Purpose of This PDQ Summary
General Information
Cellular Classification
Stage Information
Treatment Option Overview
Stage I Endometrial Cancer

Current Clinical Trials

Stage II Endometrial Cancer

Stage IIA Stage IIB Current Clinical Trials

Stage III Endometrial Cancer

Current Clinical Trials

Stage IV Endometrial Cancer

Current Clinical Trials

Recurrent Endometrial Cancer

Current Clinical Trials

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Changes to This Summary (05/16/2008)
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Purpose of This PDQ Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of endometrial cancer. This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board ¹.

Information about the following is included in this summary:

• Prognostic factors.
• Cellular classification.
• Staging.
• Treatment options by cancer stage.

This summary 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.

Some of the reference citations in the 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 ² in developing its level-of-evidence designations. Based on the strength of the available evidence, treatment options are described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for reimbursement determinations.

This summary is available in a patient version ³, written in less technical language, and in Spanish ⁴.

General Information

Note: Separate PDQ summaries on Uterine Sarcoma Treatment ⁵, Endometrial Cancer Screening ⁶, and Endometrial Cancer Prevention ⁷ are also available.

Note: Estimated new cases and deaths from endometrial (uterine corpus) cancer in the United States in 2008:[1]

• New cases: 40,100.
• Deaths: 7,470.

Cancer of the endometrium is the most common gynecologic malignancy and accounts for 6% of all cancers in women. It is a highly curable tumor. 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, though a retrospective study found a strong correlation between positive cervical cytology and high-risk disease (i.e., high-grade tumor and deep myometrial invasion) [2] as well as an increased risk of nodal disease.[3] 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.[4,5] In contrast, combined estrogen and progesterone therapy prevents the increase in risk of endometrial cancer associated with unopposed estrogen use.[6,7] 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) ⁸, perhaps related to the estrogenic effect of tamoxifen on the endometrium.[8,9] Because of this increase, patients on tamoxifen should have follow-up pelvic examinations and should be examined if there is any abnormal uterine bleeding.

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.[10,11] Metastatic spread occurs in a characteristic pattern. Spread to the pelvic and para-aortic nodes is common. Distant metastases can occur and most commonly involve the lungs, inguinal and supraclavicular nodes, liver, bones, brain, and vagina.

Another factor found to correlate with extrauterine and nodal spread of tumor is involvement of the capillary-lymphatic space on histopathologic examination.[12] 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 or positive washings) have a low risk (<5%) of nodal involvement.[13] 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 four statistically significant adverse prognostic factors: myometrial invasion, vascular invasion, eight or more mitoses per ten high-power fields, and an absence of progesterone receptors.[14]

Another group identified aneuploidy and a high S-phase fraction as predictive of poor prognosis.[15] 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.[16,17]

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.[18-23] The preponderance of evidence, however, would suggest that 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.[24] Other reports confirm the importance of hormone receptor status as an independent prognostic factor.[25] 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.[26-28] 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. Oncogene expression, DNA ploidy, and the fraction of cells in S-phase have also been found to be prognostic indicators of clinical outcome.[28] For example, overexpression of the Her-2/neu oncogene has been associated with a poor overall prognosis.[29] A general review of prognostic factors has been published.[30]

References

1. American Cancer Society.: Cancer Facts and Figures 2008. Atlanta, Ga: American Cancer Society, 2008. Also available online. ⁹ Last accessed October 1, 2008. 
   
   
2. DuBeshter B, Warshal DP, Angel C, et al.: Endometrial carcinoma: the relevance of cervical cytology. Obstet Gynecol 77 (3): 458-62, 1991.  [PUBMED Abstract]
   
   
3. 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]
   
   
4. 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]
   
   
5. Jick SS, Walker AM, Jick H: Estrogens, progesterone, and endometrial cancer. Epidemiology 4 (1): 20-4, 1993.  [PUBMED Abstract]
   
   
6. Jick SS: Combined estrogen and progesterone use and endometrial cancer. Epidemiology 4 (4): 384, 1993.  [PUBMED Abstract]
   
   
7. Bilezikian JP: Major issues regarding estrogen replacement therapy in postmenopausal women. J Womens Health 3(4): 273-282, 1994. 
   
   
8. 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]
   
   
9. 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]
   
   
10. 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]
    
    
11. 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]
    
    
12. 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]
    
    
13. 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]
    
    
14. Tornos C, Silva EG, el-Naggar A, et al.: Aggressive stage I grade 1 endometrial carcinoma. Cancer 70 (4): 790-8, 1992.  [PUBMED Abstract]
    
    
15. 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]
    
    
16. 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]
    
    
17. 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]
    
    
18. 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]
    
    
19. 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]
    
    
20. 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]
    
    
21. 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]
    
    
22. Lurain JR: The significance of positive peritoneal cytology in endometrial cancer. Gynecol Oncol 46 (2): 143-4, 1992.  [PUBMED Abstract]
    
    
23. 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]
    
    
24. 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]
    
    
25. Creasman WT: Prognostic significance of hormone receptors in endometrial cancer. Cancer 71 (4 Suppl): 1467-70, 1993.  [PUBMED Abstract]
    
    
26. 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]
    
    
27. 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]
    
    
28. Gurpide E: Endometrial cancer: biochemical and clinical correlates. J Natl Cancer Inst 83 (6): 405-16, 1991.  [PUBMED Abstract]
    
    
29. 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]
    
    
30. Homesley HD, Zaino R: Endometrial cancer: prognostic factors. Semin Oncol 21 (1): 71-8, 1994.  [PUBMED Abstract]
    
    

Cellular Classification

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;[1] 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.[2] 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. 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]
   
   
2. Gusberg SB: Virulence factors in endometrial cancer. Cancer 71 (4 Suppl): 1464-6, 1993.  [PUBMED Abstract]
   
   

Stage Information

A hysterectomy is required to determine the degree of myometrial invasion. The following surgical staging has been adopted by the International Federation of Gynecology and Obstetrics (FIGO) and by the American Joint Committee on Cancer:[1-3]

Stage I

Stage I endometrial cancer is carcinoma confined to the corpus uteri.

• Stage IA: tumor limited to endometrium.
• Stage IB: invasion to less than 50% of the myometrium.
• Stage IC: invasion to greater than 50% of the myometrium.

Stage II

Stage II endometrial cancer involves the corpus and the cervix but has not extended outside the uterus.

• Stage IIA: endocervical glandular involvement only.
• Stage IIB: cervical stromal invasion.

Stage III

Stage III endometrial cancer extends outside of the uterus but is confined to the true pelvis.

• Stage IIIA: tumor invades serosa and/or adnexa and/or positive peritoneal cytology.
• Stage IIIB: vaginal metastases.
• Stage IIIC: metastases to pelvic and/or para-aortic lymph nodes.

Stage IV

Stage IV endometrial cancer involves the bladder or bowel mucosa or has metastasized to distant sites.

• Stage IVA: tumor invasion of bladder and/or bowel mucosa.
• Stage IVB: distant metastases, including intra-abdominal and/or inguinal lymph nodes.

Endometrial cancer can be grouped with regard to the degree of differentiation of the adenocarcinoma, as follows:

• G1: no more than 5% of a nonsquamous or nonmorular solid growth pattern.
• G2: 6% to 50% of a nonsquamous or nonmorular solid growth pattern.
• G3: greater than 50% of a nonsquamous or nonmorular solid growth pattern.

FIGO staging for endometrial cancer:

• Stage IA G123: tumor limited to endometrium.
• Stage IB G123: invasion to less than 50% of the myometrium.
• Stage IC G123: invasion to greater than 50% of the myometrium.
• Stage IIA G123: endocervical glandular involvement only.
• Stage IIB G123: cervical stromal invasion.
• Stage IIIA G123: tumor invades serosa and/or adnexa and/or positive peritoneal cytology.
• Stage IIIB G123: vaginal metastases.
• Stage IIIC G123: metastases of pelvic and/or para-aortic lymph nodes.
• Stage IVA G123: tumor invasion of bladder and/or bowel mucosa.
• Stage IVB: distant metastases including intra-abdominal and/or inguinal lymph nodes.

References

1. Shepherd JH: Revised FIGO staging for gynaecological cancer. Br J Obstet Gynaecol 96 (8): 889-92, 1989.  [PUBMED Abstract]
   
   
2. FIGO staging for corpus cancer. Br J Obstet Gynaecol 99(5): 440, 1992. 
   
   
3. Corpus uteri. In: American Joint Committee on Cancer.: AJCC Cancer Staging Manual. 6th ed. New York, NY: Springer, 2002, pp 267-73. 
   
   

Treatment Option Overview

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence ² for more information.)

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 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.[1-3][Level of evidence: 1iiDii]

Vaginal cuff brachytherapy may be associated with less radiation-related morbidity than pelvic radiation. It has been shown to reduce the risk of vaginal cuff recurrence without an effect on survival.

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]
   
   

Stage I Endometrial Cancer

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence ² for more information.)

Standard treatment options:

If the tumor is well or moderately differentiated, involves the upper 66% of the corpus, has negative peritoneal cytology, is without vascular space invasion, and has less than a 50% myometrial invasion, a total abdominal hysterectomy and bilateral salpingo-oophorectomy should be done. 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.[1]

For all other cases and cell types, a periaortic and selective pelvic node sampling should be combined with the total abdominal 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.[2] While the radiation therapy will reduce the incidence of local and regional recurrence, improved survival has not been proven and toxic effects are worse.[3-6] 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.[6-8][Level of evidence: 1iiDii]

If the pelvic nodes are positive and the periaortic nodes are negative, total pelvic radiation therapy, including the common iliac nodes, should be given. The incidence of bowel complications is approximately 4%, and it can be even higher if the radiation therapy is given after pelvic lymphadenectomy.[9] If the surgery is done using a retroperitoneal approach, the toxic effects are lessened. If the periaortic nodes are positive, the patient is a candidate for clinical trials that could include radiation therapy and/or chemotherapy. Patients who have medical contraindications to surgery should be treated with radiation therapy alone, but inferior cure rates below those attained with surgery may occur.[1,10,11]

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage I endometrial carcinoma ¹⁰. 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 ¹¹.

References

1. 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]
   
   
2. 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]
   
   
3. 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]
   
   
4. 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]
   
   
5. 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]
   
   
6. 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]
   
   
7. 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]
   
   
8. 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]
   
   
9. Greven KM, Lanciano RM, Herbert SH, et al.: Analysis of complications in patients with endometrial carcinoma receiving adjuvant irradiation. Int J Radiat Oncol Biol Phys 21 (4): 919-23, 1991.  [PUBMED Abstract]
   
   
10. 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]
    
    
11. 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 II Endometrial Cancer

Many combinations of preoperative intracavitary and external-beam radiation therapy (EBRT) with hysterectomy and bilateral salpingo-oophorectomy are used for treatment of stage II endometrial cancer, with careful biopsy of the para-aortic nodes at the time of surgery. When microscopic cervical stromal involvement is found, postoperative radiation therapy (EBRT and vaginal radiation therapy) should be used.

Stage IIA (endocervical glandular involvement only) should be treated the same as stage I disease.

Standard treatment options:

1. Hysterectomy, bilateral salpingo-oophorectomy, and node sampling followed by postoperative radiation therapy.
2. Preoperative intracavitary and EBRT followed by hysterectomy and bilateral salpingo-oophorectomy. (A biopsy of the para-aortic nodes should be done at the time of surgery.)
3. Radical hysterectomy and pelvic lymphadenectomy in selected cases.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage II endometrial carcinoma ¹². 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 ¹¹.

Stage III Endometrial Cancer

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence ² for more information.)

Standard treatment options:

In general, patients with stage III endometrial cancer are treated with surgery and radiation therapy. Patients with inoperable disease, caused by the tumor that extends to the pelvic wall, may be treated with radiation therapy. The usual approach is to use a combination of intracavitary and external-beam radiation therapy.

Patients who are not candidates for either surgery or radiation therapy may be treated with progestational agents. Postoperative radiation therapy is used in patients who were thought to have had more localized disease (clinical stage I or stage II) but are found during a hysterectomy to have positive lymph nodes or adnexa. 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.[1]

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).[2] 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 to 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%).[3][Level of evidence: 1iiA] In a subsequent trial, paclitaxel with doxorubicin had a similar outcome to cisplatin with doxorubicin.[4,5] 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. [4,5][Level of evidence: 1iiDiv]

Treatment options under clinical evaluation:

• Clinical trials such as GOG 94 ¹³.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage III endometrial carcinoma ¹⁴. 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 ¹¹.

References

1. 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]
   
   
2. 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]
   
   
3. 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]
   
   
4. 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]
   
   
5. 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]
   
   

Stage IV Endometrial Cancer

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence ² for more information.)

Standard treatment options:

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.

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 (Delalutin), medroxyprogesterone (Provera), and megestrol (Megace).[1]

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).[2] 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 to 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%).[3][Level of evidence: 1iiA] In a subsequent trial, paclitaxel with doxorubicin had a similar outcome to cisplatin with doxorubicin.[4,5] 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.[4,5][Level of evidence: 1iiDiv]

Treatment options under clinical evaluation:

No standard chemotherapy program is available for patients with metastatic uterine cancer, though doxorubicin has activity. Some studies have demonstrated activity of doxorubicin-containing combinations, though no prospective comparison of single-agent versus combination chemotherapy is available that has demonstrated superiority of the combinations.[6,7]

Paclitaxel has demonstrated antitumor activity and has been evaluated.[8]

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

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage IV endometrial carcinoma ¹⁵. 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 ¹¹.

References

1. Lentz SS: Advanced and recurrent endometrial carcinoma: hormonal therapy. Semin Oncol 21 (1): 100-6, 1994.  [PUBMED Abstract]
   
   
2. 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]
   
   
3. 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]
   
   
4. 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]
   
   
5. 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]
   
   
6. Hancock KC, Freedman RS, Edwards CL, et al.: Use of cisplatin, doxorubicin, and cyclophosphamide to treat advanced and recurrent adenocarcinoma of the endometrium. Cancer Treat Rep 70 (6): 789-91, 1986.  [PUBMED Abstract]
   
   
7. Seski JC, Edwards CL, Herson J, et al.: Cisplatin chemotherapy for disseminated endometrial cancer. Obstet Gynecol 59 (2): 225-8, 1982.  [PUBMED Abstract]
   
   
8. 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]
   
   

Recurrent Endometrial Cancer

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence ² for more information.)

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 to 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 to 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]

Clinical trials are appropriate for patients whose disease recurs with distant metastases and who are unresponsive to hormonal therapy.[8] 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 also has significant activity.[9]

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with recurrent endometrial carcinoma ¹⁶. 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 ¹¹.

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. 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]
   
   
9. 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]
   
   

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• PDQ® Cancer Information Summaries: Pediatric Treatment ²²

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Glossary Terms

Randomized, controlled, nonblinded clinical trial with total mortality as an endpoint. See Levels of Evidence for Adult and Pediatric Cancer Treatment Studies (PDQ®) for more information.

Randomized, controlled, nonblinded clinical trial with disease-free survival as an endpoint. See Levels of Evidence for Adult and Pediatric Cancer Treatment Studies (PDQ®) for more information.

Randomized, controlled, nonblinded clinical trial with tumor response rate as an endpoint. See Levels of Evidence for Adult and Pediatric Cancer Treatment Studies (PDQ®) for more information.