versus laparotomy in early-stage endometrial cancer: a randomised trial. Lancet Oncol 11 (8): 763-71, 2010. [PUBMED Abstract]
  21. Kornblith AB, Huang HQ, Walker JL, et al.: Quality of life of patients with endometrial cancer undergoing laparoscopic international federation of gynecology and obstetrics staging compared with laparotomy: a Gynecologic Oncology Group study. J Clin Oncol 27 (32): 5337-42, 2009. [PUBMED Abstract]
  22. Walker JL, Piedmonte MR, Spirtos NM, et al.: Recurrence and survival after random assignment to laparoscopy versus laparotomy for comprehensive surgical staging of uterine cancer: Gynecologic Oncology Group LAP2 Study. J Clin Oncol 30 (7): 695-700, 2012. [PUBMED Abstract]
  23. Galaal K, Bryant A, Fisher AD, et al.: Laparoscopy versus laparotomy for the management of early stage endometrial cancer. Cochrane Database Syst Rev 9: CD006655, 2012. [PUBMED Abstract]
  24. Aalders J, Abeler V, Kolstad P, et al.: Postoperative external irradiation and prognostic parameters in stage I endometrial carcinoma: clinical and histopathologic study of 540 patients. Obstet Gynecol 56 (4): 419-27, 1980. [PUBMED Abstract]
  25. Morrow CP, Bundy BN, Kurman RJ, et al.: Relationship between surgical-pathological risk factors and outcome in clinical stage I and II carcinoma of the endometrium: a Gynecologic Oncology Group study. Gynecol Oncol 40 (1): 55-65, 1991. [PUBMED Abstract]
  26. Marchetti DL, Caglar H, Driscoll DL, et al.: Pelvic radiation in stage I endometrial adenocarcinoma with high-risk attributes. Gynecol Oncol 37 (1): 51-4, 1990. [PUBMED Abstract]
  27. Creutzberg CL, van Putten WL, Koper PC, et al.: Surgery and postoperative radiotherapy versus surgery alone for patients with stage-1 endometrial carcinoma: multicentre randomised trial. PORTEC Study Group. Post Operative Radiation Therapy in Endometrial Carcinoma. Lancet 355 (9213): 1404-11, 2000. [PUBMED Abstract]
  28. Kong A, Johnson N, Kitchener HC, et al.: Adjuvant radiotherapy for stage I endometrial cancer: an updated Cochrane systematic review and meta-analysis. J Natl Cancer Inst 104 (21): 1625-34, 2012. [PUBMED Abstract]
  29. Nout RA, Smit VT, Putter H, et al.: Vaginal brachytherapy versus pelvic external beam radiotherapy for patients with endometrial cancer of high-intermediate risk (PORTEC-2): an open-label, non-inferiority, randomised trial. Lancet 375 (9717): 816-23, 2010. [PUBMED Abstract]
  30. Onsrud M, Cvancarova M, Hellebust TP, et al.: Long-term outcomes after pelvic radiation for early-stage endometrial cancer. J Clin Oncol 31 (31): 3951-6, 2013. [PUBMED Abstract]
  31. Keys HM, Roberts JA, Brunetto VL, et al.: A phase III trial of surgery with or without adjunctive external pelvic radiation therapy in intermediate risk endometrial adenocarcinoma: a Gynecologic Oncology Group study. Gynecol Oncol 92 (3): 744-51, 2004. [PUBMED Abstract]
  32. Scholten AN, van Putten WL, Beerman H, et al.: Postoperative radiotherapy for Stage 1 endometrial carcinoma: long-term outcome of the randomized PORTEC trial with central pathology review. Int J Radiat Oncol Biol Phys 63 (3): 834-8, 2005. [PUBMED Abstract]
  33. Bertelsen K, Ortoft G, Hansen ES: Survival of Danish patients with endometrial cancer in the intermediate-risk group not given postoperative radiotherapy: the Danish Endometrial Cancer Study (DEMCA). Int J Gynecol Cancer 21 (7): 1191-9, 2011. [PUBMED Abstract]
  34. Nout RA, Putter H, Jürgenliemk-Schulz IM, et al.: Five-year quality of life of endometrial cancer patients treated in the randomised Post Operative Radiation Therapy in Endometrial Cancer (PORTEC-2) trial and comparison with norm data. Eur J Cancer 48 (11): 1638-48, 2012. [PUBMED Abstract]
  35. Eltabbakh GH, Piver MS, Hempling RE, et al.: Excellent long-term survival and absence of vaginal recurrences in 332 patients with low-risk stage I endometrial adenocarcinoma treated with hysterectomy and vaginal brachytherapy without formal staging lymph node sampling: report of a prospective trial. Int J Radiat Oncol Biol Phys 38 (2): 373-80, 1997. [PUBMED Abstract]
  36. Stokes S, Bedwinek J, Kao MS, et al.: Treatment of stage I adenocarcinoma of the endometrium by hysterectomy and adjuvant irradiation: a retrospective analysis of 304 patients. Int J Radiat Oncol Biol Phys 12 (3): 339-44, 1986. [PUBMED Abstract]
  37. Grigsby PW, Kuske RR, Perez CA, et al.: Medically inoperable stage I adenocarcinoma of the endometrium treated with radiotherapy alone. Int J Radiat Oncol Biol Phys 13 (4): 483-8, 1987. [PUBMED Abstract]

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.[1,2]

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.[3]

Evidence (surgery followed by chemotherapy or radiation therapy):

  1. Several randomized trials by the Gynecologic Oncology Group (GOG) have utilized the known antitumor activity of doxorubicin.[4]
    • The addition of cisplatin to doxorubicin increased response rates and progression-free survival (PFS) above those of doxorubicin alone but without an effect on overall survival (OS).
  2. A three-drug regimen of doxorubicin, cisplatin, and paclitaxel with granulocyte-colony stimulating factor (G-CSF) was significantly superior to cisplatin and doxorubicin, as shown by the following:[5,6][Level of evidence: 1iiDiv]
    • Response rate was 57% with the three-drug regimen, compared with 34% with the cisplatin and doxorubicin regimen.
    • PFS was 8.3 months with the three-drug regimen, compared with 5.3 months with the cisplatin and doxorubicin regimen.
    • OS was 15.3 months with the three-drug regimen, compared with 12.3 months with the cisplatin and doxorubicin regimen.
    • The superior regimen (doxorubicin, cisplatin, and paclitaxel with G-CSF ) was associated with 12% grade 3 and 27% grade 2 peripheral neuropathy.

    Given the toxicity and limited efficacy of these regimens, other treatment options have been widely sought. Several observational studies [7,8] and phase II studies [9-12] suggest clinical activity with the combination of platinum chemotherapy and paclitaxel in patients with endometrial cancer and measurable disease either after primary surgery or at recurrence.

  3. The GOG protocol GOG-0209 (NCT000063999) is a noninferiority trial comparing the combination of paclitaxel, doxorubicin, and cisplatin (TAP) with G-CSF to carboplatin and paclitaxel.[13]
    • The interim results, currently available in abstract form, show that the combination of carboplatin and paclitaxel was not inferior to TAP and have led to the use of carboplatin and paclitaxel as the standard for adjuvant treatment of stages III and IV disease.
  4. The use of cisplatin and doxorubicin compared with whole-abdominal radiation therapy was studied in a trial of patients with stage III or IV disease with residual tumors smaller than 2 cm and no parenchymal organ involvement.[14][Level of evidence: 1iiA]
    • Results suggest that cisplatin and doxorubicin improved OS, compared with whole-abdominal radiation therapy (adjusted hazard ratio [HR], 0.68; 95% confidence interval [CI], 0.52–0.89; P = .02; 5-year survival rates of 55% for cisplatin and doxorubicin vs. 42% for whole-abdominal radiation).
  5. Several trials support combination chemotherapy for stage III, stage IV, and recurrent carcinosarcoma patients.
    1. The GOG-108 trial of ifosfamide with or without cisplatin as first-line therapy in patients with measurable advanced or recurrent carcinosarcomas demonstrated a higher response rate (54% vs. 34%) and longer PFS on the combination arm (6 months vs. 4 months), but there was no significant improvement in survival (9 months vs. 8 months).[15][Level of evidence: 1iiA]
    2. The follow-up GOG-0161 (NCT00003128) study utilized 3-day ifosfamide regimens (instead of the more-toxic 5-day regimen in the preceding study) for the control and ifosfamide combined with paclitaxel (with G-CSF starting on day 4) for the study arm.[16]

      • The combination was superior in response rates (45% vs. 29%), PFS (8.4 months vs. 5.8 months), and OS (13.5 months vs. 8.4 months). The HR for death also favored the combination (HR, 0.69; 95% CI, 0.49–0.97).[16][Level of evidence: 1iiA]
      • In this study, 52% of 179 evaluable patients had recurrent disease; 18% had stage III disease; and 30% had stage IV disease. In addition, there were imbalances between the treatment arms with respect to the sites of disease and the use of prior radiation therapy, and 30 patients were excluded for wrong pathology.
    3. A phase II trial evaluated carboplatin with paclitaxel in patients with stage III, stage IV, or recurrent carcinosarcoma.[17] After noting a favorable response rate, the GOG activated GOG-0261 (NCT00954174), a randomized phase III trial of carboplatin with paclitaxel versus ifosfamide with paclitaxel. This study is closed to accrual, and results are awaited.

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.[18,19]

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.[20] 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.[20]

Standard progestational agents include the following:[20]

  • Hydroxyprogesterone.
  • Medroxyprogesterone.
  • Megestrol.

Evidence (progestin therapy):

  1. One study followed 115 patients with advanced endometrial cancer treated with progestins.[21]
    • Seventy-five percent of patients (42 of 56) with progesterone receptor–positive tumors before treatment responded.
    • Seven percent of patients (4 of 59) without detectable progesterone receptors before treatment responded.

A receptor-poor status may predict a poor response to progestins and a better response to cytotoxic chemotherapy.[22]

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.[23]

Aromatase inhibitors have also been evaluated for the treatment of advanced and recurrent endometrial cancer, although they yield lower response rates than progestational agents.[24]

Biologic therapy

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

  1. Mammalian target of rapamycin (mTOR) inhibitors.

    Endometrial cancers often show alterations in the AKT-PI3K pathway, making mTOR inhibitors an attractive choice for clinical study in patients with metastatic or recurrent disease. Phase II studies of single-agent everolimus [25] and ridaforolimus [26,27] have predominantly shown disease stabilization. A phase II study of the combination of everolimus and letrozole showed a response rate of 32%.[28][Level of evidence: 3iiiDiv]

  2. Bevazicumab.
    • Bevacizumab was utilized as a single agent in a phase II trial; the overall response rate was 13.5%.[29][Level of evidence: 3iiiDiv]
    • Bevacizumab and temsirolimus.[30]

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.[31] 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:

  1. Paclitaxel and carboplatin with or without metformin in stages III, IV, and recurrent endometrial cancer (GOG-0286B [NCT02065687]).
  2. PI3K/mTOR inhibitor in recurrent or persistent endometrial cancer (15-079 [NCT02549989]).
  3. Everolimus and letrozole or hormonal therapy in recurrent or persistent endometrial cancer (GOG-3007 [NCT02228681]).
  4. Everolimus, letrozole, and metformin in patients with advanced or recurrent endometrial cancer (2012-0543 [NCT01797523]).
  5. Paclitaxel and carboplatin versus paclitaxel and ifosfamide in patients with newly diagnosed stages I to IV persistent or recurrent uterine, ovarian, fallopian tube, or peritoneal cavity cancer (GOG-0261 [NCT00954174]).

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.

References
  1. Shih KK, Yun E, Gardner GJ, et al.: Surgical cytoreduction in stage IV endometrioid endometrial carcinoma. Gynecol Oncol 122 (3): 608-11, 2011. [PUBMED Abstract]
  2. Barlin JN, Puri I, Bristow RE: Cytoreductive surgery for advanced or recurrent endometrial cancer: a meta-analysis. Gynecol Oncol 118 (1): 14-8, 2010. [PUBMED Abstract]
  3. Ball HG, Blessing JA, Lentz SS, et al.: A phase II trial of paclitaxel in patients with advanced or recurrent adenocarcinoma of the endometrium: a Gynecologic Oncology Group study. Gynecol Oncol 62 (2): 278-81, 1996. [PUBMED Abstract]
  4. Thigpen JT, Brady MF, Homesley HD, et al.: Phase III trial of doxorubicin with or without cisplatin in advanced endometrial carcinoma: a Gynecologic Oncology Group study. J Clin Oncol 22 (19): 3902-8, 2004. [PUBMED Abstract]
  5. Fleming GF, Brunetto VL, Cella D, et al.: Phase III trial of doxorubicin plus cisplatin with or without paclitaxel plus filgrastim in advanced endometrial carcinoma: a Gynecologic Oncology Group Study. J Clin Oncol 22 (11): 2159-66, 2004. [PUBMED Abstract]
  6. Fleming GF, Filiaci VL, Bentley RC, et al.: Phase III randomized trial of doxorubicin + cisplatin versus doxorubicin + 24-h paclitaxel + filgrastim in endometrial carcinoma: a Gynecologic Oncology Group study. Ann Oncol 15 (8): 1173-8, 2004. [PUBMED Abstract]
  7. Arimoto T, Nakagawa S, Yasugi T, et al.: Treatment with paclitaxel plus carboplatin, alone or with irradiation, of advanced or recurrent endometrial carcinoma. Gynecol Oncol 104 (1): 32-5, 2007. [PUBMED Abstract]
  8. Sovak MA, Hensley ML, Dupont J, et al.: Paclitaxel and carboplatin in the adjuvant treatment of patients with high-risk stage III and IV endometrial cancer: a retrospective study. Gynecol Oncol 103 (2): 451-7, 2006. [PUBMED Abstract]
  9. Hoskins PJ, Swenerton KD, Pike JA, et al.: Paclitaxel and carboplatin, alone or with irradiation, in advanced or recurrent endometrial cancer: a phase II study. J Clin Oncol 19 (20): 4048-53, 2001. [PUBMED Abstract]
  10. Pectasides D, Xiros N, Papaxoinis G, et al.: Carboplatin and paclitaxel in advanced or metastatic endometrial cancer. Gynecol Oncol 109 (2): 250-4, 2008. [PUBMED Abstract]
  11. Nomura H, Aoki D, Takahashi F, et al.: Randomized phase II study comparing docetaxel plus cisplatin, docetaxel plus carboplatin, and paclitaxel plus carboplatin in patients with advanced or recurrent endometrial carcinoma: a Japanese Gynecologic Oncology Group study (JGOG2041). Ann Oncol 22 (3): 636-42, 2011. [PUBMED Abstract]
  12. Dimopoulos MA, Papadimitriou CA, Georgoulias V, et al.: Paclitaxel and cisplatin in advanced or recurrent carcinoma of the endometrium: long-term results of a phase II multicenter study. Gynecol Oncol 78 (1): 52-7, 2000. [PUBMED Abstract]
  13. Miller D, Filiaci V, Fleming G, et al.: Late-breaking abstract 1: Randomized phase III noninferiority trial of first line chemotherapy for metastatic or recurrent endometrial carcinoma: A Gynecologic Oncology Group study. [Abstract] Gynecol Oncol 125 (3): 771, 2012.
  14. Randall ME, Filiaci VL, Muss H, et al.: Randomized phase III trial of whole-abdominal irradiation versus doxorubicin and cisplatin chemotherapy in advanced endometrial carcinoma: a Gynecologic Oncology Group Study. J Clin Oncol 24 (1): 36-44, 2006. [PUBMED Abstract]
  15. Sutton G, Brunetto VL, Kilgore L, et al.: A phase III trial of ifosfamide with or without cisplatin in carcinosarcoma of the uterus: A Gynecologic Oncology Group Study. Gynecol Oncol 79 (2): 147-53, 2000. [PUBMED Abstract]
  16. Homesley HD, Filiaci V, Markman M, et al.: Phase III trial of ifosfamide with or without paclitaxel in advanced uterine carcinosarcoma: a Gynecologic Oncology Group Study. J Clin Oncol 25 (5): 526-31, 2007. [PUBMED Abstract]
  17. Powell MA, Filiaci VL, Rose PG, et al.: Phase II evaluation of paclitaxel and carboplatin in the treatment of carcinosarcoma of the uterus: a Gynecologic Oncology Group study. J Clin Oncol 28 (16): 2727-31, 2010. [PUBMED Abstract]
  18. Wegner RE, Beriwal S, Heron DE, et al.: Definitive radiation therapy for endometrial cancer in medically inoperable elderly patients. Brachytherapy 9 (3): 260-5, 2010 Jul-Sep. [PUBMED Abstract]
  19. Kupelian PA, Eifel PJ, Tornos C, et al.: Treatment of endometrial carcinoma with radiation therapy alone. Int J Radiat Oncol Biol Phys 27 (4): 817-24, 1993. [PUBMED Abstract]
  20. Lentz SS: Advanced and recurrent endometrial carcinoma: hormonal therapy. Semin Oncol 21 (1): 100-6, 1994. [PUBMED Abstract]
  21. Kauppila A: Oestrogen and progestin receptors as prognostic indicators in endometrial cancer. A review of the literature. Acta Oncol 28 (4): 561-6, 1989. [PUBMED Abstract]
  22. Kauppila A, Friberg LG: Hormonal and cytotoxic chemotherapy for endometrial carcinoma. Steroid receptors in the selection of appropriate therapy. Acta Obstet Gynecol Scand Suppl 101: 59-64, 1981. [PUBMED Abstract]
  23. Quinn MA, Campbell JJ: Tamoxifen therapy in advanced/recurrent endometrial carcinoma. Gynecol Oncol 32 (1): 1-3, 1989. [PUBMED Abstract]
  24. Lindemann K, Malander S, Christensen RD, et al.: Examestane in advanced or recurrent endometrial carcinoma: a prospective phase II study by the Nordic Society of Gynecologic Oncology (NSGO). BMC Cancer 14: 68, 2014. [PUBMED Abstract]
  25. Slomovitz BM, Lu KH, Johnston T, et al.: A phase 2 study of the oral mammalian target of rapamycin inhibitor, everolimus, in patients with recurrent endometrial carcinoma. Cancer 116 (23): 5415-9, 2010. [PUBMED Abstract]
  26. Colombo N, McMeekin DS, Schwartz PE, et al.: Ridaforolimus as a single agent in advanced endometrial cancer: results of a single-arm, phase 2 trial. Br J Cancer 108 (5): 1021-6, 2013. [PUBMED Abstract]
  27. Tsoref D, Welch S, Lau S, et al.: Phase II study of oral ridaforolimus in women with recurrent or metastatic endometrial cancer. Gynecol Oncol 135 (2): 184-9, 2014. [PUBMED Abstract]
  28. Slomovitz BM, Jiang Y, Yates MS, et al.: Phase II study of everolimus and letrozole in patients with recurrent endometrial carcinoma. J Clin Oncol 33 (8): 930-6, 2015. [PUBMED Abstract]
  29. Aghajanian C, Sill MW, Darcy KM, et al.: Phase II trial of bevacizumab in recurrent or persistent endometrial cancer: a Gynecologic Oncology Group study. J Clin Oncol 29 (16): 2259-65, 2011. [PUBMED Abstract]
  30. Alvarez EA, Brady WE, Walker JL, et al.: Phase II trial of combination bevacizumab and temsirolimus in the treatment of recurrent or persistent endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol 129 (1): 22-7, 2013. [PUBMED Abstract]
  31. Greven KM, Curran WJ Jr, Whittington R, et al.: Analysis of failure patterns in stage III endometrial carcinoma and therapeutic implications. Int J Radiat Oncol Biol Phys 17 (1): 35-9, 1989. [PUBMED Abstract]

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 <MM/DD/YYYY>. Available at: http://www.cancer.gov/types/uterine/hp/endometrial-treatment-pdq. Accessed <MM/DD/YYYY>. [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.

Contact Us

More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s Email Us.

  • Updated: February 2, 2017

Most text on the National Cancer Institute website may be reproduced or reused freely. The National Cancer Institute should be credited as the source. Please note that blog posts that are written by individuals from outside the government may be owned by the writer, and graphics may be owned by their creator. In such cases, it is necessary to contact the writer, artist, or publisher to obtain permission for reuse.

We welcome your comments on this post. All comments must follow our comment policy.