gynecology and obstetrics
Endometrial Cancer
Treatment of Endometrial Cancer
Total hysterectomy and bilateral salpingo-oophorectomy Pelvic and para-aortic lymphadenectomy for grade 1 or 2 with deep (> 50%) myometrial invasion, any grade 3, and for all cancers with high-risk histology Pelvic radiation therapy with or without chemotherapy for stage II or III Multimodal therapy usually recommended for stage IV (See alsoNational Comprehensive Cancer Network (NCCN): NCCN Clinical Practice Guidelines in Oncology: Uterine Neoplasms.) Endometrial cancer should be removed en bloc, usually by doing a total hysterectomy and bilateral salpingo-oophorectomy. Intraperitoneal tumor fragmentation or morcellation must be avoided. Surgery can be done by any route (vaginal, open, robotic, laparoscopic). For patients with tumors confined to the uterus, minimally invasive surgery is the preferred approach because its rate of perioperative and postoperative complications is lower, hospital stays are shorter ( Treatment references ), cost is lower, and oncologic outcomes are comparable ( Evidence generally supports comparable oncologic outcomes for laparoscopic surgery and laparotomy. In the Gynecologic Oncology Group LAP2 study, women with clinical stage I to IIA uterine cancer were randomly assigned to have laparoscopic surgery or laparotomy in a 2 to 1 ratio. The study did not demonstrate the statistical noninferiority of the laparoscopic approach. However, after a median follow-up time of 59 months, survival rates for both approaches were similar; 5-year overall survival rate was 90% in both groups. Estimated 5-year recurrence rates were also similar (14% versus 12% [ Treatment references ]). The Laparoscopic Approach to Cancer of the Endometrium (LACE) trial was a prospective, international, randomized trial that included 760 patients with stage I endometrioid uterine cancer. They were randomly assigned to have laparoscopic hysterectomy or open hysterectomy. Disease-free survival at 4.5 years (82% versus 81%) and overall survival (mortality: 7.4% versus 6.8%) were similar ( 2% ( Treatment references ). In these patients, treatment is usually total hysterectomy and bilateral salpingo-oophorectomy via laparotomy, laparoscopy, or robotic-assisted surgery. However, for young women with stage IA or IB endometrioid adenocarcinoma, ovarian preservation is usually safe and recommended to preserve ovarian function. If patients have any of the following, pelvic and para-aortic lymphadenectomy is also done (unless Sentinel lymph node mapping in endometrial cancer identified bilateral SLNs): Grade 1 or 2 cancer with deep (> 50%) myometrial invasion Any grade 3 cancer All cancers with high-risk histology (papillary serous carcinoma, clear cell carcinoma, carcinosarcoma) Any suspicious or grossly enlarged nodes, regardless of mapping If SLNs are identified bilaterally, no lymphadenectomy is indicated, regardless of tumor characteristics. If a sentinel node is not identified on one side, complete lymphadenectomy is necessary on that side. Stage II or III endometrial cancerrequires pelvic radiation therapy with or without chemotherapy. Treatment of stage III cancer must be individualized, but surgery is an option; generally, patients who have combined surgery and radiation therapy have a better prognosis. Except in patients with bulky parametrial disease, a total abdominal hysterectomy and bilateral salpingo-oophorectomy should be done. Treatment ofstage IV endometrial canceris variable and patient-dependent but typically involves a combination of surgery, radiation therapy, and chemotherapy. Occasionally, endocrine therapy should also be considered. Treatment of stage IV endometrial cancer is variable and patient-dependent but typically involves a combination of surgery, radiation therapy, and chemotherapy. Occasionally, endocrine therapy should also be considered ( Treatment references ). Several cytotoxic drugs (particularlycarboplatinpluspaclitaxel) are effective. They are given mainly to women with metastatic or recurrent cancer. Another option isdoxorubicin. , a monoclonal antibody that inhibits programmed cell death-1 (PD-1) activity. A recent phase II trial showed an objective response rate of 39.6% in patients taking this combination ( Treatment references ). (an aromatase inhibitor) showed a clinical benefit rate of 40% and an objective response rate of 32% ( Treatment references ). increased progression-free survival from 8 months to 12.6 months ( Treatment references ). group versus 18.1% in the placebo group; hazard ratio, 0.64) ( Treatment references ). Overall survival (OS) at 24 months was 71.3% with group (PFS 74% versus 38%; 13.1 versus 8.7 months; hazard ratio, 0.54) ( Treatment references ). Patients with complex endometrial hyperplasia and atypia have up to a 50% risk of having concurrent endometrial cancer. Treatment of endometrial hyperplasia consists of progestins or definitive surgery, depending on the complexity of the lesion and the patient’s desire to preserve fertility. If young patients with grade 1 tumors and no myometrial invasion (documented by MRI) wish to preserve fertility, progestin alone is an option. approximately 46 to 80% of patients have a complete response within 3 months of initiation of therapy. After 3 months, patients should be evaluated via dilation and curettage (D & C) rather than endometrial biopsy. -releasing intrauterine device (IUD) is being increasingly used to treat patients with complex atypical hyperplasia or grade 1 endometrial cancer. In a prospective, single-arm trial, the 12-month pathologic response rate was 90.6% for complex atypical hyperplasia and 66.7% for grade 1 endometrioid endometrial cancer. Adverse events were mild, and treatment had no negative effects on quality of life ( Treatment references ). Surgery is recommended if conservative treatment is not effective (endometrial cancer is still present after 6 to 9 months of treatment) or if patients have completed childbearing. Fertility-sparing treatment is contraindicated in patients with high-grade endometrioid adenocarcinomas, uterine papillary serous carcinoma, clear cell carcinoma, or carcinosarcoma. In young women with stage IA or IB endometrioid adenocarcinoma, ovarian preservation is safe and recommended. Uterine papillary serous carcinoma, clear cell carcinomas, and carcinosarcomas are considered histologically aggressive, high-risk cancers and are thus more likely to have spread outside the uterus at presentation. Multimodality therapy is typically recommended for these histologically aggressive endometrial tumors. Primary treatment includes abdominal hysterectomy, bilateral salpingo-oophorectomy with pelvic and para-aortic lymphadenectomy, and omental and peritoneal biopsies. In patients with gross extrauterine disease, cytoreduction should be done to reduce the bulk of the tumor to no gross residual disease. Adjuvant therapy for papillary serous and clear cell carcinomas depends on the stage: Stage IA without myometrial invasion and without residual disease in the hysterectomy specimen: Observation and close follow-up (an acceptable approach) Other stage IA and IB or stage II cancers: Usually vaginal brachytherapy followed by systemic chemotherapy withcarboplatinandpaclitaxel More advanced disease: Standard chemotherapy withcarboplatinandpaclitaxel Adjuvant therapy for carcinosarcoma also depends on the stage: Stage IA without myometrial invasion and without residual disease in the hysterectomy specimen: Observation and close follow-up (an acceptable approach) All other stages: Usually systemic chemotherapy withifosfamidepluspaclitaxel 1.Walker JL, Piedmonte MR, Spirtos NM, et al: Laparoscopy compared with laparotomy for comprehensive surgical staging of uterine cancer: Gynecologic Oncology Group Study LAP2.Clin Oncol27 (32):5331-5336, 2009. doi: 10.1200/JCO.2009.22.3248 2.Galaal K, Donkers H, Bryant A, Lopes AD: Laparoscopy versus laparotomy for the management of early stage endometrial cancer.Cochrane Database Syst Rev10 (10):CD006655, 2018. doi: 10.1002/14651858.CD006655.pub3 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 Oncol30 (7):695–700, 2012. doi: 10.1200/JCO.2011.38.8645 4.Janda M, Gebski V, Davies LC, et al: Effect of total laparoscopic hysterectomy vs total abdominal hysterectomy on disease-free survival among women with stage I endometrial cancer: A randomized clinical trial.JAMA317 (12):1224-1233, 2017. doi: 10.1001/jama.2017.2068 5.Kumar S, Podratz KC, Bakkum-Gamez JN, et al: Prospective assessment of the prevalence of pelvic, paraaortic and high paraaortic lymph node metastasis in endometrial cancer.Gynecol Oncol132(1):38-43, 2014. doi:10.1016/j.ygyno.2013.10.002 6.Decruze SB, Green JA: Hormone therapy in advanced and recurrent endometrial cancer: a systematic review.Int J Gynecol Cancer17(5):964-978, 2007. doi:10.1111/j.1525-1438.2007.00897.x 7.Makker V, Rasco D, Vogelzang NJ, et al:Lenvatinibpluspembrolizumabin patients with advanced endometrial cancer: An interim analysis of a multicentre, open-label, single-arm, phase 2 trial.Lancet Oncol20 (5):711–718, 2019. doi: 10.1016/S1470-2045(19)30020-8 8.Slomovitz BM, Jiang Y, Yates MS, et al: Phase II study ofeverolimusandletrozolein patients with recurrent endometrial carcinoma.J Clin Oncol33 (8):930–936, 2015. doi: 10.1200/JCO.2014.58.3401 9.Fader AN, Roque DM, Siegel E, et al: Randomized phase II trial ofcarboplatin-paclitaxelversuscarboplatin-paclitaxel-trastuzumabin uterine serous carcinomas that overexpress human epidermal growth factor receptor 2/neu.J Clin Oncol36 (20):2044–2051, 2018. doi: 10.1200/JCO.2017.76.5966 10.Mirza MR, Chase DM, Slomovitz BM, et al:Dostarlimabfor Primary Advanced or Recurrent Endometrial Cancer.N Engl J Med388(23):2145-2158, 2023. doi:10.1056/NEJMoa2216334 11.Eskander RN, Sill MW, Beffa L, et al:Pembrolizumabplus Chemotherapy in Advanced Endometrial Cancer.N Engl J Med388(23):2159-2170, 2023. doi:10.1056/NEJMoa2302312 12.Westin SN, Fellman B, Sun CC, et al: Prospective phase II trial oflevonorgestrelintrauterine device: Nonsurgical approach for complex atypical hyperplasia and early-stage endometrial cancer.Am J Obstet Gynecol224 (2):191.e1-191.e15, 2021. doi: 10.1016/j.ajog.2020.08.032 