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Endometrial Cancer Treatment (PDQ®)

Health Professional Version
Last Modified: 04/23/2014

General Information About Endometrial Cancer



Incidence and Mortality

Estimated new cases and deaths from endometrial (uterine corpus) cancer in the United States in 2014:[1]

  • New cases: 52,630.
  • Deaths: 8,590.

Cancer of the endometrium is the most common gynecologic malignancy in the United States and accounts for 6% of all cancers in women.

Clinical Features

Irregular vaginal bleeding is an early sign, the foremost symptom, and the reason why the majority of patients with the highly curable endometrial tumor are diagnosed with stage I disease.

Risk Factors

Risk factors for the development of endometrial cancer include the following:

  • Obesity.
  • Hypertension.
  • Diabetes mellitus.

Cardiovascular disease is the most common cause of death in patients diagnosed with endometrial cancer because of the early stage of the cancer at diagnosis and the metabolic risk factors.[2]

Diagnostics

To detect endometrial cancer, a technique that directly samples the endometrial tissue is mandatory. The Pap smear is not reliable as a screening procedure in endometrial cancer, although a retrospective study found a strong correlation between positive cervical cytology and high-risk disease (i.e., high-grade tumor and deep myometrial invasion) [3] as well as an increased risk of nodal disease.[4] The degree of tumor differentiation has an important impact on the natural history of this disease and on treatment selection. An increased incidence of endometrial cancer has been found in association with prolonged, unopposed estrogen exposure.[5,6] In contrast, combined estrogen and progesterone therapy prevents the increase in risk of endometrial cancer associated with unopposed estrogen use.[7,8] In some patients, an antecedent history of complex hyperplasia with atypia can be demonstrated. An increased incidence of endometrial cancer has also been found in association with tamoxifen treatment of breast cancer (NSABP-B-14), related to the estrogenic effect of tamoxifen on the endometrium.[9,10] Because of this increase, patients on tamoxifen should have follow-up pelvic examinations and should be examined if there is any abnormal uterine bleeding.

Histopathology

The pattern of 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 extension is less common. In patients with poorly differentiated tumors, myometrial invasion occurs much more frequently. Myometrial invasion is frequently a harbinger of lymph node involvement and distant metastases and is often independent of the degree of differentiation.[11,12] Metastatic spread occurs in a characteristic pattern. Spread to the pelvic and para-aortic nodes is common. When distant metastasis occurs, it most commonly involves the following:

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

Another factor found to correlate with extrauterine and nodal spread of tumor is involvement of the capillary-lymphatic space on histopathologic examination.[13] Three prognostic groupings of clinical stage I disease become possible by careful operative staging. Patients with grade 1 tumors involving only endometrium and no evidence of intraperitoneal disease (i.e., adnexal spread) have a low risk (<5%) of nodal involvement.[14] Patients with grade 2 or 3 tumors and invasion of less than 50% of the myometrium and no intraperitoneal disease have a 5% to 9% incidence of pelvic node involvement and a 4% incidence of positive para-aortic nodes. Patients with deep muscle invasion and high-grade tumors and/or intraperitoneal disease have a significant risk of nodal spread, 20% to 60% to pelvic nodes and 10% to 30% to para-aortic nodes. One study was directed specifically at stage I, grade 1 carcinomas of favorable histologic type. The authors identified the following four statistically significant adverse prognostic factors:[15]

  • Myometrial invasion.
  • Vascular invasion.
  • Eight or more mitoses per ten high-power fields.
  • An absence of progesterone receptors.

Another group identified aneuploidy and a high S-phase fraction as predictive of poor prognosis.[16] A Gynecologic Oncology Group study related surgical-pathologic parameters and postoperative treatment to recurrence-free interval and recurrence site. For patients without extrauterine spread, the greatest determinants of recurrence were grade 3 histology and deep myometrial invasion. In this study, the frequency of recurrence was greatly increased with positive pelvic nodes, adnexal metastasis, positive peritoneal cytology, capillary space involvement, involvement of the isthmus or cervix, and, particularly, positive para-aortic 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.[17,18]

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.[19-24] As a result, 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.

One report found progesterone receptor levels to be the single most important prognostic indicator of 3-year survival in clinical stage I and II disease. Patients with progesterone receptor levels higher than 100 had a 3-year disease-free survival of 93% compared with 36% for a level lower than 100. Only cervical involvement and peritoneal cytology were significant prognostic variables after adjusting for progesterone receptor levels.[25] Other reports confirm the importance of hormone receptor status as an independent prognostic factor.[26] Additionally, immunohistochemical staining of paraffin-embedded tissue for both estrogen and progesterone receptors has been shown to correlate with International Federation of Gynecology and Obstetrics grade as well as survival.[27-29] On the basis of these data, progesterone and estrogen receptors, assessed either by biochemical or immunohistochemical methods, should be included, when possible, in the evaluation of stage I and II patients. The following have also been found to be prognostic indicators of clinical outcome:[29]

  • Oncogene expression.
  • DNA ploidy.
  • The fraction of cells in S-phase.

For example, overexpression of the Her-2/neu oncogene has been associated with a poor overall prognosis.[30] A general review of prognostic factors has been published.[31]

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 2014. Atlanta, Ga: American Cancer Society, 2014. Available online. Last accessed May 21, 2014. 

  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. DuBeshter B, Warshal DP, Angel C, et al.: Endometrial carcinoma: the relevance of cervical cytology. Obstet Gynecol 77 (3): 458-62, 1991.  [PUBMED Abstract]

  4. 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]

  5. 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]

  6. Jick SS, Walker AM, Jick H: Estrogens, progesterone, and endometrial cancer. Epidemiology 4 (1): 20-4, 1993.  [PUBMED Abstract]

  7. Jick SS: Combined estrogen and progesterone use and endometrial cancer. Epidemiology 4 (4): 384, 1993.  [PUBMED Abstract]

  8. Bilezikian JP: Major issues regarding estrogen replacement therapy in postmenopausal women. J Womens Health 3 (4): 273-82, 1994. 

  9. 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]

  10. 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]

  11. 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]

  12. 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]

  13. 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]

  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. Tornos C, Silva EG, el-Naggar A, et al.: Aggressive stage I grade 1 endometrial carcinoma. Cancer 70 (4): 790-8, 1992.  [PUBMED Abstract]

  16. 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]

  17. 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]

  18. 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]

  19. 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]

  20. 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]

  21. 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]

  22. 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]

  23. Lurain JR: The significance of positive peritoneal cytology in endometrial cancer. Gynecol Oncol 46 (2): 143-4, 1992.  [PUBMED Abstract]

  24. 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]

  25. 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]

  26. Creasman WT: Prognostic significance of hormone receptors in endometrial cancer. Cancer 71 (4 Suppl): 1467-70, 1993.  [PUBMED Abstract]

  27. 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]

  28. 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]

  29. Gurpide E: Endometrial cancer: biochemical and clinical correlates. J Natl Cancer Inst 83 (6): 405-16, 1991.  [PUBMED Abstract]

  30. 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]

  31. Homesley HD, Zaino R: Endometrial cancer: prognostic factors. Semin Oncol 21 (1): 71-8, 1994.  [PUBMED Abstract]

Cellular Classification of Endometrial Cancer

Endometrial cancers are classified in one of the following two categories:

  • 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.

Characteristic activating oncogenic mutations or amplification and inactivating mutations or deletion of tumor suppressors are seen more in association with one type of mutation versus the other type, but some overlap exists. With the Cancer Genome Atlas and a full genetic display of hundreds of endometrial cancers, four subtypes have been identified that will refine classification and provide prognostic and therapeutic implications.[1]

The most common endometrial cancer cell type is endometrioid adenocarcinoma, which is composed of malignant glandular epithelial elements; an admixture of squamous metaplasia is not uncommon. Adenosquamous tumors contain malignant elements of both glandular and squamous epithelium;[2] clear cell and papillary serous carcinoma of the endometrium are tumors that are histologically similar to those noted in the ovary and the fallopian tube, and the prognosis is worse for these tumors.[3] Mucinous, squamous, and undifferentiated tumors are rarely encountered. Frequency of endometrial cancer cell types is as follows:

  1. Endometrioid (75%–80%).
    1. Ciliated adenocarcinoma.
    2. Secretory adenocarcinoma.
    3. Papillary or villoglandular.
    4. Adenocarcinoma with squamous differentiation.
      1. Adenoacanthoma.
      2. Adenosquamous.
  2. Uterine papillary serous (<10%).
  3. Mucinous (1%).
  4. Clear cell (4%).
  5. Squamous cell (<1%).
  6. Mixed (10%).
  7. Undifferentiated.
References
  1. Kandoth C, Schultz N, Cherniack AD, et al.: Integrated genomic characterization of endometrial carcinoma. Nature 497 (7447): 67-73, 2013.  [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. Gusberg SB: Virulence factors in endometrial cancer. Cancer 71 (4 Suppl): 1464-6, 1993.  [PUBMED Abstract]

Stage Information for Endometrial Cancer



Definitions: FIGO

The Féderation Internationale de Gynécologie et d’Obstétrique (FIGO) and the American Joint Committee on Cancer (AJCC) have designated staging to define endometrial cancer; the FIGO system is most commonly used.[1,2]

Carcinosarcomas should be staged as carcinoma.[2] FIGO stages are further subdivided by the histologic grade of the tumor, for example, stage IC G2.

Table 1. Carcinoma of the Endometriuma
Stage  
IbTumor confined to the corpus uteri.
IAbNo or less than half myometrial invasion.
IBbInvasion equal to or more than half of the myometrium.
IIbTumor invades cervical stroma but does not extend beyond the uterus.c
IIIbLocal and/or regional spread of the tumor.
IIIAbTumor invades the serosa of the corpus uteri and/or adnexae.d
IIIBbVaginal and/or parametrial involvement.d
IIICbMetastases to pelvic and/or para-aortic lymph nodes.d
IIIC1bPositive pelvic nodes.
IIIC2bPositive para-aortic lymph nodes with or without positive pelvic lymph nodes.
IVbTumor invades bladder and/or bowel mucosa, and/or distant metastases.
IVAbTumor invasion of bladder and/or bowel mucosa.
IVBbDistant metastases, including intra-abdominal metastases and/or inguinal lymph nodes.

aAdapted from FIGO Committee on Gynecologic Oncology.[1]
bEither G1, G2, or G3 (G = grade).
cEndocervical glandular involvement only should be considered as stage I and no longer as stage II.
dPositive cytology has to be reported separately without changing the stage.

Even if it no longer influences staging, retrospective data based on the Surveillance, Epidemiology, and End Results Program suggest that positive peritoneal cytology is an independent risk factor in patients with early-stage endometrial cancer.[3]

References
  1. Pecorelli S: Revised FIGO staging for carcinoma of the vulva, cervix, and endometrium. Int J Gynaecol Obstet 105 (2): 103-4, 2009.  [PUBMED Abstract]

  2. 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. 

  3. 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]

Treatment Option Overview

Patients with endometrial cancer who have localized disease are usually curable by hysterectomy and bilateral salpingo-oophorectomy. Best results are obtained with either of two standard treatments: hysterectomy or hysterectomy and adjuvant radiation therapy (when deep invasion of the myometrial muscle [50% of the depth] or grade 3 tumor with myometrial invasion is present). Results of two randomized trials on the use of external-beam radiation therapy (EBRT) in patients with stage I disease did not show improved survival but did show reduced locoregional recurrence (3%–4% vs. 12%–14% after 5–6 years' median follow-up, P <.001) with an increase in side effects.[1-3][Level of evidence: 1iiDii] Results of a study by the Danish Endometrial Cancer Group also suggest that the absence of radiation does not improve the survival of patients with stage I, intermediate-risk disease (grade 1 and 2 with >50% myometrial invasion or grade 3 with <50% myometrial invasion).[4]

Vaginal cuff brachytherapy is associated with less radiation-related morbidity than is EBRT and has been shown to be equivalent to EBRT in the adjuvant setting for patients with stage I disease.[5] A subset of patients with stage I disease are at a high risk of recurrence and are eligible for adjuvant therapy. Most patients will do well with surgery alone.

Some patients have regional and distant metastases that, though occasionally responsive to standard hormone therapy, are rarely curable. For these patients, standard therapy is inadequate.

Progestational agents have been evaluated as adjuvant therapy in a randomized clinical trial of stage I disease and have been shown to be of no benefit. These studies, however, were not stratified according to level of progesterone receptor in the primary tumor. No trials of adjuvant progestins in more advanced disease are reported. Determination of progesterone receptors in the primary tumor is encouraged, and entry onto an appropriate adjuvant trial (if receptor levels are high) should be considered. If no trial is available, data from receptors on the primary tumor may help guide therapy for recurrent disease, should it occur.

References
  1. 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]

  2. 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]

  3. 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]

  4. 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]

  5. 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]

Stage I Endometrial Cancer

Uterine serous histologies have higher rates of recurrence than do other stage I endometrioid carcinomas. The outcomes in institutional case series that utilize a policy of adjuvant carboplatin plus paclitaxel, occasionally including radiation therapy, for this histologic subtype, have been published and form the basis of management guidelines.[1-7] The Gynecologic Oncology Group (GOG-0249 [NCT00807768]) trial is comparing this chemotherapy regimen to pelvic radiation.

Standard treatment options:

A total hysterectomy and bilateral salpingo-oophorectomy should be done if the tumor:

  • Is well or moderately differentiated.
  • Involves the upper 66% of the corpus.
  • Has negative peritoneal cytology.
  • Is without vascular space invasion.
  • Has less than a 50% myometrial invasion.

Selected pelvic lymph nodes may be removed. If they are negative, no postoperative treatment is indicated. Postoperative treatment with a vaginal cylinder is advocated by some clinicians.[8]

For all other cases and cell types, a pelvic and selective periaortic node sampling should be combined with the total hysterectomy and bilateral salpingo-oophorectomy, if there are no medical or technical contraindications. One study found that node dissection per se did not significantly add to the overall morbidity from hysterectomy.[9] While the radiation therapy will reduce the incidence of local and regional recurrence, improved survival has not been proven and toxic effects are worse.[10-14] Results of two randomized trials on the use of adjuvant radiation therapy in patients with stage I disease did not show improved survival but did show reduced locoregional recurrence (3%–4% vs. 12%–14% after 5–6 years' median follow-up, P <.001) with an increase in side effects.[13,15,16][Level of evidence: 1iiDii] Results of a study by the Danish Endometrial Cancer Group also suggest that the absence of radiation does not improve the survival of patients with stage I, intermediate-risk disease (grade 1 and 2 with >50% myometrial invasion or grade 3 with <50% myometrial invasion).[17]

The PORTEC-2 (NCT00411138) trial randomly assigned patients with stage I endometrial cancer who did not undergo lymph node dissection to undergo vaginal brachytherapy (VBT) or external-beam radiation therapy (EBRT), with prevention of vaginal recurrence as the primary outcome.[18] At 5 years, there was no difference in the rates of vaginal recurrence, locoregional recurrence, progression-free survival or overall survival (OS) (84.8% [95% confidence interval—CI—, 79.3–90.3] vs. 79.6% [95% CI, 71.2–88.0] for VBT and EBRT, respectively; P = .57). There were significantly fewer gastrointestinal toxic effects and significantly improved quality of life in the VBT group, making VBT the preferred option for adjuvant treatment of patients with stage I disease.[18,19][Level of evidence: 1iA]

Patients who have medical contraindications to surgery may be treated with radiation therapy alone, but inferior cure rates below those attained with surgery may occur.[8,20,21]

Several randomized trials have compared total laparoscopic hysterectomy (TLH) with the standard open procedure, total abdominal hysterectomy (TAH), for patients with early-stage endometrial cancer. Feasibility of the laparoscopic approach has been confirmed, although TLH is associated with a longer operative time.[22-24] TLH had an improved [22,23] or similar [24] adverse event profile and a shorter hospital stay [22-24] when compared with TAH. TLH was associated with less pain and quicker resumption of daily activities,[24,25] 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.[24,25]

The completed GOG-Lamina-associated polypeptide 2 (GOG-LAP2) trial included 2,616 patients with clinical stage I to IIA disease and randomly assigned them two-to-one to comprehensive surgical staging via laparoscopy or laparotomy.[26] 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. The recurrence rate at 3 years was 10.24% for patients in the laparotomy arm, compared with 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 a lower-than-expected number of recurrences in both groups. A Cochrane Review of the use of laparoscopic staging included four randomized controlled trials that reported OS and PFS, although 90% of the patients were from the GOG-LAP2 trial. Overall, laparoscopy was associated with similar OS and PFS rates when it was compared with laparotomy.[27][Level of evidence: 1iiA]The OS at 5 years was 89.8% in both groups. Future analyses may determine whether there are subgroups of patients for whom there is a clinically significant decrement when laparoscopic staging is utilized.[26][Level of evidence: 1iiDiii]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage I 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 Web site.

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. 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]

  9. Homesley HD, Kadar N, Barrett RJ, et al.: Selective pelvic and periaortic lymphadenectomy does not increase morbidity in surgical staging of endometrial carcinoma. Am J Obstet Gynecol 167 (5): 1225-30, 1992.  [PUBMED Abstract]

  10. 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]

  11. 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]

  12. 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]

  13. 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]

  14. 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]

  15. 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]

  16. 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]

  17. 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]

  18. 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]

  19. 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]

  20. 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]

  21. 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]

  22. 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]

  23. 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]

  24. 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]

  25. 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]

  26. 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]

  27. 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]

Stage II Endometrial Cancer

Uterine serous histologies have higher rates of recurrence than do other stage II endometrioid carcinomas. The outcomes in institutional case series that utilize a policy of adjuvant carboplatin plus paclitaxel, occasionally including radiation therapy, for this histologic subtype have been published and form the basis of management guidelines.[1,2] The GOG-0249 (NCT00807768) trial is comparing this chemotherapy regimen to pelvic radiation.

Standard treatment options:

  1. If cervical involvement is documented, options include radical hysterectomy, bilateral salpingo-oophorectomy, and pelvic and para-aortic lymph node dissection.

  2. If the cervix is clinically uninvolved but extension to the cervix is documented on postoperative pathology, radiation therapy should be considered.

The completed GOG-LAP2 trial included 2,616 patients with clinical stage I to IIA disease and randomly assigned them two-to-one to comprehensive surgical staging via laparoscopy or laparotomy.[3] 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. The recurrence rate at 3 years was 10.24% for patients in the laparotomy arm, compared with 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 a lower-than-expected number of recurrences in both groups. The OS at 5 years was 89.8% in both groups. Future analyses may determine whether there are subgroups of patients for whom there is a clinically significant decrement when laparoscopic staging is utilized.[3][Level of evidence: 1iiDiii]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with 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 Web site.

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. Fader AN, Nagel C, Axtell AE, et al.: Stage II uterine papillary serous carcinoma: Carboplatin/paclitaxel chemotherapy improves recurrence and survival outcomes. Gynecol Oncol 112 (3): 558-62, 2009.  [PUBMED Abstract]

  3. 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]

Stage III Endometrial Cancer

Standard treatment options:

In general, patients with stage III endometrial cancer are treated with surgery, followed by chemotherapy, or radiation therapy, or both. 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. In a trial conducted in a subset of patients with stage III or IV disease with residual tumors smaller than 2 cm and no parenchymal organ involvement, the use of the combination of cisplatin and doxorubicin resulted in improved overall survival (OS) compared with whole-abdominal radiation therapy (adjusted hazard ratio, 0.68; 95% confidence interval limits, 0.52–0.89; P = .02; 5-year survival rates of 55% vs. 42%).[1][Level of evidence: 1iiA]

In a subsequent trial, paclitaxel with doxorubicin had an outcome similar to that of cisplatin with doxorubicin.[2,3] The three-drug regimen (doxorubicin, cisplatin, and paclitaxel) with granulocyte colony-stimulating factor (G-CSF), however, was significantly superior to cisplatin plus doxorubicin: response rates were 57% versus 34%; progression-free survival was 8.3 months versus 5.3 months; and OS was 15.3 months versus 12.3 months, respectively. The superior regimen was associated with a 12% grade 3 and a 27% grade 2 peripheral neuropathy.[2,3][Level of evidence: 1iiDiv]

Given the toxicity and limited efficacy of these regimens, other treatment options have been widely sought. Several observational studies [4,5] and phase II studies [6-9] suggested clinical activity with the combination of platinums and paclitaxel in endometrial cancer patients with measurable disease either following primary surgery or at recurrence. As a result, the Gynecologic Oncology Group (GOG) opened protocol GOG-0209 (NCT000063999), a noninferiority trial that compared the combination of doxorubicin, cisplatin, and paclitaxel (TAP) with G-CSF to carboplatin and paclitaxel. The interim results, currently available in abstract form, showing that carboplatin and paclitaxel is not inferior to TAP have lent credence to the use of carboplatin and paclitaxel as the standard for adjuvant treatment of stage III and IV disease.

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 is to use a combination of intracavitary radiation therapy and external-beam radiation therapy.

Patients who are not candidates for either surgery or radiation therapy may be treated with progestational agents. Studies of patterns of failure have found a high rate of distant metastases in the upper abdominal and extra-abdominal sites. For this reason, patients with stage III disease may be candidates for innovative clinical trials.[10]

Treatment options under clinical evaluation:

  • The use of biological agents alone, or in combination with chemotherapy, is being investigated in multiple clinical trials.
Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage III 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 Web site.

References
  1. 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]

  2. 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]

  3. 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]

  4. 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]

  5. 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]

  6. 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]

  7. 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]

  8. 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]

  9. 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]

  10. 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]

Stage IV Endometrial Cancer

Treatment of patients with stage IV endometrial cancer is dictated by the site of metastatic disease and symptoms related to disease sites. For bulky pelvic disease, radiation therapy consisting of a combination of intracavitary and external-beam radiation therapy is used. When distant metastases, especially pulmonary metastases, are present, hormonal therapy is indicated and useful. 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.

When possible, patients with stage IV endometrial cancer are treated with surgery, followed by chemotherapy, or radiation therapy, or both. 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. In a trial conducted in a subset of patients with stage III or IV disease with residual tumors smaller than 2 cm and no parenchymal organ involvement, the use of the combination of cisplatin and doxorubicin resulted in improved overall survival (OS) compared with whole-abdominal radiation therapy (adjusted hazard ratio, 0.68; 95% confidence interval limits, 0.52–0.89; P = .02; 5-year survival rates of 55% vs. 42%).[1][Level of evidence: 1iiA]

In a subsequent trial, paclitaxel with doxorubicin had an outcome similar to that of cisplatin with doxorubicin.[2,3] The three-drug regimen (doxorubicin, cisplatin, and paclitaxel) with granulocyte colony-stimulating factor (G-CSF), however, was significantly superior to cisplatin plus doxorubicin: response rates were 57% versus 34%; progression-free survival was 8.3 months versus 5.3 months; and OS was 15.3 months versus 12.3 months, respectively. The superior regimen was associated with a 12% grade 3 and a 27% grade 2 peripheral neuropathy.[2,3][Level of evidence: 1iiDiv]

Given the toxicity and limited efficacy of these regimens, other treatment options have been widely sought. Several observational studies [4,5] and phase II studies [6-9] suggested clinical activity with the combination of platinums and paclitaxel in endometrial cancer patients with measurable disease either following primary surgery or at recurrence. As a result, the Gynecologic Oncology Group (GOG) opened protocol GOG-0209 (NCT000063999), a noninferiority trial that compared the combination of doxorubicin, cisplatin, and paclitaxel (TAP) and G-CSF with carboplatin and paclitaxel. The interim results, currently available in abstract form, showing that carboplatin and paclitaxel is not inferior to TAP have lent credence to the use of carboplatin and paclitaxel as the standard for adjuvant treatment in stage III and IV disease.

The most common hormonal treatment has been progestational agents, which produce good antitumor responses in as many as 15% to 30% of patients. These responses are associated with significant improvement in survival. Progesterone and estrogen hormone receptors have been identified in endometrial carcinoma tissues. Responses to hormones are correlated with the presence and level of hormone receptors and the degree of tumor differentiation. Standard progestational agents include hydroxyprogesterone, medroxyprogesterone, and megestrol.[10]

Biologic agents under evaluation for patients with advanced and recurrent endometrial cancer include:

  • Bevacizumab, which was given as a single agent in a phase II trial, and the overall response rate was 13.5%.[11]
  • Bevacizumab and temsirolimus.[12]

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

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage IV 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 Web site.

References
  1. 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]

  2. 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]

  3. 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]

  4. 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]

  5. 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]

  6. 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]

  7. 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]

  8. 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]

  9. 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]

  10. Lentz SS: Advanced and recurrent endometrial carcinoma: hormonal therapy. Semin Oncol 21 (1): 100-6, 1994.  [PUBMED Abstract]

  11. 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]

  12. 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]

Recurrent Endometrial Cancer

For patients with localized recurrences (pelvis and periaortic lymph nodes) or distant metastases in selected sites, radiation therapy may be an effective palliative therapy. In rare instances, pelvic radiation therapy may be curative in pure vaginal recurrence when no prior radiation therapy has been used. Patients positive for estrogen and progesterone receptors respond best to progestin therapy. Among 115 patients with advanced endometrial cancer who were treated with progestins, 75% (42 of 56 patients) of those with detectable progesterone receptors in their tumors before treatment responded, compared with only 7% without detectable progesterone receptors (4 of 59 patients).[1] A receptor-poor status may predict not only poor response to progestins but also a better response to cytotoxic chemotherapy.[2] Evidence suggests that tamoxifen (20 mg twice a day) will give a response rate of 20% in those who do not respond to standard progesterone therapy.[3]

Several randomized trials by the Gynecologic Oncology Group have utilized the known antitumor activity of doxorubicin. The addition of cisplatin to doxorubicin increased response rates and progression-free survival (PFS) over doxorubicin alone but without an effect on overall survival (OS).[4] However, in a trial conducted in a subset of patients with stage III or IV disease with residual tumors smaller than 2 cm and no parenchymal organ involvement, the use of the combination of cisplatin and doxorubicin resulted in improved OS compared with whole-abdominal radiation therapy (adjusted hazard ratio, 0.68; 95% confidence interval limits, 0.52–0.89; P = .02; 5-year survival rate of 55% vs. 42%).[5][Level of evidence: 1iiA] In a subsequent trial, paclitaxel with doxorubicin had a similar outcome to cisplatin with doxorubicin.[6,7] The three-drug regimen (doxorubicin, cisplatin, and paclitaxel) with granulocyte colony-stimulating factor, however, was significantly superior to cisplatin plus doxorubicin: response rates were 57% versus 34%, PFS was 8.3 months versus 5.3 months, and OS was 15.3 months versus 12.3 months, respectively. The superior regimen was associated with a 12% grade 3 and a 27% grade 2 peripheral neuropathy.[6,7][Level of evidence: 1iiDiv]

Biologic agents under evaluation for patients with advanced and recurrent endometrial cancer include:

  • Bevacizumab, which was given as a single agent in a phase II trial, and the overall response rate was 13.5%.[8]
  • Bevacizumab and temsirolimus.[9]

Clinical trials are appropriate for patients whose disease recurs with distant metastases and who are unresponsive to hormonal therapy.[10] Doxorubicin is the most active anticancer agent employed, with useful but temporary responses obtained in as many as 33% of patients with metastatic disease. Paclitaxel, in combination with platinums or as a single agent, also has significant activity.[11]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with 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 Web site.

References
  1. 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]

  2. 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]

  3. Quinn MA, Campbell JJ: Tamoxifen therapy in advanced/recurrent endometrial carcinoma. Gynecol Oncol 32 (1): 1-3, 1989.  [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. 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]

  6. 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]

  7. 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]

  8. 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]

  9. 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]

  10. Cornelison TL, Baker TR, Piver MS, et al.: Cisplatin, adriamycin, etoposide, megestrol acetate versus melphalan, 5-fluorouracil, medroxyprogesterone acetate in the treatment of endometrial carcinoma. Gynecol Oncol 59 (2): 243-8, 1995.  [PUBMED Abstract]

  11. 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]

Changes to This Summary (04/23/2014)

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 2014 (cited American Cancer Society as reference 1).

Revised text to state that irregular vaginal bleeding is an early sign, the foremost symptom, and the reason why the majority of patients with the highly curable endometrial tumor are diagnosed with stage I disease.

Added text to state that risk factors for the development of endometrial cancer include obesity, hypertension, and diabetes mellitus.

Added text to state that cardiovascular disease is the most common cause of death in patients diagnosed with endometrial cancer because of the early stage of the cancer at diagnosis and the metabolic risk factors (cited Ward et al. as reference 2).

Cellular Classification of Endometrial Cancer

Added text to state that endometrial cancers are classified in one of two categories; namely, 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.

Added text to state that characteristic activating oncogenic mutations or amplification and inactivating mutations or deletion of tumor suppressors are seen more in association with one type of mutation versus the other type, but some overlap exists. Also added that with the Cancer Genome Atlas and a full genetic display of hundreds of endometrial cancers, four subtypes have been identified that will refine classification and provide prognostic and therapeutic implications (cited Kandoth et al. as reference 1).

Stage Information for Endometrial Cancer

Added text to state that even if it no longer influences staging, retrospective data based on the Surveillance, Epidemiology, and End Results Program suggest that positive peritoneal cytology is an independent risk factor in patients with early-stage endometrial cancer (cited Garg et al. as reference 3).

Stage I Endometrial Cancer

Added text to state that uterine serous histologies have higher rates of recurrence than do other stage I endometrioid carcinomas; the outcomes in institutional case series that utilize a policy of adjuvant carboplatin plus paclitaxel, occasionally including radiation therapy, for this histologic subtype, have been published and form the basis of management guidelines (cited Kiess et al., Boruta et al., Huh et al., Fader et al., Kelly et al., Havrilesky et al., and Dietrich et al., as references 1, 2, 3, 4, 5, 6, and 7, respectively). Also added that the Gynecologic Oncology Group (GOG-0249 [NCT00807768]) trial is comparing this chemotherapy regimen to pelvic radiation.

Added Kong et al. as reference 14.

Revised text to state that there were significantly fewer gastrointestinal toxic effects and significantly improved quality of life in the vaginal brachytherapy (VBT) group, making VBT the preferred option for adjuvant treatment of patients with stage I disease (cited Nout et al. as reference 19).

Added text to state that a Cochrane Review of the use of laparoscopic staging included four randomized controlled trials that reported overall survival (OS) and progression-free survival (PFS), although 90% of the patients were from the GOG-Lamina-associated polypeptide 2 (GOG-LAP2) trial; laparoscopy was associated with similar OS and PFS rates when it was compared with laparotomy (cited Galaal et al. as reference 27 and level of evidence 1iiA).

Stage II Endometrial Cancer

Added text to state that uterine serous histologies have higher rates of recurrence than do other stage II endometrioid carcinomas. Also added that the outcomes in institutional case series that utilize a policy of adjuvant carboplatin plus paclitaxel, occasionally including radiation therapy for this histologic subtype have been published and form the basis of management guidelines (cited Kiess et al. and Fader et al. as references 1 and 2). The GOG-0249 (NCT00807768) trial is comparing this chemotherapy regimen to pelvic radiation.

Stage IV Endometrial Cancer

Added text to state that biologic agents under evaluation for patients with advanced and recurrent endometrial cancer include bevacizumab, which was given as a single agent in a phase II trial with an overall response of 13.5% (cited Aghajanian et al. as reference 11) and bevacizumab and temsirolimus (cited Alvarez et al. as reference 12).

Recurrent Endometrial Cancer

Added text to state that biologic agents under evaluation for patients with advanced and recurrent endometrial cancer include bevacizumab, which was given as a single agent in a phase II trial with an overall response of 13.5% (cited Aghajanian et al. as reference 8), and bevacizumab and temsirolimus (cited Alvarez et al. as reference 9).

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 Web site's Contact Form. 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.

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The preferred citation for this PDQ summary is:

National Cancer Institute: PDQ® Endometrial Cancer Treatment. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://cancer.gov/cancertopics/pdq/treatment/endometrial/HealthProfessional. Accessed <MM/DD/YYYY>.

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