By Alexandra Morell, MD
Synopsis: This retrospective cohort study using the National Cancer Database demonstrated similar overall survival between fertility-sparing treatment and hysterectomy for patients younger than 40 years of age with clinical stage 1, low-grade endometrial cancer (hazard ratio [HR], 1.00; 95% confidence interval [CI], 0.50-2.00) but an increased mortality risk for patients aged 40-49 years receiving fertility-sparing treatment (HR, 4.94; 95% CI, 1.89-12.91).
Source: Suzuki Y, Huang Y, Xu X, et al. Survival after fertility-preserving hormonal therapy vs hysterectomy for early-stage endometrial cancer. JAMA Oncol. 2025;11(10):1212-1221.
Endometrial cancer is the most common gynecologic malignancy among women in the United States.1 Surgical staging typically includes total hysterectomy, bilateral salpingo-oophorectomy, and assessment of pelvic and para-aortic lymph nodes, most commonly performed using sentinel lymph node mapping and dissection.2,3 In patients with high-risk histologic subtypes, peritoneal washings and omentectomy also may be indicated.2,3 Although the majority of patients are postmenopausal at diagnosis, up to 14% are premenopausal, and some may wish to preserve fertility and pursue conservative, fertility-sparing management.4
This was a retrospective cohort study using the National Cancer Database that aimed to investigate long-term survival of fertility-sparing treatment for clinical stage I endometrial cancer. It included 15,849 women aged younger than 50 years who were diagnosed with clinical stage I, grade 1 or 2 endometrioid endometrial cancer from 2004 to 2020 and compared primary fertility-sparing treatment (hormone therapy) with primary surgical treatment (hysterectomy). Primary treatment was defined as the first treatment received after diagnosis. The primary outcome was time to all-cause mortality, measured at two, five, and 10 years. A Cochran-Armitage test was used to evaluate trends in the use of hormone therapy over time and multivariable logistic regression was used to assess factors associated with receiving primary fertility-sparing treatment. Propensity score matching was used to create balanced comparison groups based on baseline characteristics. Cox proportional hazards models, Kaplan-Meier curves, and log-rank tests were used to compare survival outcomes between patients who underwent primary hysterectomy and those who received hormone therapy.
A total of 14,662 patients (92.5%) received primary surgical treatment, and 1,187 patients (7.5%) received primary fertility-sparing treatment. The median age was older in the hysterectomy group (44 years vs. 34 years, P < 0.001). Hormonal therapy use increased over time from 5.2% in 2004 to 13.8% in 2020 (P < 0.001). In patients younger than 35 years of age, hormone therapy use increased from 24.3% to 42.5% and in patients aged 35 to 39 years, use increased from 4.6% to 16.3% during the same period. Factors associated with fertility-sparing treatment included younger age (P < 0.001), race other than non-Hispanic white (P < 0.001), metropolitan residence (P = 0.001), later year of diagnosis (P < 0.001), treatment at an academic program (P < 0.001), earlier stage (P < 0.001), and lower grade (P < 0.001).
After propensity score matching, a total of 1,039 patients were included in each of the two groups for comparison. Median overall survival was 59.8 months for surgical treatment compared with 59.4 months for fertility-sparing treatment. Two-year overall survival was 99.4% (95% confidence interval [CI], 98.6-99.7) for surgery compared with 98.6% (95% CI, 97.7-99.2) for hormonal therapy, five-year overall survival was 98.5% (95% CI, 97.3-99.2) for surgery compared with 96.8% (95% CI 95.3-97.8) for hormonal therapy, and 10-year overall survival was 96.8% (95% CI, 94.7-98.1) for surgery vs. 92.7% (95% CI, 89.8-94.8) for hormonal therapy. This represented a hazard ratio (HR) of 1.84 (95% CI, 1.06-3.21) for fertility-sparing treatment compared with surgery at five years. In a subsequent analysis evaluating overall survival for patients younger than 40 years of age and those 40-49 years of age, no difference in survival was noted for patients younger than age 40 years (HR, 1.00; 95% CI, 0.50-2.00); however, for patients aged 40-49 years, fertility-sparing treatment was associated with a significantly higher risk of death (HR, 4.94; 95% CI, 1.89-12.91).
Commentary
The National Comprehensive Cancer Network (NCCN) has indicated very specific situations where fertility-sparing treatment for endometrial cancer is indicated.5 Patients must meet all the following criteria: grade 1 endometrioid adenocarcinoma diagnosed via dilation and curettage, no myometrial invasion, no evidence of metastatic disease, and no contraindications to receiving hormonal therapy, and patients must receive counseling indicating that fertility-sparing treatment is not the standard of care. For patients who desire future fertility, magnetic resonance imaging is recommended to assess for myometrium invasion and evaluate for lymphadenopathy and adnexal pathology.4
If the patient meets appropriate criteria for fertility-sparing treatment, the main treatment strategy is progestins. Treatment options include a levonorgestrel-containing intrauterine device or oral medroxyprogesterone acetate or megestrol acetate.4 After starting progestin therapy, repeat evaluation of the endometrium is recommended in three to six months. A recent retrospective cohort study evaluating oncologic and reproductive outcomes for patients receiving progestin therapy with grade 1 endometrioid adenocarcinoma of the endometrium demonstrated complete regression of disease in 60% of patients with a median time to complete regression of 8.3 months.6 Patients should undergo definitive treatment with hysterectomy when childbearing is complete or reconsider fertility-sparing treatment if there is concern for persistence or progression of disease prior to achieving pregnancy.4
This study highlights a significant increase in the use of fertility-sparing treatment for endometrial cancer over the past two decades, with the most notable rise observed among patients diagnosed before 35 years of age. The study further demonstrates that in patients younger than 40 years of age, overall survival rates are comparable between those receiving fertility-sparing hormonal therapy and those undergoing standard surgical treatment with hysterectomy. Therefore, conservative treatment is unlikely to negatively affect long-term cancer outcomes. However, among patients aged 40 to 49 years, fertility-sparing treatment was associated with a nearly five-fold increase in the risk of death. This elevated risk coincides with a natural age-related decline in fertility, particularly after 40 years of age, and reduced success rates of assisted reproductive technologies.7 As such, women in this age group face both a higher risk of mortality and a lower likelihood of achieving a successful pregnancy.
It is essential that patients in this age group receive thorough, individualized counseling regarding the increased mortality risk associated with fertility-sparing treatment and receive realistic information about reproductive potential. Counseling ideally should be multidisciplinary and involve both a gynecologic oncologist and a reproductive endocrinologist/infertility specialist to help patients make informed, patient-centered decisions.
Alexandra Morell, MD, is Adjunct Instructor, Department of Obstetrics and Gynecology, University of Rochester Medical Center, Rochester, NY.
References
1. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022;72(1):7-33.
2. [No authors listed]. Practice Bulletin No. 149: Endometrial cancer. Obstet Gynecol. 2015;125(4):1006-1026.
3. Hamilton CA, Pothuri B, Arend RC, et al. Endometrial cancer: A society of gynecologic oncology evidence-based review and recommendations. Gynecol Oncol. 2021;160(3):817-826.
4. Hamilton CA, Pothuri B, Arend RC, et al. Endometrial cancer: A society of gynecologic oncology evidence-based review and recommendations, part II. Gynecol Oncol. 2021;160(3):827-834.
5. Abu-Rustum N, Yashar C, Arend R, et al. Uterine neoplasms, version 1.2023, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2023;21(2):181-209.
6. Dzyubak O, Glass K, Watts M, et al. Oncologic and fertility outcomes of progestin therapy for atypical hyperplasia and grade 1 cancer of the endometrium: Results of a specialized oncofertility program. Gynecol Oncol. 2025;199:72-78.
7. American College of Obstetricians and Gynecologists Committee on Gynecologic Practice and Practice Committee. Female age-related fertility decline. Committee Opinion No. 589. Fertil Steril. 2014;101(3):633-634.
