adjuvant; consensus; endometrial neoplasms; practice guideline; surgery; treatment; Combined Modality Therapy; Early Detection of Cancer; Endometrial Neoplasms/diagnosis; Endometrial Neoplasms/therapy; Female; Follow-Up Studies; Humans; Mass Screening; Practice Guidelines as Topic; Hematology; Oncology
Abstract :
[en] The first joint European Society for Medical Oncology (ESMO), European SocieTy for Radiotherapy & Oncology (ESTRO) and European Society of Gynaecological Oncology (ESGO) consensus conference on endometrial cancer was held on 11-13 December 2014 in Milan, Italy, and comprised a multidisciplinary panel of 40 leading experts in the management of endometrial cancer. Before the conference, the expert panel prepared three clinically relevant questions about endometrial cancer relating to the following four areas: prevention and screening, surgery, adjuvant treatment and advanced and recurrent disease. All relevant scientific literature, as identified by the experts, was reviewed in advance. During the consensus conference, the panel developed recommendations for each specific question and a consensus was reached. Results of this consensus conference, together with a summary of evidence supporting each recommendation, are detailed in this article. All participants have approved this final article.
Disciplines :
Oncology
Author, co-author :
Colombo, N; Division of Medical Gynecologic Oncology, European Institute of Oncology and University of Milan-Bicocca, Milan, Italy clinicalguidelines@esmo.org
Creutzberg, C; Department of Radiation Oncology, Leiden University Medical Center, Leiden, The Netherlands
Amant, F; Department of Gynecological Oncology, University Hospital Leuven, Leuven, Belgium Center for Gynecological Oncology Amsterdam (CGOA), Antoni van Leeuwenhoek, Amsterdam
Bosse, T; Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
González-Martín, A; Department of Medical Oncology, GEICO Cancer Center, Madrid Department of Medical Oncology, MD Anderson Cancer Center, Madrid, Spain
Ledermann, J; Department of Oncology and Cancer Trials, UCL Cancer Institute, London, UK
Marth, C; Department of Obstetrics and Gynecology, Innsbruck Medical University, Innsbruck, Austria
Nout, R; Department of Radiotherapy, Leiden University Medical Center, Leiden, The Netherlands
Querleu, D; Department of Surgery, Institut Bergonié, Bordeaux, France Department of Gynecology and Obstetrics, McGill University Health Centre, Montreal, Canada
Mirza, M R; Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
Sessa, C; Department of Medical Oncology, Oncology Institute of Southern Switzerland, Ospedale San Giovanni, Bellinzona, Switzerland
ESMO-ESGO-ESTRO Endometrial Consensus Conference Working Group
Goffin, Frédéric ; Centre Hospitalier Universitaire de Liège - CHU > > Service de gynécologie-obstétrique (CHR) ; As Member of The ESMO–ESGO–ESTRO Endometrial Consensus Conference Working Group
Angela Corstorphine of Kstorfin Medical Communications Ltd provided medical writing support with the preparation of this manuscript. This support was funded by ESMO.
WHO. GLOBOCAN 2012: Estimated cancer incidence, mortality and prevalence worldwide in 2012. 2012; http://globocan.iarc.fr/Pages/fact_sheets_population. aspx (3 April 2015, date last accessed).
Lee NK, Cheung MK, Shin JY et al. Prognostic factors for uterine cancer in reproductive-aged women. Obstet Gynecol 2007; 109: 655-662.
National Cancer Institute. Endometrial cancer treatment Physician Data Query (PDQ). 2015; http://www.cancer.gov/cancertopics/pdq/treatment/endometrial/ healthprofessional (1 April 2015, date last accessed).
ACOG. ACOG practice bulletin, clinical management guidelines for obstetriciangynecologists, number 65, August 2005: management of endometrial cancer. Obstet Gynecol 2005; 106: 413-425.
Kandoth C, Schultz N, Cherniack AD et al. Integrated genomic characterization of endometrial carcinoma. Nature 2013; 497: 67-73.
Reid-Nicholson M, Iyengar P, Hummer AJ et al. Immunophenotypic diversity of endometrial adenocarcinomas: implications for differential diagnosis. Mod Pathol 2006; 19: 1091-1100.
Broaddus RR, Lynch HT, Chen LM et al. Pathologic features of endometrial carcinoma associated with HNPCC: a comparison with sporadic endometrial carcinoma. Cancer 2006; 106: 87-94.
Colombo N, Preti E, Landoni F et al. Endometrial cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013; 24(Suppl 6): vi33-vi38.
Dykewicz CA. Summary of the guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients. Clin Infect Dis 2001; 33: 139-144.
World Cancer Research Fund/American Institute for Cancer Research. Continuous Update Project Report. Food, Nutrition, Physical Activity, and the Prevention of Endometrial Cancer. 2013; http://www.dietandcancerreport.org (2 April 2015, date last accessed).
Garg K, Soslow RA. Endometrial carcinoma in women aged 40 years and younger. Arch Pathol Lab Med 2014; 138: 335-342.
Esposito K, Chiodini P, Capuano A et al. Metabolic syndrome and endometrial cancer: a meta-analysis. Endocrine 2014; 45: 28-36.
Zhang Y, Liu H, Yang S et al. Overweight, obesity and endometrial cancer risk: results from a systematic review and meta-analysis. Int J Biol Markers 2014; 29: e21-e29.
Rosato V, Zucchetto A, Bosetti C et al. Metabolic syndrome and endometrial cancer risk. Ann Oncol 2011; 22: 884-889.
Luo J, Beresford S, Chen C et al. Association between diabetes, diabetes treatment and risk of developing endometrial cancer. Br J Cancer 2014; 111: 1432-1439.
Barry JA, Azizia MM, Hardiman PJ. Risk of endometrial, ovarian and breast cancer in women with polycystic ovary syndrome: a systematic review and metaanalysis. Hum Reprod Update 2014; 20: 748-758.
Fader AN, Arriba LN, Frasure HE, von Gruenigen VE. Endometrial cancer and obesity: epidemiology, biomarkers, prevention and survivorship. Gynecol Oncol 2009; 114: 121-127.
Ali AT. Reproductive factors and the risk of endometrial cancer. Int J Gynecol Cancer 2014; 24: 384-393.
Peiretti M, Colombo N. Sex cord-stromal tumors of the ovary. In Textbook of Gynaecological Oncology. Ankara and Istanbul: Günes Publishing, 2012; 453-456.
Brinton LA, Berman ML, Mortel R et al. Reproductive, menstrual, and medical risk factors for endometrial cancer: results from a case-control study. Am J Obstet Gynecol 1992; 167: 1317-1325.
Zucchetto A, Serraino D, Polesel J et al. Hormone-related factors and gynecological conditions in relation to endometrial cancer risk. Eur J Cancer Prev 2009; 18: 316-321.
Fisher B, Costantino JP, Wickerham DL et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 1998; 90: 1371-1388.
Lancaster JM, Powell CB, Chen LM, Richardson DL. Society of Gynecologic Oncology statement on risk assessment for inherited gynecologic cancer predispositions. Gynecol Oncol 2015; 136: 3-7.
Smith RA, Cokkinides V, Brawley OW. Cancer screening in the United States, 2009: a review of current American Cancer Society guidelines and issues in cancer screening. CA Cancer J Clin 2009; 59: 27-41.
Jacobs I, Gentry-Maharaj A, Burnell M et al. Sensitivity of transvaginal ultrasound screening for endometrial cancer in postmenopausal women: a case-control study within the UKCTOCS cohort. Lancet Oncol 2011; 12: 38-48.
National Cancer Institute. Endometrial Cancer Screening Physician Data Query (PDQ). 2015; www.cancer.gov/cancertopics/pdq/screening/endometrial/ HealthProfessional/ (2 April 2015, date last accessed).
Fu Y, Zhuang Z. Long-term effects of levonorgestrel-releasing intrauterine system on tamoxifen-treated breast cancer patients: a meta-analysis. Int J Clin Exp Pathol 2014; 7: 6419-6429.
Manchanda R, Saridogan E, Abdelraheim A et al. Annual outpatient hysteroscopy and endometrial sampling (OHES) in HNPCC/Lynch syndrome (LS). Arch Gynecol Obstet 2012; 286: 1555-1562.
Vasen HF, Blanco I, Aktan-Collan K et al. Revised guidelines for the clinical management of Lynch syndrome (HNPCC): recommendations by a group of European experts. Gut 2013; 62: 812-823.
Duska LR, Garrett A, Rueda BR et al. Endometrial cancer in women 40 years old or younger. Gynecol Oncol 2001; 83: 388-393.
Evans-Metcalf ER, Brooks SE, Reale FR, Baker SP. Profile of women 45 years of age and younger with endometrial cancer. Obstet Gynecol 1998; 91: 349-354.
Rodolakis A, Biliatis I, Morice P et al. European Society of Gynecological Oncology Task Force for Fertility Preservation: clinical recommendations for fertility-sparing management in young endometrial cancer patients. Int J Gynecol Cancer 2015; 25: 1258-1265.
Leitao MM, Jr, Kehoe S, Barakat RR et al. Comparison of D&C and office endometrial biopsy accuracy in patients with FIGO grade 1 endometrial adenocarcinoma. Gynecol Oncol 2009; 113: 105-108.
Ushijima K, Yahata H, Yoshikawa H et al. Multicenter phase II study of fertilitysparing treatment with medroxyprogesterone acetate for endometrial carcinoma and atypical hyperplasia in young women. J Clin Oncol 2007; 25: 2798-2803.
Kinkel K, Kaji Y, Yu KK et al. Radiologic staging in patients with endometrial cancer: a meta-analysis. Radiology 1999; 212: 711-718.
Minig L, Franchi D, Boveri S et al. Progestin intrauterine device and GnRH analogue for uterus-sparing treatment of endometrial precancers and well-differentiated early endometrial carcinoma in young women. Ann Oncol 2011; 22: 643-649.
Kim MK, Seong SJ, Song T et al. Comparison of dilatation & curettage and endometrial aspiration biopsy accuracy in patients treated with high-dose oral progestin plus levonorgestrel intrauterine system for early-stage endometrial cancer. Gynecol Oncol 2013; 130: 470-473.
Gallos ID, Yap J, Rajkhowa M et al. Regression, relapse, and live birth rates with fertility-sparing therapy for endometrial cancer and atypical complex endometrial hyperplasia: a systematic review and metaanalysis. Am J Obstet Gynecol 2012; 207: 266.e1-266.e12.
Park JY, Kim DY, Kim JH et al. Long-term oncologic outcomes after fertilitysparing management using oral progestin for young women with endometrial cancer (KGOG 2002). Eur J Cancer 2013; 49: 868-874.
Tangjitgamol S, Manusirivithaya S, Hanprasertpong J. Fertility-sparing in endometrial cancer. Gynecol Obstet Invest 2009; 67: 250-268.
Erkanli S, Ayhan A. Fertility-sparing therapy in young women with endometrial cancer: 2010 update. Int J Gynecol Cancer 2010; 20: 1170-1187.
Yamazawa K, Hirai M, Fujito A et al. Fertility-preserving treatment with progestin, and pathological criteria to predict responses, in young women with endometrial cancer. Hum Reprod 2007; 22: 1953-1958.
Koskas M, Uzan J, Luton D et al. Prognostic factors of oncologic and reproductive outcomes in fertility-sparing management of endometrial atypical hyperplasia and adenocarcinoma: systematic review and meta-analysis. Fertil Steril 2014; 101: 785-794.
Mittal K, Soslow R, McCluggage WG. Application of immunohistochemistry to gynecologic pathology. Arch Pathol Lab Med 2008; 132: 402-423.
Sun H, Enomoto T, Fujita M et al. Mutational analysis of the PTEN gene in endometrial carcinoma and hyperplasia. Am J Clin Pathol 2001; 115: 32-38.
Orbo A, Nilsen MN, Arnes MS et al. Loss of expression of MLH1, MSH2, MSH6, and PTEN related to endometrial cancer in 68 patients with endometrial hyperplasia. Int J Gynecol Pathol 2003; 22: 141-148.
Hecht JL, Pinkus JL, Pinkus GS. Enhanced detection of atypical hyperplasia in endometrial polyps by PTEN expression. Appl Immunohistochem Mol Morphol 2004; 12: 36-39.
Monte NM, Webster KA, Neuberg D et al. Joint loss of PAX2 and PTEN expression in endometrial precancers and cancer. Cancer Res 2010; 70: 6225-6232.
Allison KH, Upson K, Reed SD et al. PAX2 loss by immunohistochemistry occurs early and often in endometrial hyperplasia. Int J Gynecol Pathol 2012; 31: 151-159.
Quick CM, Laury AR, Monte NM, Mutter GL. Utility of PAX2 as a marker for diagnosis of endometrial intraepithelial neoplasia. Am J Clin Pathol 2012; 138: 678-684.
Tashiro H, Isacson C, Levine R et al. p53 gene mutations are common in uterine serous carcinoma and occur early in their pathogenesis. Am J Pathol 1997; 150: 177-185.
Zheng W, Khurana R, Farahmand S et al. p53 immunostaining as a significant adjunct diagnostic method for uterine surface carcinoma: precursor of uterine papillary serous carcinoma. Am J Surg Pathol 1998; 22: 1463-1473.
Jia L, Liu Y, Yi X et al. Endometrial glandular dysplasia with frequent p53 gene mutation: a genetic evidence supporting its precancer nature for endometrial serous carcinoma. Clin Cancer Res 2008; 14: 2263-2269.
Lax SF, Kendall B, Tashiro H et al. The frequency of p53, K-ras mutations, and microsatellite instability differs in uterine endometrioid and serous carcinoma: evidence of distinct molecular genetic pathways. Cancer 2000; 88: 814-824.
Castrillon DH, Lee KR, Nucci MR. Distinction between endometrial and endocervical adenocarcinoma: an immunohistochemical study. Int J Gynecol Pathol 2002; 21: 4-10.
Saad RS, Mashhour M, Noftech-Mozes S et al. P16INK4a expression in undifferentiated carcinoma of the uterus does not exclude its endometrial origin. Int J Gynecol Pathol 2012; 31: 57-65.
Netzer IM, Kerner H, Litwin L et al. Diagnostic implications of p16 expression in serous papillary endometrial cancer. Int J Gynecol Cancer 2011; 21: 1441-1445.
Bagby C, Ronnett BM, Yemelyanova A et al. Clinically occult tubal and ovarian high-grade serous carcinomas presenting in uterine samples: diagnostic pitfalls and clues to improve recognition of tumor origin. Int J Gynecol Pathol 2013; 32: 433-443.
Hashi A, Yuminamochi T, Murata S et al. Wilms tumor gene immunoreactivity in primary serous carcinomas of the fallopian tube, ovary, endometrium, and peritoneum. Int J Gynecol Pathol 2003; 22: 374-377.
Köbel M, Kalloger SE, Carrick J et al. A limited panel of immunomarkers can reliably distinguish between clear cell and high-grade serous carcinoma of the ovary. Am J Surg Pathol 2009; 33: 14-21.
Al-Hussaini M, Stockman A, Foster H, McCluggage WG. WT-1 assists in distinguishing ovarian from uterine serous carcinoma and in distinguishing between serous and endometrioid ovarian carcinoma. Histopathology 2004; 44: 109-115.
Egan JA, Ionescu MC, Eapen E et al. Differential expression of WT1 and p53 in serous and endometrioid carcinomas of the endometrium. Int J Gynecol Pathol 2004; 23: 119-122.
Eriksson LS, Lindqvist PG, Flöter Rådestad A et al. Transvaginal ultrasound assessment of myometrial and cervical stromal invasion in women with endometrial cancer: interobserver reproducibility among ultrasound experts and gynecologists. Ultrasound Obstet Gynecol 2015; 45: 476-482.
Epstein E, Blomqvist L. Imaging in endometrial cancer. Best Pract Res Clin Obstet Gynaecol 2014; 28: 721-739.
Scholten AN, Smit VT, Beerman H et al. Prognostic significance and interobserver variability of histologic grading systems for endometrial carcinoma. Cancer 2004; 100: 764-772.
Helpman L, Kupets R, Covens A et al. Assessment of endometrial sampling as a predictor of final surgical pathology in endometrial cancer. Br J Cancer 2014; 110: 609-615.
Stephan JM, Hansen J, Samuelson M et al. Intra-operative frozen section results reliably predict final pathology in endometrial cancer. Gynecol Oncol 2014; 133: 499-505.
Antonsen SL, Høgdall E, Christensen IJ et al. HE4 and CA125 levels in the preoperative assessment of endometrial cancer patients: a prospective multicenter study (ENDOMET). Acta Obstet Gynecol Scand 2013; 92: 1313-1322.
Yildiz A, Yetimalar H, Kasap B et al. Preoperative serum CA 125 level in the prediction of the stage of disease in endometrial carcinoma. Eur J Obstet Gynecol Reprod Biol 2012; 164: 191-195.
Mutz-Dehbalaie I, Egle D, Fessler S et al. HE4 is an independent prognostic marker in endometrial cancer patients. Gynecol Oncol 2012; 126: 186-191.
Sun C, Chen G, Yang Z et al. Safety of ovarian preservation in young patients with early-stage endometrial cancer: a retrospective study and meta-analysis. Fertil Steril 2013; 100: 782-787.
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 2009; 27: 5331-5336.
Mourits MJ, Bijen CB, Arts HJ et al. Safety of laparoscopy versus laparotomy in early-stage endometrial cancer: a randomised trial. Lancet Oncol 2010; 11: 763-771.
Zullo F, Falbo A, Palomba S. Safety of laparoscopy vs laparotomy in the surgical staging of endometrial cancer: a systematic review and metaanalysis of randomized controlled trials. Am J Obstet Gynecol 2012; 207: 94-100.
Pakish J, Soliman PT, Frumovitz M et al. A comparison of extraperitoneal versus transperitoneal laparoscopic or robotic para-aortic lymphadenectomy for staging of endometrial carcinoma. Gynecol Oncol 2014; 132: 366-371.
Tozzi R, Malur S, Koehler C, Schneider A. Analysis of morbidity in patients with endometrial cancer: is there a commitment to offer laparoscopy? Gynecol Oncol 2005; 97: 4-9.
Siesto G, Uccella S, Ghezzi F et al. Surgical and survival outcomes in older women with endometrial cancer treated by laparoscopy. Menopause 2010; 17: 539-544.
Palomba S, Falbo A, Mocciaro R et al. Laparoscopic treatment for endometrial cancer: a meta-analysis of randomized controlled trials (RCTs). Gynecol Oncol 2009; 112: 415-421.
Palomba S, Falbo A, Russo T, Zullo F. Updating of a recent meta-analysis of randomized controlled trials to assess the safety and the efficacy of the laparoscopic surgery for treating early stage endometrial cancer. Gynecol Oncol 2009; 114: 135-136.
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 2012; 30: 695-700.
Fader AN, Seamon LG, Escobar PF et al. Minimally invasive surgery versus laparotomy in women with high grade endometrial cancer: a multi-site study performed at high volume cancer centers. Gynecol Oncol 2012; 126: 180-185.
Han KH, Park NH, Kim HS et al. Peritoneal cytology: a risk factor of recurrence for non-endometrioid endometrial cancer. Gynecol Oncol 2014; 134: 293-296.
Garg G, Gao F, Wright JD et al. Positive peritoneal cytology is an independent risk-factor in early stage endometrial cancer. Gynecol Oncol 2013; 128: 77-82.
Lutman CV, Havrilesky LJ, Cragun JM et al. Pelvic lymph node count is an important prognostic variable for FIGO stage I and II endometrial carcinoma with high-risk histology. Gynecol Oncol 2006; 102: 92-97.
Abu-Rustum NR, Iasonos A, Zhou Q et al. Is there a therapeutic impact to regional lymphadenectomy in the surgical treatment of endometrial carcinoma? Am J Obstet Gynecol 2008; 198: 457.e1-457.e5; discussion 457.e5-457.e6.
Cragun JM, Havrilesky LJ, Calingaert B et al. Retrospective analysis of selective lymphadenectomy in apparent early-stage endometrial cancer. J Clin Oncol 2005; 23: 3668-3675.
Kilgore LC, Partridge EE, Alvarez RD et al. Adenocarcinoma of the endometrium: survival comparisons of patients with and without pelvic node sampling. Gynecol Oncol 1995; 56: 29-33.
Creasman WT, Morrow CP, Bundy BN et al. Surgical pathologic spread patterns of endometrial cancer. A Gynecologic Oncology Group Study. Cancer 1987; 60(8 Suppl): 2035-2041.
Abu-Rustum NR, Gomez JD, Alektiar KM et al. The incidence of isolated paraaortic nodal metastasis in surgically staged endometrial cancer patients with negative pelvic lymph nodes. Gynecol Oncol 2009; 115: 236-238.
Dowdy SC, Aletti G, Cliby WA et al. Extra-peritoneal laparoscopic para-aortic lymphadenectomy-a prospective cohort study of 293 patients with endometrial cancer. Gynecol Oncol 2008; 111: 418-424.
Mariani A, Dowdy SC, Cliby WA et al. Prospective assessment of lymphatic dissemination in endometrial cancer: a paradigm shift in surgical staging. Gynecol Oncol 2008; 109: 11-18.
Ballester M, Dubernard G, Lécuru F et al. Detection rate and diagnostic accuracy of sentinel-node biopsy in early stage endometrial cancer: a prospective multicentre study (SENTI-ENDO). Lancet Oncol 2011; 12: 469-476.
Abu-Rustum NR. Sentinel lymph node mapping for endometrial cancer: a modern approach to surgical staging. J Natl Compr Canc Netw 2014; 12: 288-297.
Benedetti Panici P, Basile S, Maneschi F et al. Systematic pelvic lymphadenectomy vs. no lymphadenectomy in early-stage endometrial carcinoma: randomized clinical trial. J Natl Cancer Inst 2008; 100: 1707-1716.
Kitchener H, Swart AM, Qian Q et al. Efficacy of systematic pelvic lymphadenectomy in endometrial cancer (MRC ASTEC trial): a randomised study. Lancet 2009; 373: 125-136.
Naumann RW. The role of lymphadenectomy in endometrial cancer: was the ASTEC trial doomed by design and are we destined to repeat that mistake? Gynecol Oncol 2012; 126: 5-11.
Smith DC, Macdonald OK, Lee CM, Gaffney DK. Survival impact of lymph node dissection in endometrial adenocarcinoma: a surveillance, epidemiology, and end results analysis. Int J Gynecol Cancer 2008; 18: 255-261.
Trimble EL, Kosary C, Park RC. Lymph node sampling and survival in endometrial cancer. Gynecol Oncol 1998; 71: 340-343.
Todo Y, Kato H, Kaneuchi M et al. Survival effect of para-aortic lymphadenectomy in endometrial cancer (SEPAL study): a retrospective cohort analysis. Lancet 2010; 375: 1165-1172.
Chan JK, Cheung MK, Huh WK et al. Therapeutic role of lymph node resection in endometrioid corpus cancer: a study of 12,333 patients. Cancer 2006; 107: 1823-1830.
Kim HS, Suh DH, Kim MK et al. Systematic lymphadenectomy for survival in patients with endometrial cancer: a meta-analysis. Jpn J Clin Oncol 2012; 42: 405-412.
Vargas R, Rauh-Hain JA, Clemmer J et al. Tumor size, depth of invasion, and histologic grade as prognostic factors of lymph node involvement in endometrial cancer: a SEER analysis. Gynecol Oncol 2014; 133: 216-220.
Takano M, Ochi H, Takei Y et al. Surgery for endometrial cancers with suspected cervical involvement: is radical hysterectomy needed (a GOTIC study)? Br J Cancer 2013; 109: 1760-1765.
Watanabe Y, Satou T, Nakai H et al. Evaluation of parametrial spread in endometrial carcinoma. Obstet Gynecol 2010; 116: 1027-1034.
Shih KK, Yun E, Gardner GJ et al. Surgical cytoreduction in stage IV endometrioid endometrial carcinoma. Gynecol Oncol 2011; 122: 608-611.
Vandenput I, Trovik J, Vergote I et al. The role of adjuvant chemotherapy in surgical stages I-II serous and clear cell carcinomas and carcinosarcoma of the endometrium: a collaborative study. Int J Gynecol Cancer 2011; 21: 332-336.
Gokce ZK, Turan T, Karalok A et al. Clinical outcomes of uterine carcinosarcoma: results of 94 patients. Int J Gynecol Cancer 2015; 25: 279-287.
Amant F, Moerman P, Neven P et al. Endometrial cancer. Lancet 2005; 366: 491-505.
Briët JM, Hollema H, Reesink N et al. Lymphvascular space involvement: an independent prognostic factor in endometrial cancer. Gynecol Oncol 2005; 96: 799-804.
Cohn DE, Horowitz NS, Mutch DG et al. Should the presence of lymphvascular space involvement be used to assign patients to adjuvant therapy following hysterectomy for unstaged endometrial cancer? Gynecol Oncol 2002; 87: 243-246.
Gadducci A, Cavazzana A, Cosio S et al. Lymph-vascular space involvement and outer one-third myometrial invasion are strong predictors of distant haematogeneous failures in patients with stage I-II endometrioid-type endometrial cancer. Anticancer Res 2009; 29: 1715-1720.
Gemer O, Arie AB, Levy T et al. Lymphvascular space involvement compromises the survival of patients with stage I endometrial cancer: results of a multicenter study. Eur J Surg Oncol 2007; 33: 644-647.
Guntupalli SR, Zighelboim I, Kizer NT et al. Lymphovascular space invasion is an independent risk factor for nodal disease and poor outcomes in endometrioid endometrial cancer. Gynecol Oncol 2012; 124: 31-35.
Blake P, Swart AM, Orton J et al. Adjuvant external beam radiotherapy in the treatment of endometrial cancer (MRC ASTEC and NCIC CTG EN.5 randomised trials): pooled trial results, systematic review, and meta-analysis. Lancet 2009; 373: 137-146.
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 2000; 355: 1404-1411.
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 2004; 92: 744-751.
Kong A, Johnson N, Kitchener HC, Lawrie TA. Adjuvant radiotherapy for stage I endometrial cancer: an updated Cochrane systematic review and meta-analysis. J Natl Cancer Inst 2012; 104: 1625-1634.
Soong R, Knowles S, Williams KE et al. Overexpression of p53 protein is an independent prognostic indicator in human endometrial carcinoma. Br J Cancer 1996; 74: 562-567.
Salvesen HB, Iversen OE, Akslen LA. Prognostic significance of angiogenesis and Ki-67, p53, and p21 expression: a population-based endometrial carcinoma study. J Clin Oncol 1999; 17: 1382-1390.
AlHilli MM, Mariani A, Bakkum-Gamez JN et al. Risk-scoring models for individualized prediction of overall survival in low-grade and high-grade endometrial cancer. Gynecol Oncol 2014; 133: 485-493.
Zeimet AG, Reimer D, Huszar M et al. L1CAM in early-stage type I endometrial cancer: results of a large multicenter evaluation. J Natl Cancer Inst 2013; 105: 1142-1150.
Bosse T, Nout RA, Stelloo E et al. L1 cell adhesion molecule is a strong predictor for distant recurrence and overall survival in early stage endometrial cancer: pooled PORTEC trial results. Eur J Cancer 2014; 50: 2602-2610.
Sorbe B, Nordström B, Mäenpää J et al. Intravaginal brachytherapy in FIGO stage I low-risk endometrial cancer: a controlled randomized study. Int J Gynecol Cancer 2009; 19: 873-878.
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 2010; 375: 816-823.
Sorbe B, Horvath G, Andersson H et al. External pelvic and vaginal irradiation versus vaginal irradiation alone as postoperative therapy in medium-risk endometrial carcinoma-a prospective randomized study. Int J Radiat Oncol Biol Phys 2012; 82: 1249-1255.
Bosse T, Peters EE, Creutzberg CL et al. Substantial lymph-vascular space invasion (LVSI) is a significant risk factor for recurrence in endometrial cancer-a pooled analysis of PORTEC 1 and 2 trials. Eur J Cancer 2015; 51: 1742-1750.
Bendifallah S, Canlorbe G, Raimond E et al. A clue towards improving the European Society of Medical Oncology risk group classification in apparent early stage endometrial cancer? Impact of lymphovascular space invasion. Br J Cancer 2014; 110: 2640-2646.
Creutzberg CL, van Putten WL, Koper PC et al. Survival after relapse in patients with endometrial cancer: results from a randomized trial. Gynecol Oncol 2003; 89: 201-209.
McMeekin DS, Filiaci VL, Aghajanian C et al. A randomized phase III trial of pelvic radiation therapy (PXRT) versus vaginal cuff brachytherapy followed by paclitaxel/ carboplatin chemotherapy (VCB/C) in patients with high risk (HR), early stage endometrial cancer (EC): a Gynecologic Oncology Group trial. Gynecol Oncol 2014; 134: 438 (abstract LBA 431).
Creasman WT, Odicino F, Maisonneuve P et al. Carcinoma of the corpus uter. FIGO 26th Annual Report on the Results of Treatment in Gynecological Cancer. Int J Gynaecol Obstet 2006; 95(Suppl 1): S105-S143.
Greven KM, Randall M, Fanning J et al. Patterns of failure in patients with stage I, grade 3 carcinoma of the endometrium. Int J Radiat Oncol Biol Phys 1990; 19: 529-534.
Straughn JM, Huh WK, Orr JW, Jr et al. Stage IC adenocarcinoma of the endometrium: survival comparisons of surgically staged patients with and without adjuvant radiation therapy. Gynecol Oncol 2003; 89: 295-300.
Creutzberg CL, van Putten WL, Wárlám-Rodenhuis CC et al. Outcome of highrisk stage IC, grade 3, compared with stage I endometrial carcinoma patients: the Postoperative Radiation Therapy in Endometrial Carcinoma Trial. J Clin Oncol 2004; 22: 1234-1241.
Sagae S, Susumu N, Viswanathan AN et al. Gynecologic Cancer InterGroup (GCIG) consensus review for uterine serous carcinoma. Int J Gynecol Cancer 2014; 24(9 Suppl 3): S83-S89.
Morrow CP, Bundy BN, Homesley HD et al. Doxorubicin as an adjuvant following surgery and radiation therapy in patients with high-risk endometrial carcinoma, stage I and occult stage II: a Gynecologic Oncology Group Study. Gynecol Oncol 1990; 36: 166-171.
Susumu N, Sagae S, Udagawa Y et al. Randomized phase III trial of pelvic radiotherapy versus cisplatin-based combined chemotherapy in patients with intermediate- and high-risk endometrial cancer: a Japanese Gynecologic Oncology Group study. Gynecol Oncol 2008; 108: 226-233.
Maggi R, Lissoni A, Spina F et al. Adjuvant chemotherapy vs radiotherapy in high-risk endometrial carcinoma: results of a randomised trial. Br J Cancer 2006; 95: 266-271.
Hogberg T, Signorelli M, de Oliveira CF et al. Sequential adjuvant chemotherapy and radiotherapy in endometrial cancer-results from two randomised studies. Eur J Cancer 2010; 46: 2422-2431.
Greven K, Winter K, Underhill K et al. Final analysis of RTOG 9708: adjuvant postoperative irradiation combined with cisplatin/paclitaxel chemotherapy following surgery for patients with high-risk endometrial cancer. Gynecol Oncol 2006; 103: 155-159.
Cooke EW, Pappas L, Gaffney DK. Does the revised International Federation of Gynecology and Obstetrics staging system for endometrial cancer lead to increased discrimination in patient outcomes? Cancer 2011; 117: 4231-4237.
Page BR, Pappas L, Cooke EW, Gaffney DK. Does the FIGO 2009 endometrial cancer staging system more accurately correlate with clinical outcome in different histologies? Revised staging, endometrial cancer, histology. Int J Gynecol Cancer 2012; 22: 593-598.
Pecorelli S. Revised FIGO staging for carcinoma of the vulva, cervix, and endometrium. Int J Gynaecol Obstet 2009; 105: 103-104.
Morrow CP, Bundy BN, Kurman RJ et al. Relationship between surgicalpathological risk factors and outcome in clinical stage I and II carcinoma of the endometrium: a Gynecologic Oncology Group study. Gynecol Oncol 1991; 40: 55-65.
Wright JD, Fiorelli J, Kansler AL et al. Optimizing the management of stage II endometrial cancer: the role of radical hysterectomy and radiation. Am J Obstet Gynecol 2009; 200: 419.e1-419.e7.
Klopp A, Smith BD, Alektiar K et al. The role of postoperative radiation therapy for endometrial cancer: executive summary of an American Society for Radiation Oncology evidence-based guideline. Pract Radiat Oncol 2014; 4: 137-144.
Rossi PJ, Jani AB, Horowitz IR, Johnstone PA. Adjuvant brachytherapy removes survival disadvantage of local disease extension in stage IIIC endometrial cancer: a SEER registry analysis. Int J Radiat Oncol Biol Phys 2008; 70: 134-138.
Randall ME, Wilder J, Greven K, Raben M. Role of intracavitary cuff boost after adjuvant external irradiation in early endometrial carcinoma. Int J Radiat Oncol Biol Phys 1990; 19: 49-54.
Greven K, Winter K, Underhill K et al. Preliminary analysis of RTOG 9708: adjuvant postoperative radiotherapy combined with cisplatin/paclitaxel chemotherapy after surgery for patients with high-risk endometrial cancer. Int J Radiat Oncol Biol Phys 2004; 59: 168-173.
Scotti V, Borghesi S, Meattini I et al. Postoperative radiotherapy in stage I/II endometrial cancer: retrospective analysis of 883 patients treated at the University of Florence. Int J Gynecol Cancer 2010; 20: 1540-1548.
Jobsen JJ, Lybeert ML, van der Steen-Banasik EM et al. Multicenter cohort study on treatment results and risk factors in stage II endometrial carcinoma. Int J Gynecol Cancer 2008; 18: 1071-1078.
Crosby MA, Tward JD, Szabo A et al. Does brachytherapy improve survival in addition to external beam radiation therapy in patients with high risk stage I and II endometrial carcinoma? Am J Clin Oncol 2010; 33: 364-369.
Secord AA, Geller MA, Broadwater G et al. A multicenter evaluation of adjuvant therapy in women with optimally resected stage IIIC endometrial cancer. Gynecol Oncol 2013; 128: 65-70.
Klopp AH, Jhingran A, Ramondetta L et al. Node-positive adenocarcinoma of the endometrium: outcome and patterns of recurrence with and without external beam irradiation. Gynecol Oncol 2009; 115: 6-11.
Randall ME, Filiaci VL, Muss H et al. Randomized phase III trial of wholeabdominal irradiation versus doxorubicin and cisplatin chemotherapy in advanced endometrial carcinoma: a Gynecologic Oncology Group Study. J Clin Oncol 2006; 24: 36-44.
Lee LJ, Viswanathan AN. Combined chemotherapy and radiation improves survival for node-positive endometrial cancer. Gynecol Oncol 2012; 127: 32-37.
Mundt AJ, McBride R, Rotmensch J et al. Significant pelvic recurrence in highrisk pathologic stage I-IV endometrial carcinoma patients after adjuvant chemotherapy alone: implications for adjuvant radiation therapy. Int J Radiat Oncol Biol Phys 2001; 50: 1145-1153.
Viswanathan AN, Macklin EA, Berkowitz R, Matulonis U. The importance of chemotherapy and radiation in uterine papillary serous carcinoma. Gynecol Oncol 2011; 123: 542-547.
Hasegawa K, Nagao S, Yasuda M et al. Gynecologic Cancer InterGroup (GCIG) consensus review for clear cell carcinoma of the uterine corpus and cervix. Int J Gynecol Cancer 2014; 24(9 Suppl 3): S90-S95.
Barney BM, Petersen IA, Mariani A et al. The role of vaginal brachytherapy in the treatment of surgical stage I papillary serous or clear cell endometrial cancer. Int J Radiat Oncol Biol Phys 2013; 85: 109-115.
Berton-Rigaud D, Devouassoux-Shisheboran M, Ledermann JA et al. Gynecologic Cancer InterGroup (GCIG) Consensus Review for Uterine and Ovarian Carcinosarcoma. Int J Gynecol Cancer 2014; 24(9 Suppl 3): S55-S60.
Amant F. The rationale for comprehensive surgical staging in endometrial carcinosarcoma. Gynecol Oncol 2005; 99: 521-522; author reply 522-523.
Reed NS, Mangioni C, Malmstrom H et al. Phase III randomised study to evaluate the role of adjuvant pelvic radiotherapy in the treatment of uterine sarcomas stages I and II: an European Organisation for Research and Treatment of Cancer Gynaecological Cancer Group Study (protocol 55874). Eur J Cancer 2008; 44: 808-818.
Wright JD, Seshan VE, Shah M et al. The role of radiation in improving survival for early-stage carcinosarcoma and leiomyosarcoma. Am J Obstet Gynecol 2008; 199: 536.e1-536.e8.
Clayton Smith D, Kenneth Macdonald O, Gaffney DK. The impact of adjuvant radiation therapy on survival in women with uterine carcinosarcoma. Radiother Oncol 2008; 88: 227-232.
Nemani D, Mitra N, Guo M, Lin L. Assessing the effects of lymphadenectomy and radiation therapy in patients with uterine carcinosarcoma: a SEER analysis. Gynecol Oncol 2008; 111: 82-88.
Wolfson AH, Brady MF, Rocereto T et al. A gynecologic oncology group randomized phase III trial of whole abdominal irradiation (WAI) vs. cisplatin-ifosfamide and mesna (CIM) as post-surgical therapy in stage I-IV carcinosarcoma (CS) of the uterus. Gynecol Oncol 2007; 107: 177-185.
Barlin JN, Puri I, Bristow RE. Cytoreductive surgery for advanced or recurrent endometrial cancer: a meta-analysis. Gynecol Oncol 2010; 118: 14-18.
Creasman WT, Kohler MF, Odicino F et al. Prognosis of papillary serous, clear cell, and grade 3 stage I carcinoma of the endometrium. Gynecol Oncol 2004; 95: 593-596.
Jhingran A, Burke TW, Eifel PJ. Definitive radiotherapy for patients with isolated vaginal recurrence of endometrial carcinoma after hysterectomy. Int J Radiat Oncol Biol Phys 2003; 56: 1366-1372.
Vargo JA, Kim H, Houser CJ et al. Definitive salvage for vaginal recurrence of endometrial cancer: the impact of modern intensity-modulated-radiotherapy with image-based HDR brachytherapy and the interplay of the PORTEC 1 risk stratification. Radiother Oncol 2014; 113: 126-131.
Podzielinski I, Randall ME, Breheny PJ et al. Primary radiation therapy for medically inoperable patients with clinical stage I and II endometrial carcinoma. Gynecol Oncol 2012; 124: 36-41.
Fishman DA, Roberts KB, Chambers JT et al. Radiation therapy as exclusive treatment for medically inoperable patients with stage I and II endometrioid carcinoma with endometrium. Gynecol Oncol 1996; 61: 189-196.
Gill BS, Kim H, Houser C et al. Image-based three-dimensional conformal brachytherapy for medically inoperable endometrial carcinoma. Brachytherapy 2014; 13: 542-547.
Thigpen JT, Brady MF, Alvarez RD et al. Oral medroxyprogesterone acetate in the treatment of advanced or recurrent endometrial carcinoma: a dose-response study by the Gynecologic Oncology Group. J Clin Oncol 1999; 17: 1736-1744.
Decruze SB, Green JA. Hormone therapy in advanced and recurrent endometrial cancer: a systematic review. Int J Gynecol Cancer 2007; 17: 964-978.
Tangen IL, Werner HM, Berg A et al. Loss of progesterone receptor links to high proliferation and increases from primary to metastatic endometrial cancer lesions. Eur J Cancer 2014; 50: 3003-3010.
Lentz SS, Brady MF, Major FJ et al. High-dose megestrol acetate in advanced or recurrent endometrial carcinoma: a Gynecologic Oncology Group Study. J Clin Oncol 1996; 14: 357-361.
Thigpen T, Brady MF, Homesley HD et al. Tamoxifen in the treatment of advanced or recurrent endometrial carcinoma: a Gynecologic Oncology Group study. J Clin Oncol 2001; 19: 364-367.
Ma BB, Oza A, Eisenhauer E et al. The activity of letrozole in patients with advanced or recurrent endometrial cancer and correlation with biological markers -a study of the National Cancer Institute of Canada Clinical Trials Group. Int J Gynecol Cancer 2004; 14: 650-658.
Rose PG, Brunetto VL, VanLe L et al. A phase II trial of anastrozole in advanced recurrent or persistent endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol 2000; 78: 212-216.
Whitney CW, Brunetto VL, Zaino RJ et al. Phase II study of medroxyprogesterone acetate plus tamoxifen in advanced endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol 2004; 92: 4-9.
Fiorica JV, Brunetto VL, Hanjani P et al. Phase II trial of alternating courses of megestrol acetate and tamoxifen in advanced endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol 2004; 92: 10-14.
van Wijk FH, Aapro MS, Bolis G et al. Doxorubicin versus doxorubicin and cisplatin in endometrial carcinoma: definitive results of a randomised study (55872) by the EORTC Gynaecological Cancer Group. Ann Oncol 2003; 14: 441-448.
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 2004; 22: 3902-3908.
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 2004; 22: 2159-2166.
Miller D, Filiaci V, Fleming G et al. Late-Breaking Abstract 1: randomized phase III noninferiority trial of first line chemotherapy for metastatic or recurrent endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol 2012; 125: 771.
Makker V, Hensley ML, Zhou Q et al. Treatment of advanced or recurrent endometrial carcinoma with doxorubicin in patients progressing after paclitaxel/ carboplatin: Memorial Sloan-Kettering Cancer Center experience from 1995 to 2009. Int J Gynecol Cancer 2013; 23: 929-934.
Grisham RN, Adaniel C, Hyman DM et al. Gemcitabine for advanced endometrial cancer: a retrospective study of the Memorial Sloan-Kettering Cancer Center experience. Int J Gynecol Cancer 2012; 22: 807-811.
Nagao S, Nishio S, Michimae H et al. Applicability of the concept of "platinum sensitivity" to recurrent endometrial cancer: the SGSG-012/GOTIC-004/ Intergroup study. Gynecol Oncol 2013; 131: 567-573.
Moore KN, Tian C, McMeekin DS et al. Does the progression-free interval after primary chemotherapy predict survival after salvage chemotherapy in advanced and recurrent endometrial cancer? A Gynecologic Oncology Group ancillary data analysis. Cancer 2010; 116: 5407-5414.
Matias-Guiu X, Prat J. Molecular pathology of endometrial carcinoma. Histopathology 2013; 62: 111-123.
Salvesen HB, Carter SL, Mannelqvist M et al. Integrated genomic profiling of endometrial carcinoma associates aggressive tumors with indicators of PI3 kinase activation. Proc Natl Acad Sci USA 2009; 106: 4834-4839.
Myers AP. New strategies in endometrial cancer: targeting the PI3K/ mTOR pathway-the devil is in the details. Clin Cancer Res 2013; 19: 5264-5274.
Yeramian A, Moreno-Bueno G, Dolcet X et al. Endometrial carcinoma: molecular alterations involved in tumor development and progression. Oncogene 2013; 32: 403-413.
Dutt A, Salvesen HB, Chen TH et al. Drug-sensitive FGFR2 mutations in endometrial carcinoma. Proc Natl Acad Sci USA 2008; 105: 8713-8717.
Kamat AA, Merritt WM, Coffey D et al. Clinical and biological significance of vascular endothelial growth factor in endometrial cancer. Clin Cancer Res 2007; 13: 7487-7495.
Salvesen HB, Haldorsen IS, Trovik J. Markers for individualised therapy in endometrial carcinoma. Lancet Oncol 2012; 13: e353-e361.
Dedes KJ, Wetterskog D, Ashworth A et al. Emerging therapeutic targets in endometrial cancer. Nat Rev Clin Oncol 2011; 8: 261-271.
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 2011; 29: 2259-2265.
Colombo N, McMeekin DS, Schwartz PE et al. Ridaforolimus as a single agent in advanced endometrial cancer: results of a single-arm, phase 2 trial. Br J Cancer 2013; 108: 1021-1026.
Tsoref D, Welch S, Lau S et al. Phase II study of oral ridaforolimus in women with recurrent or metastatic endometrial cancer. Gynecol Oncol 2014; 135: 184-189.
Aghajanian C, Filiaci VL, Dizon DS et al. A randomized phase II study of paclitaxel/carboplatin/bevacizumab, paclitaxel/carboplatin/temsirolimus and ixabepilone/carboplatin/bevacizumab as initial therapy for measurable stage III or IVA, stage IVB or recurrent endometrial cancer, GOG86P. J Clin Oncol 2015; 33(Suppl): abstract 5500.
Lorusso D, Ferrandina G, Colombo N et al. Randomized phase II trial of carboplatin-paclitaxel (CP) compared to carboplatin-paclitaxel-bevacizumab (CPB) in advanced (stage III-IV) or recurrent endometrial cancer: the MITO END-2 trial. J Clin Oncol 2015; 33(Suppl): abstract 5502.
Werner HM, Salvesen HB. Current status of molecular biomarkers in endometrial cancer. Curr Oncol Rep 2014; 16: 403.
Weigelt B, Banerjee S. Molecular targets and targeted therapeutics in endometrial cancer. Curr Opin Oncol 2012; 24: 554-563.
Konecny GE, Finkler N, Garcia AA et al. Phase 2 study of second-line dovitinib (TKI258) in patients with fibroblast growth factor receptor 2 (FGFR2)-mutated or -nonmutated advanced and/or metastatic endometrial cancer. Ann Oncol 2014; 25(Suppl 4): LBA27.
Mackay HJ, Eisenhauer EA, Kamel-Reid S et al. Molecular determinants of outcome with mammalian target of rapamycin inhibition in endometrial cancer. Cancer 2014; 120: 603-610.
Korn EL, Freidlin B, Abrams JS, Halabi S. Design issues in randomized phase II/III trials. J Clin Oncol 2012; 30: 667-671.
Redig AJ, Jänne PA. Basket trials and the evolution of clinical trial design in an era of genomic medicine. J Clin Oncol 2015; 33: 975-977.
