Obstetrics & Gynecology:
Pregnancy Outcomes After Fertility-Sparing Management in Young Women With Early Endometrial Cancer
Park, Jeong-Yeol MD, PhD; Seong, Seok Ju MD, PhD; Kim, Tae-Jin MD, PhD; Kim, Jae Weon MD, PhD; Kim, Seok Mo MD, PhD; Bae, Duk-Soo MD, PhD; Nam, Joo-Hyun MD, PhD
Departments of Obstetrics and Gynecology, University of Ulsan College of Medicine, Asan Medical Center, Gangnam CHA Medical Center, CHA University, Cheil General Hospital and Women's Healthcare Center, Kwandong University College of Medicine, Seoul National University College of Medicine, and Samsung Medical Center, Sungkyunkwan University of Medicine, Seoul, and Chonnam National University, School of Medicine, Gwangju, Korea.
Corresponding author: Joo-Hyun Nam, MD, PhD, Department of Obstetrics and Gynecology, College of Medicine, University of Ulsan, Asan Medical Center, #388-1 Poongnap-2 dong, Songpa-gu, Seoul, 138-736, Korea; e-mail: email@example.com.
Supported by the Korean Gynecologic Oncology Group.
Financial Disclosure The authors did not report any potential conflicts of interest.
OBJECTIVE: To analyze pregnancy outcomes in young women with stage IA, grade 1 endometrioid adenocarcinoma of the uterus after successful fertility-sparing management using progestin.
METHODS: We reviewed the medical records of 141 women with stage IA, grade 1 endometrioid adenocarcinoma of the uterus who had complete remission after progestin treatment. Statistical analysis was performed using Student’s t test or Mann-Whitney U test for continuous variables, using χ2 or Fisher’s exact test for categorical variables, and using log-rank test for survival comparison.
RESULTS: Fifty-four (38.3%) women in the study cohort had a history of infertility. Seventy (49.6%) of the 141 patients tried to conceive with 44 (62.9%) receiving fertility drugs. The median interval to attempted pregnancy after treatment was 5 months (range 1–31 months). The median age at the time of the pregnancy trial was 32.4 years (range 23–40 years). Fifty-one (73%) of 70 women who tried to conceive were successful and 46 (66%) gave birth to 58 live neonates. The spontaneous abortion rate, ectopic pregnancy rate, and preterm delivery rates in our cohort were 24%, 2.8%, and 11.5%, respectively. The 5-year disease-free survival was similar between patients who received fertility drugs (n=44) or who did not (n=97) (73% compared with 62%, P=.335), and this rate was significantly higher in patients who achieved at least one pregnancy (n=51) than those who did not (n=90) (76% compared with 62%, P=.028).
CONCLUSIONS: Although the proportion of patients with a history of subfertility or infertility was high in our cohort, the pregnancy outcomes were very promising using assisted reproductive technology. The use of fertility drugs was not associated with a higher incidence of cancer recurrence after successful fertility-sparing management in this study population.
LEVEL OF EVIDENCE: II
Endometrial cancer is the most common gynecologic cancer in developed countries1,2 and the third most common cancer in Korea, although its incidence is rapidly increasing and will likely become the most common gynecologic cancer in Korea in the near future.3,4 Endometrial cancer is usually diagnosed in postmenopausal women, but approximately 20–25% of cases are premenopausal and a further 5% of patients are diagnosed at younger 40 years of age.5–7 The current standard for the management of early endometrial cancer, which includes a total hysterectomy, is not an acceptable option for young women who want to preserve their fertility. Hence, fertility-sparing management with progestin has been adopted for many younger women with stage IA, well-differentiated endometrioid adenocarcinoma of the uterus.8–13 The most commonly used progestins for these treatments are medroxyprogesterone acetate and megestrol acetate.8–13 The complete response rate for progestin treatment ranges from 66.7% to 79.7%, whereas the recurrence rate after successful treatment ranges from 19.2% to 33.8% according to a review of the current literature.8–13 Because recurrent disease after fertility-sparing management using progestin is exclusively confined to the endometrium or myometrium, and can be successfully salvaged by definitive surgical management, it is thought that such treatment does not increase the risk of disease progression or death.9,10,12,13 Hence, progestin is regarded as an effective and safe alternative treatment for young women with early endometrial cancer who want to preserve their fertility and delay definitive surgical treatment until after childbearing.8–13 However, the pregnancy outcomes associated with these treatment options have not been well reported because most previous studies have focused on the oncologic outcomes of progestin therapies and the follow-up times of these earlier studies have all been relatively short. Hence, the aim of the present study is to analyze pregnancy outcomes in young women who received fertility-sparing management of stage IA, grade 1 endometrioid adenocarcinoma of the uterus using progestin.
MATERIALS AND METHODS
This was a multicenter, retrospective, cohort study. After obtaining institutional review board approval from each participating center (Asan Medical Center institutional review board), we reviewed the medical records of 177 young women younger than 40 years of age with a presumed stage IA (according to the 1998 International Federation of Obstetrics and Gynecology staging system), grade 1 endometrioid adenocarcinoma of the uterus and who had received fertility-sparing management using oral progestin from 1996 to 2011. Of these patients, 141 (80%) demonstrated complete remission after progestin treatment and were included in our study cohort. Patient data were gathered from their medical records from six tertiary centers in Korea.
In the present study, the pregnancy rate was defined as the percentage of women who succeeded in achieving pregnancy among patients who had been attempting to conceive. The live birth rate was defined as the percentage of women who delivered live neonates among those who had been attempting to conceive. The spontaneous abortion and ectopic pregnancy rates were defined as the percentage of spontaneous abortions and ectopic pregnancies out of the total number of pregnancies, respectively. The preterm birthrate was defined as the percentage of deliveries that occurred at less than 37 weeks of gestation among all live births.
In accordance with the normal distributions of the continuous variables by Kolmogorov-Smirnov test, differences in the mean or median values between groups were compared using the Student’s t test or Mann-Whitney U test. Differences in the frequency distributions of the categorical variables between groups were compared using the χ2, except when at least one expected frequency was less than five, in which cases the Fisher’s exact test was used. Disease-free survival was calculated as the number of months from the date of achieving complete remission to the date of relapse or censoring. Survival curves were plotted, and survival rates were thereby calculated, using the Kaplan-Meier method, and differences in the survival rates between groups were compared using the log-rank test. All P values <.05 according to two-sided tests were regarded as statistically significant. Statistical analyses were performed using SPSS for Windows 11.0.
A total of 141 patients were included in this study and a flow diagram is shown in Figure 1. The characteristics of 141 patients at the time of the initial diagnosis of endometrial cancer are shown in Table 1. The mean (±standard deviation [SD]) age of the patients was 30.9±3.8 years. All patients had presumed stage IA (according to the 1998 International Federation of Obstetrics and Gynecology staging system), well-differentiated endometrioid adenocarcinoma of the uterus. All patients demonstrated complete remission after fertility-sparing management using medroxyprogesterone acetate (n=85 [60.3%]) or megestrol acetate (n=56 [39.7%]). The median daily dose of medroxyprogesterone acetate was 500 mg/d (range 30–1,500 mg/d) and the median daily dose of megestrol acetate was 160 mg/d (range 40–320 mg/d). The median time to complete remission was 18 weeks (range 8–55 weeks). The response to progestin treatment was determined histologically by office-based endometrial biopsy, dilatation–curettage biopsy, or hysteroscopic biopsy. Complete remission was defined as the absence of evidence of hyperplasia or carcinoma. After achieving complete remission, all of the patients were followed up every 3–6 months by history-taking and by performing physical examinations and imaging studies. Some patients were also tested for cancer antigen 125 (a tumor marker). Transvaginal ultrasonography or magnetic resonance imaging was used most often during surveillance, although abdominopelvic computed tomography, positron emission tomography, or positron emission tomography–computed tomography was used on occasion. Whenever recurrence was suspected, pathologic evaluation of the endometrium was performed by office-based biopsy, dilatation–curettage biopsy, or hysteroscopic biopsy of the endometrium. The mean (±SD) and median follow-up times of all patients were 73±35 and 66 months (range 14–194 months), respectively. Forty-five (31.9%; 95% confidence interval [CI], 24.8–40%) patients had recurrent disease and the mean (±SD) and median intervals to recurrence were 24±17 and 17 months (range 4–62 months), respectively. All instances of recurrent disease were successfully retreated with progestin or surgical management. All patients were alive without evidence of disease at the time of this analysis.
Seventy patients had attempted to conceive, with 44 receiving treatments for infertility, including ovarian hyperstimulation. The mean (±SD) and median intervals to attempted conception after treatment were 7±7 and 5 months (range 1–31 months), respectively. The mean (±SD) and median ages of the patients who tried to conceive at the time of the pregnancy trial were 32.3±3.1 and 32.4 years (range 23–40 years), respectively. The types of infertility treatments included ovulation induction in four patients, controlled ovarian hyperstimulation with intrauterine insemination in 14 cases, in vitro fertilization with intracytoplasmic sperm injection in one case, and in vitro fertilization with embryo transfer in 25 patients. One patient underwent hysteroscopic lysis of an intrauterine adhesion. Figure 1 summarizes these pregnancy outcomes. Of the 44 women who received infertility treatments, 38 (86%) achieved 55 pregnancies and 35 patients (80%) gave birth to 46 live neonates. Of the 26 women who attempted natural pregnancy, 13 (50%) achieved 16 pregnancies and 11 (42%) gave birth to 12 live neonates. In total, 51 of the 70 women (73%) who tried to conceive were successful, and 46 (66%) gave birth to 58 live neonates. Hence, the pregnancy and live birth rates were 73% (95% CI 61–82%) and 66% (95% CI 54–76%), respectively, among 70 women.
The pregnancy rate (86.4% compared with 50%; P=.001) and live birth rate (70.5% compared with 42.3%; P=.020) were significantly higher in patients who received infertility treatment than in patients who attempted natural pregnancy. Of the 58 live neonates born to our patients, 56 were completely healthy; the remaining two neonates had minor congenital anomalies (clubfoot and polydactyly, respectively). In addition, 18 women achieved two pregnancies and one patient achieved three pregnancies in our study cohort. There were also five twin pregnancies and one triplet pregnancy among our patients. In addition, three patients succeeded in becoming pregnant after successful salvage treatment for recurrent disease. After the completion of their planned families, 11 women underwent prophylactic hysterectomy, but no evidence of tumor was found in the uterine specimens.
The spontaneous abortion, ectopic pregnancy, and preterm delivery rates of our present cohort were 24% (95% CI 15–35%), 2.8% (95% CI 0.2–10.3%), and 11.5% (95% CI 5–52.3%), respectively. The spontaneous abortion rate (18.8% compared with 25.5%; P=.745) and ectopic pregnancy rate (3.6% compared with 0%; P=1.000) were not different between patients who received or did not receive infertility treatment. However, the preterm delivery rate (10.9% compared with 0%; P=.326) was higher among patients who had received infertility treatment. When we stratified the occurrence of spontaneous abortions according to maternal age, we found that 10 (59%) and seven (41%) of spontaneous abortions occurred in patients younger than 35 years old and 35 years old or older, respectively. Nine of 40 patients (22.5%) who were younger than 35 years old and had a pregnancy, whereas seven of 11 patients (63.6%) who were 35 years old or older and had a pregnancy sustained a spontaneous abortion (P=.023).
To estimate the influence of pregnancy on the recurrence of endometrioid adenocarcinoma of the uterus after fertility-sparing management using progestin, we compared the disease-free survival outcomes between patients who achieved one or more pregnancies (n=51) and those who did not (n=90). Demographic factors including age (30.7 compared with 31 years; P=.720), body mass index (BMI [calculated as weight (kg)/[height (m)]2] 23.27 compared with 25.08 kg/m2; P=.100), and medical comorbidities (9.8% compared with 10%; P=.970) were found not to be significantly different between patients who achieved pregnancy and patients who did not. The median follow-up times of the patients who achieved pregnancy and those who did not were 91 months (range 38–159 months) and 58 months (range 14–194 months), respectively (P<.001). The 5-year disease-free survival rates for patients who achieved pregnancy and those who did not were 76% and 62%, respectively (P=.028; Fig. 2A).
Disease-free surviva...Image Tools
To estimate the influence of the use of fertility drugs, including clomiphene citrate and gonadotropin, on the recurrence of endometrioid adenocarcinoma after fertility-sparing management using progestin, we compared the disease-free survival rates between patients who received fertility drugs (n=44) and those who did not (n=97). Demographic factors, including age (31 compared with 30.8 years; P=.765), BMI (23.33 compared with 24.93 kg/m2; P=.159), and the diagnosis of medical comorbidities (11.4% compared with 9.3%; P=.701) were not found to be significantly different between patients who did and did not receive fertility drugs. The median follow-up times for patients who received fertility drugs and those who did not were 87 months (range 45–159 months) and 58 months (range 14–194 months), respectively (P<.001). The 5-year disease-free survival rates of patients who received infertility drugs and patients who did not were 73% and 62%, respectively (P=.335; Fig. 2B).
In our present cohort of young women diagnosed with early-stage endometrial cancer, the incidence of infertility (38.3%) was higher than that of the general population (10–15%).14 Although many of our patients required assisted reproductive technology to become pregnant, the pregnancy outcomes of this group are very promising. The pregnancy rate (86.4% compared with 50%; P=.001) and live birth rate (70.5% compared with 42.3%; P=.020) were significantly higher among patients who received infertility treatment than patients who only tried to conceive naturally. The pregnancy rate may be important for estimating the potential effect of pregnancy on subsequent remission. However, the pregnancy results are rather irrelevant to the patients themselves, who are primarily interested in live birth rates.
In the present study, only 46 of 177 patients (26%) who initially tried fertility-sparing management achieved a live birth. However, 71 patients who did not attempt to get pregnant, either because they were not married (n=46) or for other reasons (n=25), may attempt to get pregnant at some time in the future. If all of these women do try to conceive at a later date, a similar number of patients may achieve a live birth. In addition, patients who tried to conceive but did not succeed may also achieve a live birth at some point in the future. Therefore, more of the patients in this study may go on to achieve a live birth.
The spontaneous abortion rate of our patients was 24%, a somewhat higher rate than the general population (15–20%).15,16 However, the spontaneous abortion rate of patients who achieved natural pregnancy was 18.8%, which was lower than the rate of patients who received infertility treatment (25.5%; P=.745) and similar to that of the general population. If we consider the preclinical pregnancy loss and spontaneous abortion rate together, the spontaneous abortion rate of the general population is as high as 30%.17 Compared with this figure, the spontaneous abortion rate of our present cohort is not particularly high. The ectopic pregnancy rate in our current cohort was 2.8%, which is comparable to that of the general population (2%).18 The ectopic pregnancy rate in the present cohort was not different between patients who received infertility treatment and those who did not (3.6% compared with 0%; P=1.000). The preterm delivery rate of our cohort was 11.5%, similar to the rate of 10% for the general population.19 The preterm delivery rate of our study cohort was higher among patients who received infertility treatment than patients who did not (10.9% compared with 0%; P=.326).
There are few reports in the literature on pregnancy outcomes after fertility-sparing management in young women with early endometrial cancer. A recent review reported that 86 (34.8%) of 280 patients who received fertility-sparing management achieved pregnancy and gave birth to 89 live neonates. Han et al20 reported promising pregnancy outcomes of 10 patients who received assisted reproductive technology after successful fertility-sparing management. In their series, nine of 10 patients (90%) achieved nine pregnancies. There was one ectopic pregnancy (11%), two miscarriages (22%), and six patients gave birth to six healthy neonates (67%), although three of these six live births were preterm (50%). Some other previous small case series also reported promising pregnancy outcomes using assisted reproductive technology after successful fertility-sparing management.21–23
The use of fertility drugs, including clomiphene citrate and gonadotropins, is associated with increased estrogen production during the follicular phase of the ovulation induction cycle.24 Some studies have suggested a relationship between the use of fertility drugs and the risk of endometrial cancer,25,26 but this is not supported by other studies.27,28 Hence, this relationship is not clearly understood and remains controversial. In our present series, the use of fertility drugs after successful fertility-sparing management did not result in an increased recurrence of endometrial cancer and therefore did not compromise the disease-free survival of our patients. In fact, the disease-free survival of our patients who succeeded in becoming pregnant was significantly better regardless of the use of fertility drugs. Hence, fertility drugs may be used safely in these patients. It is likely that the use of these drugs after fertility-sparing management will be recommended for women with a history of subfertility or infertility. However, further evaluations are still required.
As the reviewer suggests, the patients with endometrial cancer examined in the current study are thin compared with patients in the United States. However, the World Health Organization criteria for overweight and obesity is different for Western countries and Eastern countries; therefore, our patients are not particularly thin. In addition, we believe that this has little effect on the results of our study and that BMI has no significant effect on pregnancy outcomes.
Our study is limited by its retrospective nature, missing data related to BMI, and by the fact that several patients were lost to follow-up. Also, we were not able to reliably ascertain which patients had medical comorbidities. However, our study benefits greatly from the fact that it involves a large number of patients with endometrial cancer and also incorporates a long follow-up period.
In conclusion, although the proportion of our current patients with a history of subfertility or infertility was high, the pregnancy outcomes after the use of assisted reproductive technology are very promising. Importantly, the use of fertility drugs in our present cohort was not found to be associated with a higher incidence of endometrial cancer recurrence.
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