Long-term oncologic outcomes after fertility-sparing management using oral progestin for young women with endometrial cancer (KGOG 2002)

doi:10.1016/j.ejca.2012.09.017

European Journal of Cancer

Volume 49, Issue 4, March 2013, Pages 868-874

https://doi.org/10.1016/j.ejca.2012.09.017 Get rights and content

Abstract

Objective

To analyse the long-term oncologic outcomes of a fertility-sparing management using oral progestin in young women with endometrial cancer.

Methods

We analysed 148 patients (age ⩽ 40 years) with stage IA, grade 1, endometrioid adenocarcinoma of the uterus who underwent fertility-sparing management using daily oral medroxyprogesterone acetate (MPA) or megestrol acetate (MA).

Results

115 (77.7%) showed complete response (CR) to progestin treatment, and 35 (30.4%) of them experienced recurrence after median follow-up time of 66 months. The 5-year recurrence-free survival was 68% (95% confidence interval [CI], 58.5–76.9%). However, 33 patients (22.3%) who failed to achieve CR underwent definitive surgical management, and no one had recurrence after median follow-up time of 41 months. During progestin treatment and at the time of recurrence, no patient showed clinical progression of disease over stage IA. Body mass index (BMI) ⩾25 kg/m² was the only significant factor associated with a failure to achieve CR (odds ratio [OR], 3.00; 95% CI, 1.35–6.66; P = 0.007). Upon multivariate analysis, BMI ⩾ 25 kg/m² (OR, 2.14; 95% CI, 1.06–4.31; P = 0.033) was significantly associated with a higher risk of recurrence and the use of MPA (compared to MA) (OR, 0.44; 95% CI, 0.22–0.88; P = 0.021), maintenance treatment (OR, 0.22; 95% CI, 0.05–0.94; P = 0.042) and pregnancy (OR, 0.25; 95% CI, 0.11–0.56; P = 0.001) were significantly associated with a lower risk of recurrence.

Conclusion

Fertility-sparing management was highly effective and safe. BMI < 25 kg/m², MPA (compared to MA), maintenance treatment and pregnancy were associated with higher possibility of long-term success.

Introduction

Endometrial cancer is the most common gynecologic cancer in Western countries1, 2 and the incidence in Eastern countries has been steadily increasing.3, 4, 5 About 2.9–14.4% of women with endometrial cancer are ⩽40 years of age, and cancer incidence in this age group is rising.6, 7 Most endometrial cancers in women of this age are early-stage, well-differentiated endometrioid adenocarcinomas8, 9; few show any evidence of myometrial invasion or lymph node metastasis.10, 11 Thus, such patients have a very high curative rate, and quality-of-life after treatment is an important consideration. Fertility preservation is one of the most important quality-of-life issues in women in this age range. Because the number of women who wish to have a first child at age 35–39 years is increasing, the number of women diagnosed with endometrial cancer during childbearing years, but prior to first conception, is rising, ¹² as is the need for fertility-sparing management of such patients.

The most common type of fertility-sparing management involves progestin treatment via use of oral medroxyprogesterone acetate (MPA) or megestrol acetate (MA).13, 14, 15, 16 Young patients with well-differentiated endometrioid adenocarcinoma without myometrial invasion are considered to be good candidates for such management.13, 14, 15, 16 To date, however, only individual case reports and small case series on such patients have appeared except one phase 2 trial.¹⁷ Thus, long-term treatment outcomes have not been described. We therefore analysed the long-term oncologic outcomes of a large patient cohort treated using fertility-sparing management, employing oral progestin, and we also explored the factors associated with the failure of this treatment.

Section snippets

Study population

We searched the records of eight tertiary cancer centers of Korea to gather data on young patients with endometrial cancer who were treated using fertility-sparing management employing oral progestin between January 1996 and June 2010. Inclusion criteria of this study included: (1) endometrioid type adenocarcinoma of endometrium, (2) well-differentiated tumor (grade 1); (3) presumed stage IA disease in terms of the 1988 International Federation of Obstetrics and Gynecology (FIGO) staging system

Patient’s characteristics

A total of 148 patients met the inclusion criteria and thus were included in the analysis. The mean age of patients was 31.3 years (range, 21–40 years). One hundred thirty-nine patients (93.9%) were nulliparous women. The characteristics of patients are shown in Table 1. All patients underwent transvaginal USG. As an additional imaging study, 122 patients (85%) underwent magnetic resonance imaging, and 33 patients (22%) underwent abdomino-pelvic CT, and 32 patients (22%) underwent PET or PET–CT.

Discussion

We found that fertility-sparing management using oral progestin in young women with FIGO stage IA, grade 1, endometrioid adenocarcinoma of the uterus resulted in CR rates of 77.7%. After achieving CR, recurrence rate was 30.4%. Therefore, 54.5% of patients who tried fertility-sparing management using oral progestin achieved durable CR, with median duration of 58 months (range, 14–151 months). Although the response rates in prior case reports and case series varied from 25–89%, the cited works

Source of funding

There was no financial support for this study.

Conflict of interest statement

None declared.

Acknowledgements

The authors thank Hee-Sug Ryu, MD, PhD (Department of Obstetrics and Gynecology, Ajou University Hospital, Suwon, Korea) and Seung Cheol Kim, MD, PhD (Department of Obstetrics and Gynecology, Ewha Womans University Mokdong Hospital, College of Medicine, Ewha Womans University, Seoul, Korea) for participating in this study. The authors also thank the Korean Gynecologic Oncology Group (KGOG) for supporting the work.

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To compare the effects of levonorgestrel-intrauterine system (LNG-IUS) with or without oral megestrol acetate (MA) versus MA alone on fertility-preserving treatment in patients with atypical endometrial hyperplasia (AEH).
This was a single-center phase II study with an open-label, randomized, controlled trial conducted between July 2017 and June 2020 at the Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China. A total of 180 patients (18–45 years) with primary AEH were randomly assigned (1:1:1) to the MA (N = 60), LNG-IUS (N = 60), or MA + LNG-IUS (N = 60) groups, in which the patients received MA (160 mg orally daily), LNG-IUS, or MA + LNG-IUS (MA 160 mg orally daily plus LNG-IUS), respectively. The primary endpoint was complete response (CR) rate at 16 weeks of treatment. The secondary endpoints were CR rate at 32 weeks of treatment, adverse events, and recurrence and pregnancy rates. All analyses were conducted in a modified intention to treat (ITT) population who underwent randomization and in whom treatment was initiated.
The Kaplan-Meier estimate of 16-week CR rates (with 95% confidence interval) were 19.2% (9.0–29.4%) in the MA group, 35.0% (22.8–47.2%) in the LNG-IUS group, and 29.4% (17.2–41.6%) in the MA + LNG-IUS groups. Side effects such as weight gain, increased nocturnal urine, night sweat, insomnia and edema face seemed to occur less frequently in LNG-IUS group compared with MA group. No difference was found among groups regarding second endpoints.
LNG-IUS or LNG-IUS plus MA did not show significant therapeutic benefit compared with MA alone. Further studies including sufficient sample-size are needed to validate these findings due to the underpowered design of this trial.
This study was supported by the National Key Research and Development Program of China (Grant No 2019YFC1005200 and 2019YFC1005204), Shanghai Medical Centre of Key Programs for Female Reproductive Diseases (Grant No. 2017ZZ010616), Shanghai sailing program (Grant No. 19YF1404200), and Shen Kang clinical project (SHDC22021219).
Trial registration ClinicalTrials.gov NCT03241888. https://www.clinicaltrials.gov/ct2/show/NCT03241888?term=NCT03241888&draw=2&rank=1
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Reproductive and pregnancy outcomes of fertility-sparing treatments for early-stage endometrial cancer or atypical hyperplasia: A systematic review and meta-analysis
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To report the pregnancy outcomes of women with prior endometrial cancer and endometrial hyperplasia managed with fertility-sparing treatments.
Medline and Embase databases were searched. Inclusion criteria were studies reporting the pregnancy outcomes of women who had undergone fertility-sparing treatments for endometrial hyperplasia or early endometrioid endometrial cancer. Outcomes explored were pregnancy, miscarriage and livebirth rates according to the type of progestin treatment used. Subgroup analyses according to the type of diagnostic follow-up were also performed. Meta-analyses of proportions using a random effects model were used to combine data.
Twenty-nine studies (1036 women) were included, and 82.8% [95% confidence interval (CI) 72.3–91.2] of women achieved complete remission. Pregnancy rates were 56.3% (95% CI 41.6–70.5) with megestrol (MA) or medroxyprogesterone acetate (MPA), 63.1% (95% CI 37.0–85.6) with levonorgestrel-releasing intrauterine device (LNG-IUD), 57.9% (95% CI 37.7–76.8) with MA or MPA and metformin, 59.8% (95% CI 48.3–70.7) with MPA and LNG-IUD, 15.4% (95% CI 4.3–42.2) with gonadotropin-releasing hormone analogue (GnRHa) combined with LNG-IUD or letrozole, and 40.7% (95% CI 24.5–59.3) with LNG-IUD and GnRHa. Miscarriage rates were 17.4% (95% CI 12.2–23.4), 14.3% (95% CI 6.4–24.7), 57.9% (95% CI 37.7–76.8), 26.9% (95% CI 14.6–39.3), 100% (95% CI 34.0–100) and 18.2% (95% CI 5.1–47.7), respectively, and livebirth rates were 68.8% (95% CI 56.0–80.3), 80.8% (95% CI 69.5–90.0), 69.9% (95% CI 56.1–82.0), 25.97 (95% CI 14.6–39.3), 0% (95% CI 0–66.0) and 81.8% (95% CI 52.3–94.8), respectively. Finally, stratifying the analysis considering the endometrial sampling method alone, the pregnancy rate was 68.6% (95% CI 51.2–83.6; 10 studies, I² = 83.5%) in women who underwent hysteroscopy and 60.5% (95% CI 53.4–67.5; 13 studies, I² = 39.8%) in women managed with dilatation and curettage biopsy; the miscarriage and livebirth rates were 13.2% (95% CI 8.0–19.5; I² = 0%) and 81.2% (95% CI 67.4–91.8; I² = 67.3%), respectively, for hysteroscopy, and 25.2% (95% CI 17.8–33.3; I² = 15.5%) and 67.5% (95% CI 58.8–75.5; I² = 0%), respectively, for dilatation and curettage biopsy.
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Long-term oncologic outcomes after fertility-sparing management using oral progestin for young women with endometrial cancer (KGOG 2002)

Abstract

Objective

Methods

Results

Conclusion

Introduction

Section snippets

Study population

Patient’s characteristics

Discussion

Source of funding

Conflict of interest statement

Acknowledgements

Gynecol Oncol

Gynecol Oncol

Pathol Res Pract

Gynecol Oncol

Steroids

Lancet

Geographic and temporal variations in cancer of the corpus uteri: incidence and mortality in pre- and postmenopausal women in Europe

Int J Cancer

Cancer statistics, 2010

CA Cancer J Clin

Prediction of cancer incidence and mortality in Korea, 2011

Cancer Res Treat

Current status of gynecologic cancer in Japan

J Gynecol Oncol

Current status in the management of uterine corpus cancer in Korea

J Gynecol Oncol

Endometrial carcinoma in women 40 years of age or younger

Obstet Gynecol

Adenocarcinoma of the endometrium in women 40 years of age or younger

Obstet Gynecol